From tooth pain to trigeminal sensitization: translational models, experimental readouts, and mechanism-guided therapeutic opportunities in odontogenic and headache-related orofacial pain

Abstract

Odontogenic pain is one of the most intense forms of orofacial pain, yet durable mechanism-directed therapies remain limited. Traditionally, tooth pain has been framed as a local consequence of pulpal, dentinal, periodontal, or periapical disease. However, contemporary orofacial pain and headache frameworks increasingly position dental pain within a broader trigeminal pain network, where nociceptive input from the teeth and surrounding tissues may contribute to referred facial pain, headache-related orofacial pain overlap, and trigeminal sensitization. In this review, we synthesize odontogenic pain as a clinically accessible model for studying peripheral-to-central trigeminal pain mechanisms. To align the review questions, scope, and content, the review is structured around five linked domains: clinically relevant phenotypes, peripheral-to-central mechanisms, phenotype-matched models and readouts, biomarker-based target engagement, and mechanism-guided therapeutic and trial-design strategies. We emphasize the hot tooth phenotype, most commonly associated with symptomatic irreversible pulpitis, as a translational state in which severe peripheral inflammation, tissue acidosis, ion-channel remodeling, local anesthetic difficulty, neuroimmune activation, and central amplification converge. We summarize key molecular and circuit-level mechanisms, including inflammatory mediator release, ion-channel and receptor pathways related to thermal, acid, purinergic, sodium, calcium, mechanosensitive, and G protein-coupled signaling, trigeminal ganglion plasticity, satellite glial activation, calcitonin gene-related peptide signaling, trigeminocervical convergence, and central sensitization. We also discuss how preclinical models and experimental readouts can be aligned with specific clinical phenotypes, including five clinical phenotype domains: dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. By linking clinical phenotypes, mechanistic models, experimental readouts, biomarkers, target engagement, therapeutic strategies, and trial-design considerations, this framework may help bridge the gap between preclinical pain research and clinical application. Reframing odontogenic pain as a biologically informative trigeminal pain state may support the development of biomarker-guided, mechanism-informed, and more durable analgesic strategies for refractory dental and headache-related orofacial pain. Importantly, persistent or refractory odontogenic and headache-related orofacial pain is shaped not only by peripheral and central neurobiological mechanisms but also by patient-level contextual contributors such as sleep disruption, stress, prior pain and treatment experience, and affective-motivational processing, which help explain why patients with comparable dental findings differ in pain intensity, disability, and treatment response.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s10194-026-02452-6.

Background

Odontogenic pain is one of the most common and clinically urgent forms of orofacial pain. It arises from innervated structures within or immediately surrounding the tooth, including the pulp–dentin complex, periodontal tissues, and periapical region [1]. Although dental pain is often managed as a local symptom of caries, pulpitis, trauma, infection, or periodontal disease, its biology is not confined to the tooth. The dental pulp is a densely innervated, vascularized, immunologically active tissue in which mechanical, thermal, microbial, acidic, and inflammatory stimuli can produce rapid nociceptor activation and sustained sensitization [2–4]. In severe inflammatory states, particularly symptomatic irreversible pulpitis, pain may become spontaneous, poorly localized, referred, emotionally distressing, and difficult to control with conventional local anesthesia [5].

The classification of odontogenic pain within modern orofacial pain and headache frameworks highlights its broader relevance. The International Classification of Orofacial Pain (ICOP) defines dental pain as pain caused by lesions or disorders affecting one or more teeth and/or their direct supporting structures, including the pulp, periodontium, and gingivae [6]. In parallel, the International Classification of Headache Disorders, 3rd edition (ICHD-3), recognizes headache attributed to disorders of the teeth or jaw, indicating that dental and periodontal disorders can generate pain perceived as headache [7]. Conversely, primary headache disorders may present with pain localized to the face, jaw, or dental region, creating diagnostic overlap and sometimes leading to unnecessary dental procedures [8]. This overlap is anatomically plausible because dental, facial, cervical, meningeal, and cranial vascular inputs are processed through trigeminal pathways [9].

The trigeminal system provides a shared neurobiological substrate for dental pain, orofacial pain, and headache. The maxillary and mandibular branches of the trigeminal nerve innervate the upper and lower teeth, while trigeminal afferents converge centrally within the trigeminal ganglion, trigeminal brainstem complex, trigeminocervical pathways, thalamus, and cortical–limbic networks [9–11]. This organization explains why dental pain may be diffuse, poorly localized, or referred to the ear, temple, jaw, face, or head. It also explains why migraine and trigeminal autonomic cephalalgias can sometimes mimic dental pain and why oral inflammatory inputs may influence trigeminovascular excitability [8, 12].

Despite advances in understanding inflammatory and neural mechanisms of dental pain, therapeutic management remains largely symptom based. Current approaches include dental source control, local anesthesia, nonsteroidal anti-inflammatory drugs, acetaminophen, corticosteroids, antibiotics when infection is present, and procedural treatment [13, 14]. These interventions are clinically essential but do not always explain or prevent local anesthetic failure, referred pain, persistent sensitization, or pain disproportionate to peripheral tissue findings. Similar to recent translational reviews in headache medicine, a major gap is not simply the absence of mechanistic data, but the lack of an integrated framework that aligns clinically relevant phenotypes with appropriate experimental models, readouts, biomarkers, mechanism-guided therapeutic strategies, and trial-design principles.

Previous studies have approached odontogenic pain from separate but complementary perspectives. Classification-based literature has positioned dental pain within the broader ICOP/ICHD framework and highlighted its diagnostic overlap with headache-related orofacial pain [8, 15]. Headache and orofacial pain studies have emphasized shared trigeminal mechanisms, including calcitonin gene-related peptide (CGRP) signaling, trigeminovascular activation, and trigeminal convergence [2, 5, 12, 16]. In parallel, endodontic and preclinical studies have focused on pulpal inflammation, ion-channel sensitization, purinergic signaling, neuroimmune activation, and local anesthetic failure in the hot tooth phenotype [2, 3, 13]. However, these domains are usually discussed separately. This review synthesizes them into a unified translational framework in which odontogenic pain, particularly the hot tooth phenotype, is conceptualized as a clinically accessible model of trigeminal sensitization, linking peripheral dental inflammation, central amplification, headache-related orofacial overlap, experimental readouts, biomarker-guided target engagement, and mechanism-directed therapy. Rather than presenting receptor and mediator systems as an isolated catalogue, we organize the review around five linked review questions: Which clinical phenotypes best capture the translational problem? Which peripheral, central, and neuroimmune mechanisms explain these phenotypes? Which preclinical models and readouts can test these mechanisms? Which biomarkers can confirm target engagement? Which mechanism-guided therapeutic and trial-design strategies may move beyond short-acting palliation?

Accordingly, this review is organized around a single five-question translational framework. The five phenotype domains considered throughout the review are dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. The review follows these five questions in sequence. It first delineates the clinically relevant phenotypes and establishes the hot tooth as the index phenotype that bridges clinical presentation and mechanistic analysis (Sections “Clinical phenotypes and classification of odontogenic and headache-related orofacial pain” and “The hot tooth as the index translational phenotype”), and then traces the peripheral, ganglionic, central, and neuroimmune mechanisms that underlie them (Sections “Peripheral nociceptive transduction in dental tissues”, “Trigeminal ganglion plasticity and central amplification” and “Neuroimmune crosstalk, cGAS–STING signaling, and sex-dependent pain mechanisms”). It next maps these phenotype domains onto phenotype-matched preclinical models and experimental readouts (Section “Phenotype-matched preclinical models and experimental readouts”), considers the biomarkers by which target engagement can be confirmed (Section “Biomarkers and target engagement”), and finally integrates mechanism-guided therapeutic strategies with clinical trial design considerations (Section “Mechanism-guided therapeutic strategies and trial design”). The integrated tooth-to-trigeminal framework, including the pulp–dentin–odontoblast interface, trigeminal sensory pathway, trigeminal ganglion excitability, and trigeminal nucleus-level synaptic amplification, is summarized in Fig. 1.

Fig. 1.

Tooth-to-trigeminal pathway and neurobiological sensitization mechanisms in odontogenic pain. (A) The pulp–dentin–odontoblast interface provides the peripheral entry point for odontogenic nociception, where pulpal nerves, odontoblasts, the plexus of Raschkow, and free nerve endings extending into dentinal tubules can respond to microbial, inflammatory, thermal, osmotic, mechanical, and acidic stimuli. (B) Tooth-derived nociceptive input is transmitted through Aδ and C fibers to the trigeminal ganglion and then through central trigeminal pathways, including the spinal trigeminal tract, trigeminal brainstem complex, thalamus, and primary somatosensory cortex. (C) At the trigeminal ganglion level, sustained stimulation can alter primary sensory neuron excitability through voltage-gated channels, Na+/K+ pump activity, TRPV1 gating, mechanosensitive channels such as PIEZO, and GPCR-linked second messenger pathways. These changes may lower firing thresholds and support persistent afferent hyperexcitability. (D) At the trigeminal nucleus caudalis/trigeminal brainstem level, repeated nociceptive input can promote synaptic amplification through glutamate release, AMPA and NMDA receptor activation, calcium influx, neuropeptide signaling, glial activation, inflammatory cytokines, and kinase-linked pathways such as MAPK, PKA, and PKC. Together, these peripheral, ganglion-level, and brainstem-level mechanisms link odontogenic pain to trigeminal sensitization and pain amplification

Clinical phenotypes and classification of odontogenic and headache-related orofacial pain

Clinical relevance

This section answers the first review question: which clinical phenotypes best capture the translational problem? It defines odontogenic pain within the ICOP/ICHD framework, clarifies its overlap with headache-related orofacial pain, and establishes the five phenotype domains used consistently throughout this review: dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. A classification-based framework is essential for understanding why odontogenic pain is relevant to headache medicine. ICOP preserves the dental specificity of odontogenic pain by defining it as pain arising from lesions or disorders of the teeth and their direct supporting structures, including the dental pulp, periodontium, and gingivae [6]. ICHD-3, in parallel, recognizes headache attributed to disorders of the teeth or jaw, most commonly in relation to dental or periodontal infection, pericoronitis, or other inflammatory dental conditions [7]. These two classification systems meet at an important clinical boundary: tooth-related disease can generate pain perceived beyond the tooth, while headache disorders can present with pain localized to the face, jaw, or dental region.

Beyond classification, the clinical and epidemiological texture of this overlap is relevant to everyday practice. Toothache is among the most common acute pain complaints in the orofacial region and may be readily mistaken for or masked by primary headache disorders. Clinically, odontogenic disease may produce pain perceived not only in the affected tooth but also in the jaw, cheek, temple, ear, or head because dental and craniofacial inputs converge within trigeminal pathways. Conversely, migraine or neurovascular orofacial pain may present with pulsating, pressure-like, or toothache-like pain localized to V2 or V3 territories and may be accompanied by cold sensitivity, mild autonomic features, nausea, photophobia, phonophobia, or a prior history of headache attacks [8]. These features can create diagnostic ambiguity, particularly when dental findings are mild, incidental, or not concordant with the patient’s pain pattern [17].

Common misdiagnosis scenarios include migraine-related or neurovascular orofacial pain being treated as dental disease, trigeminal autonomic cephalalgias presenting with unilateral facial or dental localization, trigeminal neuralgia being interpreted as toothache, and persistent dentoalveolar pain being attributed to unresolved local pathology despite apparently adequate dental treatment [18]. Persistent pain after dental treatment also provides a practical epidemiological context for this overlap: persistent dentoalveolar pain has been reported in approximately 3–6% of teeth after root canal therapy, although estimates vary according to case definition, follow-up duration, and whether all-cause persistent pain or non-odontogenic pain is included [19, 20]. This does not mean that post-treatment pain is always non-odontogenic; rather, it highlights the need to reassess the dominant pain mechanism when symptoms persist despite adequate source control.

High-risk features that should prompt reassessment rather than further irreversible intervention include pain that is poorly localized, affects multiple teeth, migrates over time, persists after apparently adequate source control, is disproportionate to clinical and radiographic findings, or is accompanied by headache features, autonomic symptoms, sensory change, allodynia, or widespread facial pain. In these situations, re-evaluation against ICOP and ICHD-3 criteria and referral to orofacial pain, headache, neurology, or pain medicine services may be preferable to repeated dental procedures. A practical comparison of features favoring true odontogenic pain versus orofacial presentations of primary headache and neuropathic or nociplastic pain is provided in Table 1.

Table 1.

Practical differential features distinguishing odontogenic pain from non-odontogenic and overlapping orofacial pain

Feature	True odontogenic pain	Migraine/neurovascular orofacial pain	Trigeminal autonomic cephalalgias (esp. cluster headache)	Neuropathic/nociplastic orofacial pain
Localisation	Localised to a tooth or quadrant; reproducible on testing	Diffuse, midface or maxillary; crosses tooth boundaries	Strictly unilateral, orbital or temporal	Poorly localised; neuropathic may follow a nerve territory; nociplastic/PIFP regional
Temporal pattern	Stimulus-evoked or continuous with active disease	Episodic attacks; prior headache history	Short, severe attacks—cluster 15–180 min, circadian; paroxysmal hemicrania 2–30 min; SUNCT/SUNA seconds, very frequent	Persistent or daily; may begin after a procedure
Provoking factors	Cold or heat, biting, percussion on the tooth	Migraine triggers; movement, light, sound	Alcohol; circadian timing	Light touch (allodynia); often non-mechanical
Associated features	Caries, deep restoration, crack, periapical change	Nausea, photophobia/phonophobia, pulsating quality	Ipsilateral autonomic signs (lacrimation, rhinorrhoea, ptosis); paroxysmal hemicrania and hemicrania continua respond to indomethacin	Neuropathic: sensory change (hypo-/hyperaesthesia), allodynia. Nociplastic/PIFP: usually no somatosensory deficit; affective burden common
Response to dental treatment	Resolves after appropriate dental care	Persists despite adequate treatment	Persists despite treatment	Persists or worsens; may begin after treatment
Imaging–clinical concordance	Pain proportionate to demonstrable pathology	Disproportionate to dental findings	No dental pathology explains attacks	Disproportionate; neuropathic may show sensory signs without active disease; nociplastic/PIFP no demonstrable pathology
Clinical action	Treat the dental source	Reassess by ICOP/ICHD-3; refer for headache care	Reassess by ICHD-3; urgent referral	Avoid further irreversible procedures; refer to orofacial pain/pain medicine

This overlap is anatomically grounded in shared trigeminal processing. Convergence within the trigeminal ganglion and trigeminocervical complex can produce referred pain and diagnostic ambiguity [9], and the classification-based overlap between odontogenic pain, headache attributed to disorders of the teeth or jaw, and orofacial pain resembling primary headache disorders is summarized in Table 2.

Table 2.

Classification of pain types relevant to odontogenic and headache-related orofacial pain

Pain category	Working definition	Dominant mechanism	Typical clinical features	Relevance to this review
Acute pain	Pain arising after tissue injury, inflammation, infection, or procedural trauma and resolving as healing occurs	Peripheral nociceptor activation and inflammatory mediator release	Sharp, warning, stimulus-dependent, time-limited	Represents the early protective phase of caries, trauma, pulp exposure, or post-operative dental pain
Chronic pain	Pain persisting beyond expected tissue healing, often > 3–6 months	Peripheral and central plasticity, altered descending modulation, neuroimmune activation	Persistent, recurrent, emotionally distressing, functionally disabling	Relevant to persistent dentoalveolar pain, post-traumatic trigeminal neuropathic pain, and refractory orofacial pain
Nociceptive pain	Pain caused by activation of nociceptors by actual or threatened tissue damage	Activation of Aδ and C fibers by mechanical, thermal, chemical, acidic, or inflammatory stimuli	Localized or referred pain; usually linked to tissue pathology	Main mechanism in acute pulpitis, apical periodontitis, dental trauma, and dentin hypersensitivity
Neuropathic pain	Pain caused by lesion or disease of the somatosensory nervous system	Ectopic firing, demyelination, maladaptive channel expression, neuron–glia coupling	Burning, electric shock-like, shooting, spontaneous, allodynia, hyperalgesia	Relevant to painful post-traumatic trigeminal neuropathic pain and persistent post-procedural dental pain
Nociplastic pain	Pain arising from altered nociception without sufficient evidence of tissue damage or somatosensory lesion	Central sensitization, altered pain modulation, augmented sensory processing	Disproportionate pain, hypersensitivity, sleep/mood comorbidity	Useful when persistent orofacial pain is not fully explained by peripheral dental disease
Dental/odontogenic pain	Pain arising from lesions or disorders affecting teeth and/or direct supporting structures	Pulpal, dentinal, periodontal, periapical, infectious, inflammatory, traumatic mechanisms	Thermal hypersensitivity, biting pain, spontaneous pain, referred pain	Core pain entity of this review; framed as a trigeminal pain state
Hot tooth phenotype	Severe dental pain, commonly symptomatic irreversible pulpitis, often with anesthetic difficulty	Intense peripheral inflammation, Nav/TRP sensitization, tissue acidosis, central amplification	Severe lingering thermal pain, biting pain, spontaneous pain, referred pain, local anesthetic failure	Proposed as a clinical model of trigeminal sensitization and treatment resistance
Headache attributed to teeth/jaw	Headache caused by dental, periodontal, jaw, or related inflammatory pathology	Referred trigeminal pain and convergence	Head pain temporally related to dental disease and improved after source control	Links odontogenic pain to headache classification and diagnostic overlap
Orofacial pain resembling primary headache	Facial/intraoral pain resembling migraine, cluster headache, or other primary headache disorders	Trigeminovascular activation, central sensitization, autonomic activation, CGRP signaling	Dental/facial localization without sufficient odontogenic pathology	Essential for differential diagnosis when headache disorders present as tooth, jaw, or facial pain

A trigeminal framework for odontogenic pain is strengthened, not weakened, by recognizing patient-level contextual contributors. Pain persistence, disability, and treatment response are shaped not only by peripheral and central neurobiology but also by sleep disruption, stress, anxiety and depressive symptoms, dental fear, heightened attention to oral sensation, treatment expectation, and pain catastrophizing. In orofacial pain populations, catastrophizing is consistently associated with greater pain intensity, depression, anxiety, and insomnia, and prospective data identify catastrophizing and depressive symptoms among the most reliable predictors of an unfavorable pain trajectory [21, 22]. These factors do not contradict the biological model; rather, they help explain why patients with similar dental findings can differ markedly in pain intensity, distress, and response to identical treatment. Using validating, mechanism-neutral language, contextual contributors, pain modulation, affective-motivational processing, and patient-level modifiers rather than dismissive terminology is itself clinically important because clear and respectful communication can reduce mistrust and help prevent repeated, unnecessary procedures.

Nociplastic mechanisms are particularly relevant when persistent orofacial pain is not fully explained by peripheral dental disease. Persistent dentoalveolar and post-procedural pain, burning mouth symptoms, temporomandibular disorder pain, and headache-related orofacial pain overlap may share trigeminal sensitization and altered pain modulation even in the absence of clear ongoing tissue damage, which is why they can persist after technically adequate dental care.

Translational implication

The relationship between oral disorders and headache is not limited to referral patterns. Inflammatory and pathological inputs from oral and craniofacial structures may influence trigeminovascular excitability through both peripheral and central mechanisms [12]. CGRP provides a particularly important molecular bridge. It is a major mediator in migraine pathophysiology and a therapeutic target for migraine, but it is also involved in dental pulp inflammation, periodontal pathology, temporomandibular disorder pain, neurogenic inflammation, and trigeminal sensitization [12, 16, 23–25]. In pulpitis, CGRP-positive fibers, substance P release, cytokine signaling, and purinergic activation may amplify peripheral nociceptive traffic [26–28]. In susceptible individuals, persistent or intense input from the teeth or periodontium may enhance trigeminal ganglion excitability, trigeminocervical activation, and central sensitization, potentially aggravating headache-related orofacial pain overlap.

Although CGRP is a uniquely informative molecular bridge between dental pain and headache biology, refractory orofacial pain is unlikely to be explained by any single mediator. CGRP is best understood as one node within a wider network that includes peripheral inflammatory drive, trigeminal ganglion plasticity, central sensitization, descending pain modulation, and the influence of sleep, stress, and affective-motivational processing on pain expression. This framing preserves a clear mechanistic focus while avoiding an overly narrow, single-target interpretation of treatment resistance.

Design consideration

A mechanistic review of odontogenic pain should not treat the tooth as an isolated organ. It should treat the tooth as an entry point into the trigeminal pain network. This perspective helps explain why some dental pain states are difficult to localize, why pain may persist despite local intervention, why local anesthesia may fail in inflamed pulp, and why headache-related mechanisms such as CGRP signaling, central sensitization, and descending modulation are relevant to dental pain. Thus, the classification framework in this section does more than define diagnostic categories; it establishes the clinical phenotype map that is used in later sections to align mechanisms, models, biomarkers, and therapeutic strategies. Within this map, the hot tooth phenotype is introduced as one of the five phenotype domains and is developed in the next section as the index phenotype that bridges clinical presentation with mechanistic analysis.

The hot tooth as the index translational phenotype

Clinical relevance

Building on the phenotypes defined above, this section develops the hot tooth as the index translational phenotype that links peripheral inflammation to trigeminal sensitization. It completes the first review question by focusing on the most clinically recognizable severe inflammatory pulpitis phenotype and bridges toward the second review question by showing how this phenotype connects clinical presentation with peripheral, ganglionic, central, and neuroimmune mechanisms. Among odontogenic pain phenotypes, the hot tooth is particularly valuable for translational research. It typically refers to symptomatic irreversible pulpitis characterized by intense, often debilitating pain triggered by biting or thermal stimuli [17, 29, 30]. Clinically, hot tooth presentations may include deep or defective restorations, extensive carious lesions, cracks or fractures in the coronal portion of the tooth, increased tooth mobility, widening of the periodontal ligament space, lingering cold sensitivity, heat-induced pain temporarily relieved by cold water, spontaneous pain, and diffuse or referred pain radiating toward the ear or temple [31]. This phenotype combines severe peripheral inflammation, sensory hypersensitivity, referred pain, and local anesthetic difficulty in a single clinically recognizable state. Several peripheral components of the hot tooth phenotype, including tissue acidosis, inflammatory mediator release, ion-channel remodeling, and local anesthetic difficulty, are mechanistically detailed in Fig. 2.

Fig. 2.

Peripheral inflammatory, odontoblast-associated, and receptor-mediated mechanisms of odontogenic pain. Pulpal injury and microbial products promote DAMP/PAMP release, TLR4 activation in pulpal resident cells, immune-cell infiltration, and local release of inflammatory mediators. These mediators can activate or sensitize odontoblasts, immune cells, and peripheral trigeminal afferent endings. At the odontoblast–afferent interface and primary afferent terminal, acid-sensing ion channels, TRP channels, PIEZO channels, purinergic receptors, voltage-gated sodium channels, and voltage-gated calcium channels contribute to stimulus transduction, peripheral hypersensitivity, and sustained nociceptive input. In severe inflammatory states, tissue acidosis, increased pulpal blood flow, altered sodium-channel function, and reduced membrane penetration may also contribute to local anesthetic difficulty

Mechanistic model

At the peripheral level, bacterial products, tissue injury, ischemia, local acidosis, prostaglandins, bradykinin, cytokines, NGF, ATP, CGRP, and substance P generate a sensitizing inflammatory milieu [32–34]. At the neuronal level, inflammation lowers the activation thresholds of transient receptor potential (TRP) channels, acid-sensing ion channels (ASICs), purinergic P2X/P2Y receptors, voltage-gated sodium (Nav) channels, voltage-gated calcium (Cav) channels, mechanosensitive PIEZO channels, and G protein-coupled receptor (GPCR)-linked pathways [26, 35–38] (Fig. 2). At the central level, persistent input from trigeminal afferents may increase excitability in the trigeminal ganglion, trigeminal nucleus caudalis, thalamus, and cortical–limbic pain networks [39–41]. This multi-level biology helps explain why conventional local anesthesia may fail in symptomatic irreversible pulpitis and why procedural source control may not immediately eliminate pain-related sensitization [5, 14]. For this reason, the hot tooth phenotype is not used here as a separate disease category, but as an index severe inflammatory pulpitis state in which peripheral drive, trigeminal amplification, and treatment resistance can be examined together. A caveat is warranted here. By definition, the hot tooth is an acute state, whereas central sensitization is most firmly established in chronic or sustained-input conditions. Direct evidence for central sensitization in human symptomatic irreversible pulpitis remains limited, and much of the supporting rationale is extrapolated from migraine and from preclinical nerve-injury models [9, 40, 42, 43]. The hot tooth is therefore most defensibly framed not as a fully developed central sensitization state, but as a clinically accessible window for studying the transition from intense peripheral nociceptive drive toward trigeminal amplification, a transition that may be incomplete, reversible after source control in most patients, and consolidated only in a susceptible subset. This framing aligns with the cautious, evidence-anchored use of central sensitization developed in Section “Trigeminal ganglion plasticity and central amplification”.

Implications for model selection

Because this section functions primarily as the clinical and mechanistic bridge between Sections “Clinical phenotypes and classification of odontogenic and headache-related orofacial pain” and “The hot tooth as the index translational phenotype” and Sections “Peripheral nociceptive transduction in dental tissues”, “Trigeminal ganglion plasticity and central amplification” and “Neuroimmune Crosstalk, cGAS–STING Signaling, and Sex-Dependent Pain Mechanisms”, the detailed mapping of hot tooth-related models and experimental readouts is addressed later in Section “Phenotype-matched preclinical models and experimental readouts”. In brief, the hot tooth phenotype can be approximated experimentally using pulpitis models that combine peripheral inflammation with behavioral and neurobiological readouts. Relevant readouts include thermal hypersensitivity, mechanical sensitivity, bite-force changes, orofacial von Frey responses, feeding behavior, grimace scores, pulpal cytokine expression, CGRP and substance P expression, transient receptor potential vanilloid 1 (TRPV1), Nav1.8/Nav1.9 expression, activating transcription factor 3 (ATF3), phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated cAMP response element-binding protein (pCREB), satellite glial activation, ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and potassium-chloride cotransporter 2 (KCC2) changes in central trigeminal pathways [44–49]. Readouts should be selected according to the specific translational question: anesthetic failure, thermal hypersensitivity, referred pain, persistent sensitization, or therapeutic target engagement.

Translational value and design considerations

No single model fully captures the hot tooth phenotype. Mechanical pulp exposure, chemical pulpitis, caries-related pulpitis, and human-derived pulpitis models each reproduce different aspects of the clinical phenotype [45, 46, 50]. A reductionist approach is therefore necessary, but it should be clinically anchored. Models should be chosen because they recapitulate a specific feature that is difficult to study mechanistically in patients, such as pulpal acidosis, Nav remodeling, TRPV1 sensitization, local anesthetic failure, neuroimmune activation, or central amplification. This logic mirrors the translational design approach used in migraine modeling, where each model is selected for its ability to capture a defined clinical or mechanistic component rather than the entire disorder [42, 43].

The hot tooth phenotype is also clinically more complete when the behavioral sequelae of severe acute dental pain are acknowledged. Beyond peripheral inflammation, anesthetic difficulty, and trigeminal amplification, an episode of intense and poorly controlled tooth pain can leave a lasting imprint: fear of recurrence, heightened monitoring of oral sensation, avoidance of chewing on the affected side, and a strong expectation for further dental intervention. These learned and attentional responses may persist after source control and can influence reported pain, perceived treatment success, and the demand for additional procedures. Incorporating measures of fear, vigilance, and treatment expectation into hot tooth studies would therefore strengthen, rather than dilute, the biological model by capturing why similar peripheral pathology can yield divergent clinical trajectories. Thus, the hot tooth serves as a clinically anchored entry point into the mechanistic sections that follow, rather than as an isolated phenotype detached from the broader tooth-to-trigeminal framework.

Peripheral nociceptive transduction in dental tissues

Clinical relevance

This section begins the answer to the second review question: which peripheral, central, and neuroimmune mechanisms explain the phenotype domains defined above? It focuses on the peripheral level of nociceptive transduction, particularly mechanisms relevant to dentin hypersensitivity, acute pulpitis, and the hot tooth phenotype. Odontogenic pain begins at the pulp–dentin–odontoblast interface. The pulp–dentin complex is densely innervated, vascularized, and immunologically active. Nociceptive fibers enter the pulp through the apical foramen, travel with blood vessels through the radicular pulp, and branch beneath the odontoblast layer to form the plexus of Raschkow [4, 51]. From this subodontoblastic network, fibers extend toward dentinal tubules as free nerve endings. Aδ fibers mediate sharp, localized, short-lasting pain, particularly after cold stimulation, whereas C fibers mediate dull, diffuse, persistent pain and dominate inflammatory pulpal pain [52–56](Fig. 1A, B). The major peripheral fiber types involved in dental pain, including Aδ fibers, C fibers, peptidergic nociceptors, and mechanosensitive afferents, are summarized in Supplementary Table 1.

Odontoblasts are no longer regarded only as dentin-forming cells. They may function as mechanosensory, chemosensory, thermosensory, and immunomodulatory elements [57, 58]. Current evidence supports a modulatory rather than classical synaptic role: odontoblasts respond to mechanical, thermal, osmotic, or chemical stimuli and release ATP, glutamate, cytokines, and other mediators that activate or sensitize nearby nerve endings [58–60](Fig. 2). This model places the odontoblast at the interface between tissue injury, dentinal fluid movement, immune signaling, and trigeminal afferent activation. It is therefore especially relevant to dentin hypersensitivity, early pulpal irritation, and inflammatory pulpitis, where peripheral stimulus transduction can evolve into sustained trigeminal input.

Mechanistic model

Dental tissues are exposed to multiple pain-inducing stimuli. Mechanical stimuli arise from deformation, pressure, cracks, occlusal trauma, restorative defects, or pulpal pressure changes. These forces alter membrane tension and activate mechanosensitive channels in odontoblasts and primary afferent terminals [60–62]. PIEZO1 and PIEZO2 are important mechanotransduction candidates. PIEZO2 is associated with rapidly adapting mechanically evoked currents and is expressed with nociceptive markers such as TRP channels, CGRP, and voltage-gated sodium channels in dental primary afferent neurons [38, 63]. PIEZO1 may contribute to odontoblast responses to mechanical stimuli [60]. Clinically, these pathways are most relevant to mechanical sensitivity, biting pain, cracked-tooth presentations, and force-related odontogenic or periodontal pain components.

Thermal pain is largely mediated by temperature-sensitive TRP channels. TRPV1 responds to noxious heat, capsaicin, acidic pH, inflammatory mediators, NGF, ATP, adenosine, endocannabinoid-related ligands, and arachidonic acid metabolites [32, 34, 64–66]. TRPV2, TRPV3, and TRPV4 respond to different ranges of warmth, heat, osmotic stress, and mechanical forces [67–69]. TRPM8 contributes to cold sensing and is highly relevant to oral cold sensitivity [69–72], whereas TRPA1 is implicated in chemical irritation, noxious cold, and inflammatory pain [73, 74]. Inflammatory states can sensitize these channels through PKA, PKC, PLC, ERK, and Src pathways, lowering activation thresholds and increasing channel trafficking to peripheral terminals [75–78]. This mechanism is directly relevant to dentin hypersensitivity, acute pulpitis, lingering thermal pain, and the heat- or cold-sensitive components of the hot tooth phenotype.

Chemical and inflammatory stimuli are central to pulpal pain. Bradykinin, prostaglandins, histamine, serotonin, ATP, cytokines, NGF, protons, leukotrienes, thromboxanes, chemokines, endothelin-1, and extracellular proteases form an inflammatory “soup” that activates and sensitizes nociceptors [32, 33, 79]. Recent experimental evidence further supports the purinergic axis in pulpitis-induced trigeminal sensitization: in an LPS-induced acute pulpitis model, increased P2X3 expression and neuronal activation in the trigeminal ganglion were associated with maxillofacial pain-like behavior, while P2X3 inhibition attenuated pain-like responses and reduced MAPK/NF-κB-associated inflammatory signaling [80]. These mediators act through ion channels, GPCRs, tyrosine kinase receptors, purinergic receptors, and pattern-recognition receptors to lower thresholds and increase spontaneous activity [26, 36, 81]. In severe inflammation, tissue injury also produces vasodilation, plasma extravasation, immune-cell recruitment, and neurogenic inflammation. CGRP and substance P released from sensory fibers further increase vascular permeability and immune activation, creating feed-forward amplification within the confined pulpal environment [24, 27, 28]. Key extracellular mediators that link pulpal inflammation, neurogenic inflammation, nociceptor sensitization, and trigeminal amplification are presented in Table 3. Together, these mediator systems help explain why acute pulpitis and the hot tooth phenotype can become spontaneous, poorly localized, referred, and difficult to control with local treatment alone.

Table 3.

Extracellular mediators of odontogenic pain

Mediator	Major source	Main receptor/pathway	Primary nociceptive effect	Translational relevance
CGRP	Peptidergic trigeminal afferents, pulpal sensory fibers	CGRP receptor complex	Vasodilation, neurogenic inflammation, sensitization	Shared bridge between dental pain, TMD, migraine, and trigeminovascular biology
Substance P	Sensory nerve terminals, fibroblasts, immune cells	NK1 receptor	Vascular permeability, edema, mast-cell activation	Contributes to pulpal neurogenic inflammation and persistent hypersensitivity
Bradykinin	Plasma kinin cascade, inflamed tissues	B1/B2 receptors	Direct activation and sensitization of nociceptors	Candidate target in inflammatory dental pain and hot tooth phenotypes
Histamine	Mast cells, platelets, immune cells	H1/H4 receptors	Vasodilation, immune activation, sensitization	Relevant to inflammatory components of pulpal or periodontal pain
Glutamate	Primary afferents, central terminals, peripheral cells	AMPA, kainate, NMDA, mGluRs	Excitatory transmission, central sensitization	Central to trigeminal nucleus sensitization and persistent pain amplification
ATP	Damaged cells, odontoblasts, immune cells, glia	P2X/P2Y receptors	Rapid depolarization, neuron–glia signaling, inflammasome activation	Links odontoblast transduction, P2 × 3 pain signaling, and P2 × 7/NLRP3 neuroinflammation
Protons/H+	Inflamed, ischemic, infected tissues	ASICs, TRPV1	Acid pain, hyperalgesia, local anesthetic ion trapping	Highly relevant to pulpitis, abscesses, and local anesthetic failure
Prostaglandins/PGE2	Arachidonic acid pathway	EP receptors	cAMP/PKA-mediated peripheral sensitization	Major mechanism targeted by NSAIDs and mPGES-1 strategies
IL-1β	Macrophages, microglia, immune cells, glia	IL-1 receptor	Neuronal sensitization, glial activation	Key downstream product of inflammasome signaling
IL-6	Immune cells, fibroblasts, periodontal tissues	IL-6 receptor/gp130	Inflammatory amplification and sensitization	Potential link between oral inflammation and systemic pain modulation
TNF-α	Macrophages, mast cells, glia, inflamed pulp	TNF receptors	Channel regulation and inflammatory amplification	Useful mechanistic target in inflammatory and neuroimmune pain models
NGF	Fibroblasts, immune cells, mast cells, inflamed pulp	TrkA	Long-term sensitization, TRP/Nav expression	Anti-NGF strategies may reduce persistent inflammatory dental pain
LPS/microbial PAMPs	Oral pathogens	TLR4 and other PRRs	Direct neuronal activation and immune sensitization	Mechanistic bridge between caries-related infection and pulpal pain

Acidosis is another clinically important driver. Inflamed and ischemic tissues release protons that activate acid-sensing ion channels, particularly ASIC1, ASIC2, and ASIC3 [37, 82]. ASICs detect tissue acidosis and contribute to inflammatory and ischemic pain, although their role in pure mechanotransduction remains less clear [83–85]. In dental pulp, acidosis also contributes to ion trapping of local anesthetics. Inflamed tissues have reduced extracellular pH, which increases the ionized form of local anesthetic molecules and limits membrane penetration, reducing anesthetic efficacy [5, 86]. This mechanism is particularly relevant to the hot tooth phenotype because tissue acidosis can link severe inflammation, pain hypersensitivity, and local anesthetic difficulty in the same clinical state.

Microbial products also directly engage nociceptive pathways. Bacterial components and damage-associated molecules can activate Toll-like receptors on immune cells, pulpal cells, odontoblasts, and sensory neurons [81, 87, 88]. Lipopolysaccharide from Gram-negative bacteria can upregulate TRPV1 in trigeminal ganglia, linking infection-associated pulpitis to nociceptor sensitization [89]. This direct neuroimmune activation is particularly relevant in caries-associated pulpitis, where microbial invasion and inflammation are tightly linked. The local pulpal inflammatory environment, including damage-associated molecular patterns/pathogen-associated molecular patterns (DAMPs/PAMPs) recognition, Toll-like receptor 4 (TLR4), immune cell infiltration, inflammatory mediator release, odontoblast–afferent signaling, and receptor/channel-mediated nociceptor sensitization, is summarized in Fig. 2. These microbial and danger-signal pathways also provide a bridge to the neuroimmune mechanisms discussed in Section “Neuroimmune crosstalk, cGAS–STING signaling, and sex-dependent pain mechanisms”.

Peripheral mechanism-specific readouts

Peripheral transduction can be studied using calcium imaging, patch-clamp electrophysiology, ion-channel pharmacology, immunohistochemistry, RNAscope, single-cell RNA sequencing, spatial transcriptomics, pulp tissue cytokine profiling, and behavioral assays [90–92]. Useful molecular readouts include TRPV1, TRPA1, TRPM8, TRPV4, PIEZO1/2, ASIC1/3, P2X3, P2X7, Nav1.7, Nav1.8, Nav1.9, Cav2.2, CGRP, substance P, IL-1β, IL-6, TNF-α, NGF, pERK, pCREB, and NF-κB [34, 35, 47, 93–95]. Functional readouts should be matched to mechanism: thermal thresholds for TRP channels, acid responses for ASICs, ATP-evoked currents for purinergic signaling, mechanical responses for PIEZO/TRPV4 pathways, and local anesthetic responsiveness for Nav channel and tissue-pH mechanisms. These readouts are presented here only as mechanism-specific tools for studying peripheral transduction; their phenotype-matched use in complete preclinical models is mapped later in Section “Phenotype-matched preclinical models and experimental readouts” and Table 4.

Table 4.

Animal models of odontogenic pain and translational validity

Model	Methodological principle	Main phenotype modeled	Key readouts	Strengths	Limitations
Dentin exposure/hydrodynamic stimulation	Exposure of dentinal tubules with hydrodynamic (air-blast, osmotic, thermal) stimuli; odontoblast–afferent and odontoblast–neuron co-culture	Dentin hypersensitivity	Intradental Aδ-fibre activity, fluid-flow responses, ATP release and P2 × 3 signalling, evoked behaviour	Directly models the hydrodynamic mechanism of dentin sensitivity	Limited modelling of inflammatory or persistent components
Mechanical pulp exposure	Drilling or exposure of pulp tissue	Acute pulpitis and the hot tooth phenotype (acute pulpal injury and inflammatory pain)	Histology, cytokines, CGRP, TRPV1/Nav markers; tissue pH/acidosis and local-anaesthetic response (hot tooth); behavior	Simple, reproducible, strong inflammatory signal	Does not mimic natural caries progression
Chemical pulpitis	Application/injection of inflammatory agents such as LPS	Controlled immune activation and inflammatory nociception (acute pulpitis)	TLR activation, cytokines, P2X/TLR/TRP markers, behavior	Useful for pathway-specific testing	Oversimplifies clinical disease
Caries-linked pulpitis	Bacterial/caries-related pulpal inflammation	Naturalistic progression from caries to pulpitis (acute pulpitis)	Microbial markers, inflammation, pain behavior	Clinically relevant disease process	More variable and longer duration
Human-derived pulpitis model	Human carious dentin or clinical material in animal cavities	Translational pulpal inflammation (acute pulpitis)	Histology over time, immune markers, nociceptive behavior	High clinical relevance	Larger animals and ethical/logistical burden
Zymosan-augmented pulpitis	Prolonged inflammatory stimulation	Sustained pulpal inflammation; persistent dentoalveolar/post-procedural pain	Cytokines, glial markers, behavior	Useful for persistent inflammatory pain	Artificial immune stimulus
Laser-induced pulpitis	Controlled laser injury	Graded tissue damage and inflammation	Histology, thermal response, inflammatory markers	Controlled injury severity	Thermal injury may differ from clinical pulpitis
Orthodontic-force model	Controlled tooth movement force	Adjunct model orthodontic pain and neurogenic inflammation	CGRP, substance P, inflammatory markers, behavior	Relevant to clinical orthodontic pain	Usually transient; not infectious pulpitis
Trigeminal nerve injury model	Injury to branches of trigeminal nerve	Post-traumatic trigeminal neuropathic pain (within persistent dentoalveolar/post-procedural pain)	Allodynia, ATF3, glial activation, Nav remodeling	Useful comparator for neuropathic pain	Not odontogenic unless procedure-related
Vital pulp therapy/regenerative models	Pulpotomy, capping agents, regenerative materials	Adjunct model pain–repair interface	Histology, dentin bridge, inflammation, behavior	Links pain biology with repair	Pain readouts often underdeveloped
Nanocarrier analgesic models	Local delivery of anesthetics/TRP modulators/anti-inflammatory agents	Adjunct model prolonged local analgesia and target engagement	Drug release, behavior, tissue compatibility, biomarkers	Tests translational delivery strategies	Biocompatibility and release kinetics required
Central sensitization models	Repeated or intense dental/trigeminal input	TNC/thalamocortical amplification (headache-related orofacial pain overlap)	pERK, pCREB, KCC2, Iba1/GFAP, allodynia	Links dental input to headache-relevant trigeminal pathways	Specialized methods required

The clinical phenotypes named in the Abstract are each represented above: dentin hypersensitivity (dentin exposure/hydrodynamic model); acute pulpitis and the hot tooth phenotype (mechanical, chemical, caries-linked, human-derived, and laser pulpitis models); persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain (zymosan-augmented pulpitis and trigeminal nerve injury models); and headache-related orofacial pain overlap (central sensitization models). The orthodontic-force, vital-pulp/regenerative, and nanocarrier rows are included as adjunct model categories relevant to mechanism and therapy rather than as separate clinical phenotypes

Translational value and design considerations

Peripheral receptor and channel systems should not be presented as a simple catalogue. Their translational value depends on whether they explain a clinically meaningful phenotype. TRPV1 and TRPA1 are most relevant to thermal and chemical hypersensitivity; ASICs to tissue acidosis and local anesthetic failure; P2X3/P2Y signaling to odontoblast–nerve communication; P2X7/NLRP3 signaling to neuroimmune amplification; Nav1.8/Nav1.9 to inflammatory hyperexcitability and anesthetic resistance; PIEZO/TRPV4 to mechanical and biting pain. This phenotype-to-mechanism alignment strengthens the rationale for targeted therapy and helps avoid overinterpreting isolated molecular findings. Accordingly, peripheral transduction provides the first mechanistic layer of the tooth-to-trigeminal framework: it explains how local dental stimuli become nociceptive input, while the following sections address how this input is amplified within the trigeminal ganglion, central trigeminal pathways, and neuroimmune networks.

Trigeminal ganglion plasticity and Central amplification

Clinical relevance

Continuing the second review question, this section addresses the ganglionic and central mechanisms through which peripheral odontogenic input can be amplified, referred, or prolonged. Odontogenic pain is not completed at the tooth. Once peripheral afferents are activated, signals travel through branches of the trigeminal nerve to neuronal cell bodies in the trigeminal ganglion and then centrally to the trigeminal brainstem complex. First-order neurons from the dental pulp and periodontal tissues project to the spinal trigeminal nucleus, particularly the trigeminal nucleus caudalis (TNC), where second-order nociceptive neurons process incoming signals [10, 11, 96]. From there, ascending pathways transmit pain information to the thalamus, primary somatosensory cortex, anterior cingulate cortex, insula, parabrachial nucleus, amygdala, and nucleus accumbens [41, 97, 98] (Fig. 1). These pathways contribute not only to pain location and intensity, but also to unpleasantness, fear, attention, avoidance, and motivation for relief [99, 100]. This organization is especially relevant to the hot tooth phenotype, persistent dentoalveolar or post-procedural pain, and headache-related orofacial pain overlap, where pain may extend beyond the initiating tooth or persist after peripheral source control.

Mechanistic model

The trigeminal ganglion is a critical site of plasticity. Nociceptive stimulation can upregulate TRPV1, TRPA1, Nav1.7, Nav1.8, Nav1.9, P2X receptors, cytokine receptors, and neuropeptide signaling in trigeminal neurons [47, 93–95, 101]. Satellite glial cells surrounding neuronal somata become activated and release pro-inflammatory mediators such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which further sensitize adjacent neurons [48, 102, 103]. Connexin 43-mediated communication between satellite glial cells may facilitate the spread of excitation to neighboring, initially uninjured neurons, providing a potential mechanism for referred pain, ectopic activity, and expansion of pain fields [104]. Thus, trigeminal ganglion plasticity provides a plausible bridge between intense peripheral pulpitis and clinical features such as referred pain, spread across adjacent teeth or facial regions, and persistence of pain after the initiating stimulus has been treated.

At the level of the spinal trigeminal nucleus and trigeminocervical complex, repeated or intense peripheral input can produce central sensitization. Under normal conditions, glutamate released from primary afferents activates AMPA and kainate receptors on second-order neurons, enabling appropriate transmission of nociceptive information. With sustained input, NMDA receptors become recruited as depolarization relieves the voltage-dependent magnesium block, allowing calcium influx and activation of MAPK, PKC, PKA, PI3K, Src, and CREB-linked pathways [39, 40, 105]. These processes promote long-term potentiation-like changes, increase synaptic gain, and consolidate hyperalgesia and allodynia. Intracellular signaling pathways that may consolidate peripheral and central sensitization in odontogenic pain are summarized in Supplementary Table 2. Stimulus-induced changes in trigeminal ganglion excitability and synaptic amplification within the trigeminal nucleus caudalis are illustrated in Fig. 1C and D.

KCC2-linked chloride dysregulation is an especially important but underused concept in dental pain. KCC2 normally maintains low intracellular chloride in mature neurons, allowing GABAergic and glycinergic transmission to remain inhibitory. Downregulation or dysfunction of KCC2 shifts chloride gradients and can reduce inhibitory tone or even convert inhibitory signaling into depolarizing activity [49, 106]. In a hot tooth or persistent pulpitis context, this mechanism may help explain why peripheral input becomes centrally amplified and why conventional peripheral blockade may not fully suppress pain once central disinhibition is established. This concept is particularly useful for linking severe acute inflammatory pain with longer-lasting hypersensitivity or disproportionate pain responses.

Circuit-level readouts

Central amplification can be assessed using electrophysiological recordings from trigeminal ganglion, trigeminal nucleus caudalis, or higher-order pain circuits; pERK and pCREB mapping; Iba1 and GFAP staining; satellite glial markers; Connexin 43 expression; KCC2 expression; behavioral allodynia; referred pain mapping; and quantitative sensory testing in human studies [39, 48, 49, 107, 108]. In vivo calcium imaging, fiber photometry, optogenetic or chemogenetic modulation, and functional imaging approaches may help identify how dental nociceptive input alters trigeminal and brainstem circuit activity [109, 110]. These readouts are most informative when they are linked to specific clinical features, such as referred pain, spreading pain fields, allodynia, persistent post-procedural pain, or headache-related orofacial pain overlap. Their use within complete phenotype-matched models is addressed later in Section “Phenotype-matched preclinical models and experimental readouts”.

Translational value and design considerations

The central model is essential for linking dental pain to headache-related trigeminal biology. In migraine, repeated trigeminal activation can lead to peripheral sensitization of trigeminal ganglion neurons, central sensitization of trigeminal nucleus caudalis neurons, and eventually sensitization of thalamic neurons [9]. Severe odontogenic pain may follow a comparable logic: persistent dental nociceptive input increases excitability in shared trigeminal pathways, producing referred pain, facial spread, headache-like symptoms, and susceptibility to central amplification. However, central sensitization should not be assumed in every case. To avoid using it as a nonspecific label for difficult or persistent dental pain, it should be approached as an evidence-supported clinical and mechanistic construct. Clinically, this interpretation is most relevant when pain extends beyond the initiating tooth, becomes referred or spreading, is accompanied by allodynia or hyperalgesia, persists after adequate peripheral source control, or is disproportionate to clinical and radiographic findings. In translational studies, it should be supported, where possible, by quantitative sensory testing, referred pain mapping, expanded receptive fields, or molecular and cellular readouts such as pERK/pCREB activation, glial activation, KCC2-related inhibitory dysfunction, or other markers of altered synaptic gain. Accordingly, this section provides the second mechanistic layer of the tooth-to-trigeminal framework: it explains how peripheral dental nociception may be transformed into referred, persistent, or headache-overlapping pain through trigeminal ganglion plasticity and central amplification.

The trigeminovascular interface and the headache-overlap phenotype

The headache relevance of odontogenic input depends on a specific anatomical fact: dental afferents and the dural/meningeal afferents that drive primary headache converge on the same second-order neurons of the trigeminal nucleus caudalis and the wider trigeminocervical complex. Meningeal nociceptors, predominantly carried by the ophthalmic division, and cervical afferents from the upper cervical roots share central targets with maxillary and mandibular dental afferents, so that convergent second-order neurons can receive input from both cranial vascular and intraoral sources [9]. Experimental stimulation of dural afferents increases the responsiveness of trigeminocervical neurons to subsequent cervical or facial input, and the reverse also occurs, demonstrating bidirectional facilitation across convergent inputs [111, 112]. In migraine, this convergent architecture is further engaged by cortical spreading depression, which can activate meningeal nociceptors, and by progressive sensitization that ascends from trigeminal ganglion neurons to trigeminal nucleus caudalis neurons and ultimately to third-order thalamic neurons; thalamic sensitization is thought to underlie the spread of cutaneous allodynia beyond the initially affected trigeminal territory [42, 43, 113, 114]. CGRP acts across this same pathway, which is why CGRP-targeted therapies are effective in migraine and why CGRP is mechanistically attractive as a shared node between pulpal inflammation and trigeminovascular excitability [12, 16].

Within this framework, intense or sustained dental nociceptive traffic could, in susceptible individuals, raise the gain of convergent trigeminocervical neurons and lower the threshold for headache-like referral, while reciprocally, trigeminovascular activation could contribute to facial or intraoral pain that mimics dental disease. It is important, however, not to overstate the directness of this link. The strongest experimental convergence data concern dural (ophthalmic) and cervical afferents rather than maxillary or mandibular dental afferents specifically; the contribution of tooth-derived input to trigeminovascular modulation remains largely inferential and is, at present, supported more by shared anatomy and by analogy with migraine and neuropathic models than by direct demonstration in odontogenic states. This gap is itself a translational opportunity: models that combine a defined dental nociceptive stimulus with trigeminovascular readouts (meningeal afferent activity, dural neurogenic inflammation, trigeminocervical neuronal responses, and extracephalic sensory thresholds) would directly test whether and how dental input modulates the headache-relevant circuit.

Neuroimmune crosstalk, cGAS–STING signaling, and sex-dependent pain mechanisms

Clinical relevance

Completing the answer to the second review question, this section addresses the neuroimmune mechanisms that sustain, amplify, and modify odontogenic and headache-related orofacial pain. Odontogenic pain is shaped by dynamic interactions among neurons, glial cells, odontoblasts, immune cells, fibroblasts, endothelial cells, and microbial products. Inflammation in the pulp is not merely a passive consequence of infection or injury; it actively modifies neuronal excitability. The inflammatory mediators detailed in Section “Peripheral nociceptive transduction in dental tissues” and Table 3 lower nociceptor thresholds, promote receptor and ion-channel remodeling, and create a permissive environment for sustained neuroimmune amplification [33, 64, 115]. These mechanisms are especially relevant to acute pulpitis, the hot tooth phenotype, persistent dentoalveolar or post-procedural pain, and headache-related orofacial pain overlap, where inflammatory drive may be converted into sustained trigeminal sensitization.

Mechanistic model

Glial cells are central to sustained pain. In the peripheral pulp, Schwann cells provide trophic and structural support and may participate in immune regulation and tissue repair [116, 117]. In the trigeminal ganglion, satellite glial cells become activated after nociceptive stimulation and release IL-1β, TNF-α, and other mediators that sensitize adjacent neurons [48, 102, 103]. In the trigeminal nucleus and related central pathways, microglia and astrocytes become reactive and contribute to central sensitization [108, 115](Fig. 1D). P2X7 activation on microglia can promote NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activity and IL-1β maturation, linking ATP release to neuroinflammatory amplification [118–120]. Emerging evidence also suggests that immune-cell populations within the trigeminal ganglion, including macrophages, may contribute to ectopic orofacial pain associated with pulpitis, further supporting a ganglion-level neuroimmune component beyond local pulpal inflammation [121]. Together, these glial and immune-cell mechanisms provide a bridge between peripheral pulpal inflammation, trigeminal ganglion sensitization, and central amplification.

Pattern-recognition receptors provide a direct link between microbial disease and pain. TLRs recognize pathogen-associated molecular patterns and damage-associated molecular patterns [87, 88, 122]. TLR4 detects lipopolysaccharide from Gram-negative bacteria, TLR5 detects flagellin, and TLR2 in cooperation with TLR1 or TLR6 recognizes microbial components such as peptidoglycan and lipoteichoic acid [122, 123]. TLR activation in sensory neurons and immune cells can increase ion-channel expression, cytokine release, and nociceptor sensitivity. This is particularly important in caries-associated pulpitis, where bacterial products may directly activate nociceptive neurons and indirectly amplify pain through immune responses [81, 89, 124].

Emerging immune pathways such as cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling should be interpreted cautiously. Depending on cell type, tissue context, timing, and inflammatory state, cGAS–STING signaling may contribute to host defense, interferon responses, tissue inflammation, or pain modulation. In odontogenic pain, this pathway is conceptually attractive because pulpal injury and infection involve DNA damage, microbial products, and sterile inflammatory signals. However, its role should be framed as context-dependent and investigational rather than as an established dental pain mechanism [125].

Current evidence on cGAS–STING in pain is genuinely conflicting. In some sensory contexts, STING activation appears antinociceptive by suppressing nociceptor excitability through type I interferon–dependent signaling [126]. In other contexts, STING-related signaling may amplify neuroinflammation through NF-κB-, NLRP3-, cytokine-, or glial-linked pathways, and the net effect may depend on cell type, tissue context, inflammatory stage, injury model, timing, and sex. Recent evidence also suggests that microglial STING activation may alleviate nerve injury–induced neuropathic pain in male but not female mice, indicating that sex-dependent immune signaling can alter the functional consequence of the same pathway [125]. Therefore, cGAS–STING should not be presented as uniformly pro-nociceptive or anti-nociceptive in odontogenic or trigeminal pain.

Future basic studies should define this pathway with greater biological precision. Priorities include cell-type-specific manipulation of cGAS–STING signaling in nociceptors, satellite glial cells, microglia, macrophages, and other immune-cell populations; mapping its time course across acute pulpitis, persistent pulpitis, trigeminal ganglion sensitization, and post-procedural pain; comparing infectious, sterile inflammatory, and nerve-injury models; and testing whether cGAS–STING activation produces different effects across peripheral pulp tissue, trigeminal ganglion, and central trigeminal pathways. Such studies should include both sexes and should prespecify sex-stratified analyses so that sex-dependent immune mechanisms are not missed.

Sex-dependent immune mechanisms are also relevant. Pain literature increasingly suggests that microglia-dominant mechanisms may contribute more strongly to some pain states in males, whereas T-cell-dependent mechanisms may be more relevant in females [127–129]. These differences are not yet fully mapped in odontogenic pain but should be incorporated into future preclinical and clinical studies. Stratifying by sex, inflammatory stage, age, and pain duration may help explain variability in biomarker expression and therapeutic response.

Neuroimmune readouts

Relevant readouts include cytokine profiling, immunohistochemistry for Iba1 and GFAP, satellite glial cell activation markers, Connexin 43, P2X7, NLRP3, IL-1β, TNF-α, TLR expression, NF-κB activation, single-cell or spatial transcriptomics, CyTOF immune profiling, and sex-stratified behavioral assays [91, 92, 103, 115]. Readouts should distinguish peripheral immune activation, trigeminal ganglion satellite glial activation, and central microglial/astrocytic activation because these processes may have different therapeutic windows. For cGAS–STING specifically, future studies should also distinguish interferon-linked signaling from NF-κB-, inflammasome-, cytokine-, and glial-linked readouts, and should report whether effects are sex-dependent. As with the peripheral and central readouts described above, their use within phenotype-matched preclinical models is consolidated in Section “Phenotype-matched preclinical models and experimental readouts” and Table 4.

Translational value and design considerations

Neuroimmune mechanisms are most relevant when pain persists, spreads, becomes disproportionate, or shows poor response to conventional local treatment. However, immune activation is highly context-dependent. The timing of tissue sampling, sex, age, bacterial exposure, tissue injury severity, and prior analgesic or antibiotic exposure can alter results. Future studies should avoid treating neuroimmune activation as a single pathway and instead specify which cell population, mediator, and time window are being targeted. Accordingly, this section completes the mechanistic layer of the review by showing that peripheral transduction, trigeminal ganglion plasticity, central amplification, and immune signaling are not separate explanations, but interacting levels of the same tooth-to-trigeminal pain framework. The next section uses this framework to align each phenotype domain with appropriate preclinical models and experimental readouts.

Phenotype-matched preclinical models and experimental readouts

Clinical relevance

This section answers the third review question: which preclinical models and experimental readouts can test these mechanisms? It maps each clinical phenotype domain to its corresponding preclinical models and experimental readouts. Animal models remain essential for dissecting mechanisms that cannot be directly studied in humans. However, as emphasized in translational headache research, no single animal model fully captures the multifaceted nature of a human pain disorder. Odontogenic pain is similarly heterogeneous. The five phenotype domains defined in Section “Clinical phenotypes and classification of odontogenic and headache-related orofacial pain” are biologically distinct, even though they may share trigeminal pathways. For each phenotype, Fig. 3 and Table 4 specify the corresponding preclinical models and the experimental readouts used to test them; in Fig. 3, acute pulpitis and the hot tooth phenotype are shown together as a single inflammatory spectrum.

Fig. 3.

Phenotype-driven experimental models and readouts for odontogenic and headache-related orofacial pain. Across all phenotypes, clinical outcome and experimental readouts are further modified by contextual factors such as sex, age, sleep, stress, prior pain history, previous dental experience, procedural context, treatment expectation, and emotional distress, which should be recorded and, where possible, stratified in translational studies

Model categories

Mechanical pulp exposure models are useful for studying acute injury, inflammatory mediator release, and nociceptive behavior [44, 45]. Chemical pulpitis models using agents such as lipopolysaccharide or inflammatory compounds allow more controlled activation of immune pathways [89, 130]. Caries-linked and human-derived pulpitis models better mimic the clinical trajectory from bacterial disease to reversible or irreversible pulpitis [46, 50]. Zymosan-augmented pulpitis can sustain inflammation and is useful for persistent nociception [45]. Laser-induced pulpitis produces graded tissue damage and may be valuable for controlled injury and device-testing contexts [131]. Orthodontic-force models are useful for force-related periodontal and pulpal neurogenic inflammation, although they should not be equated with infectious pulpitis [24]. Trigeminal nerve injury models provide useful comparators for painful post-traumatic trigeminal neuropathic pain but are not odontogenic unless linked to dental procedures [18, 132–134]. A phenotype-driven model–readout framework for translational odontogenic and headache-related orofacial pain research is summarized in Fig. 3.

Experimental readouts

Experimental readouts should be aligned with the specific clinical question. Peripheral inflammatory models require pulpal histology, cytokine profiling, bacterial or TLR markers, and pain behavior. Ion-channel studies require electrophysiology, calcium imaging, pharmacological blockade, and channel expression analysis. Neuroimmune models require glial markers, cytokines, inflammasome readouts, and cell-type-resolved profiling. Central sensitization models require pERK, pCREB, KCC2, NMDA-related markers, glial activation, allodynia, referred pain mapping, and behavioral persistence after peripheral source control. Therapeutic studies require target engagement rather than pain behavior alone.

Translational value and design considerations

The key question is not whether a model reproduces every feature of dental pain, but whether it reproduces a clinically meaningful phenomenon that is difficult to study in humans. Model selection should therefore be phenotype-driven. For thermal hypersensitivity, TRPV1/TRPM8 models and thermal assays are appropriate. For biting pain, mechanical and periodontal force models are more relevant. For hot tooth anesthetic failure, pulpitis models with tissue acidosis and Nav remodeling are needed. For persistent pain, models should include longitudinal behavioral and central readouts. For headache overlap, models should examine trigeminal convergence, referred pain, and trigeminocervical activation. A phenotype-driven overview of preclinical odontogenic pain models, their readouts, strengths, and limitations is provided in Table 4.

Biomarkers and target engagement

Clinical relevance

This section answers the fourth review question: which biomarkers can confirm target engagement and identify biologically meaningful subgroups? A major barrier in dental pain research is that clinical trials often evaluate pain intensity without verifying target engagement or identifying biological subgroups. Biomarker platforms can address this gap by measuring neuroinflammation, neuronal excitability, receptor occupancy, transcriptomic state, and epigenetic regulation. For odontogenic pain, biomarkers should not be limited to diagnostic confirmation of pulpal disease. They should help answer translational questions: Which pathway is active? Which target is engaged? Which patient is likely to respond? Which intervention prevents central amplification? This section therefore links the phenotype-matched model framework in Section “Phenotype-matched preclinical models and experimental readouts” with the mechanism-guided therapeutic and trial-design strategies developed in Section “Mechanism-guided therapeutic strategies and trial design”.

Biomarker platforms

Neuroinflammation imaging is one promising direction. Translocator protein positron emission tomography (TSPO-PET) can serve as an in vivo readout of glial activation and neuroinflammatory burden, while receptor-occupancy positron emission tomography (PET) can quantify pharmacodynamic engagement of specific targets [110]. Although these platforms are more established in central nervous system and chronic pain research than in dentistry, they could be adapted for severe or refractory orofacial pain states, including hot tooth phenotypes, persistent dentoalveolar pain, or post-traumatic trigeminal neuropathic pain. Such approaches may be most informative when the phenotype includes referred pain, allodynia, persistent post-procedural pain, or headache-related orofacial pain overlap rather than short-lived localized dental pain alone.

Neuronal excitability can be evaluated using in vivo calcium imaging, genetically encoded calcium indicator (GCaMP)-based approaches, fiber photometry, and electrophysiology [90, 109]. Patch-clamp recordings provide causal linkage between ion-channel expression and neuronal hyperexcitability. Cell-type-resolved platforms such as RNAscope, cytometry by time-of-flight (CyTOF), single-cell RNA sequencing, spatial transcriptomics, and immunohistochemistry can distinguish neuronal, glial, immune, odontoblast, fibroblast, endothelial, and Schwann-cell contributions [91, 92]. Epigenetic and non-coding RNA signatures, including microRNAs, lncRNAs, circRNAs, DNA methylation, and histone modifications, may help identify transitions from acute inflammatory pain to persistent sensitization [23, 135, 136]. These platforms are particularly useful when biomarkers are used not only to describe tissue pathology, but also to confirm whether a proposed target, such as a TRP channel, Nav channel, purinergic receptor, glial pathway, cytokine axis, or central sensitization mechanism, is actually engaged.

Phenotype-linked target engagement

Biomarkers should be selected according to the phenotype and mechanism being tested. In dentin hypersensitivity, target engagement may be reflected by hydrodynamic or thermal responses, Aδ-fiber activity, odontoblast–afferent ATP/P2X3 signaling, or cold-related sensory thresholds. In acute pulpitis and the hot tooth phenotype, useful biomarkers may include tissue pH or acidosis-related measures, inflammatory cytokines, CGRP and substance P expression, TRPV1/TRPA1, ASIC, P2×3, Nav1.7/Nav1.8/Nav1.9, and local anesthetic responsiveness. In persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain, biomarker strategies should consider sensory gain or loss, ATF3, Nav remodeling, satellite glial activation, macrophage or cytokine signatures, Iba1/GFAP expression, pERK/pCREB activation, and KCC2-related inhibitory dysfunction. In headache-related orofacial pain overlap, CGRP-linked readouts, trigeminocervical activation, quantitative sensory testing (QST), referred pain mapping, and neuroimaging approaches may help distinguish ongoing peripheral drive from central amplification.

Biomarkers should therefore be interpreted as mechanism- and target-engagement tools rather than as universal diagnostic labels. A cytokine signal, ion-channel change, glial marker, or sensory abnormality is most informative when it is linked to a defined phenotype, a prespecified mechanism, and a measurable therapeutic target. This approach also reduces the risk of overinterpreting isolated molecular findings that may not explain the patient’s dominant pain mechanism.

Translational value and design considerations

The translational value of biomarkers depends on whether they clarify mechanism, confirm target engagement, or improve phenotype stratification. A biomarker should not be added to a study simply because it is measurable; it should correspond to a prespecified biological question. For example, a TRP-targeted intervention should include thermal or TRP-related molecular readouts, a purinergic intervention should include ATP/P2X-linked readouts, a glial or cytokine-targeted intervention should include neuroimmune markers, and a central sensitization-targeted intervention should include sensory, circuit-level, or imaging-based measures when feasible. This target-engagement framework prepares the rationale for Section “Mechanism-guided therapeutic strategies and trial design”, where therapeutic strategies and trial designs are organized according to the dominant level of action: peripheral, neuroimmune, central, or biomarker-guided combination approaches.

Mechanism-guided therapeutic strategies and trial design

Clinical relevance

This section answers the fifth review question: which mechanism-guided therapeutic and trial-design strategies may move beyond short-acting palliation? It integrates therapeutic targets, non-pharmacological care, biomarker-guided treatment selection, and mechanism-anchored clinical trial design. Clinical trials in dental pain often focus on pain intensity reduction over short time windows. While this is clinically meaningful, it does not reveal why an intervention works, which patients benefit, or whether central amplification is prevented. A mechanism-anchored trial design would combine clinical diagnosis, sensory phenotype, biomarker evidence, and target engagement. For odontogenic pain, this approach is particularly relevant to symptomatic irreversible pulpitis, persistent dentoalveolar pain, post-traumatic trigeminal neuropathic pain, and overlapping headache-related orofacial pain.

Therapeutic strategies by level of action

In this review, mechanism-guided therapy is defined broadly. It encompasses accurate diagnosis and classification, clear explanation of the pain to the patient, appropriate dental source control, avoidance of unnecessary irreversible procedures, targeted pharmacological and biological intervention, behavioral and supportive care, and timely referral, rather than pharmacological target engagement alone. Current dental pain management depends on treating the underlying pathology, controlling inflammation, and providing short-term analgesia. NSAIDs and acetaminophen combinations reduce prostaglandin-mediated peripheral sensitization [137, 138]. Corticosteroids suppress inflammatory mediator production and may improve inferior alveolar nerve block success in symptomatic irreversible pulpitis [139]. Local anesthetics block voltage-gated sodium channels, but their effectiveness is reduced in inflamed acidic tissue because ion trapping limits membrane penetration [5, 86]. Inflammation-induced vasodilation and upregulation of TTX-resistant Nav1.8 and Nav1.9 may further reduce responsiveness to conventional local anesthesia [140, 141].

Peripheral ion-channel targeting offers more mechanism-specific options. TRPV1 antagonists and desensitizers have shown preclinical promise, although systemic TRPV1 antagonists have been limited by hyperthermia and incomplete efficacy [142, 143]. Capsaicin and resiniferatoxin can produce desensitization, and TRPV1 activation can be exploited for selective delivery of membrane-impermeant sodium-channel blockers such as QX-314 [101, 144]. The capsaicin–QX-314 strategy is particularly attractive because TRPV1 opening allows entry of the charged lidocaine derivative into activated nociceptors, producing localized, activity-dependent analgesia without generalized motor blockade.

Nav and Cav channels are additional targets. Nav1.7, Nav1.8, and Nav1.9 inhibitors are being explored for pathological pain signaling [145, 146]. Cav2.2 inhibitors reduce neurotransmitter release and may be relevant to chronic and neuropathic pain [147, 148]. Neuroimmune targets include anti-NGF approaches, cytokine or chemokine targeting, P2X7/NLRP3/IL-1β modulation, mPGES-1 inhibition, NOS inhibition, cannabinoid and FAAH modulation, and glial modulation [15, 149, 150]. Central targets include NMDA receptor modulation, KCC2 restoration, and strategies to reduce maladaptive neuron–glial coupling [151]. Candidate mechanism-guided therapeutic targets, their biological rationale, translational stage, and limitations are summarized in Table 5.

Table 5.

Mechanism-guided therapeutic targets in odontogenic and trigeminal pain

Therapeutic target	Biological rationale	Example agents/strategies	Translational stage	Main limitations
COX/prostaglandin pathway	PGE2 sensitizes nociceptors through EP/cAMP/PKA	Ibuprofen, naproxen, acetaminophen combinations; mPGES-1 inhibitors	Established for NSAIDs; mPGES-1 investigational	GI, renal, CV concerns; incomplete effect in severe hot tooth phenotype
Corticosteroid-sensitive inflammation	Suppresses inflammatory mediators and edema	Dexamethasone, prednisolone	Clinical adjunct	Systemic effects; not mechanism-specific
Local anesthetic/Nav blockade	Blocks action potential propagation	Lidocaine, articaine, bupivacaine; buffered/intraosseous/intraligamentary approaches	Established clinical standard	Reduced efficacy in acidic inflamed tissues; Nav remodeling
Nav1.7/Nav1.8/Nav1.9	Key channels for nociceptor excitability and inflammatory hyperexcitability	Selective blockers, gene-silencing approaches	Preclinical/early clinical	Selectivity, delivery, redundancy among channel subtypes
Cav2.2/Cav channels	Regulate neurotransmitter release	Ziconotide and related blockers	Clinical in severe chronic pain; limited dental use	CNS adverse effects and delivery barriers
TRPV1/TRP channels	Heat, acid, chemical, and inflammatory sensors; gateway for QX-314	Capsaicin, resiniferatoxin, TRP antagonists, capsaicin-QX-314	Preclinical/selected clinical contexts	Hyperthermia with systemic antagonists; delivery challenges
ASICs	Detect acidosis in inflamed tissues	ASIC antagonists	Preclinical	Limited clinical translation
P2 × 3/P2Y/P2 × 7	ATP-mediated neuron, odontoblast, and glial signaling	P2 × 3 antagonists, P2Y modulators, P2 × 7 antagonists	Emerging/preclinical	Taste effects for some P2 × 3 agents; dental efficacy uncertain
NGF/TrkA	Long-term nociceptor sensitization	Anti-NGF antibodies, TrkA inhibitors	Clinical development across pain fields	Safety concerns; dental-specific evidence needed
Cytokine/chemokine pathways	IL-1β, IL-6, TNF-α, CCL2 amplify neuroimmune pain	Cytokine inhibitors, chemokine antagonists	Established in inflammatory diseases; investigational in dental pain	Systemic immunomodulation; phenotype selection needed
CGRP pathway	Shared mediator in migraine and dental pulp inflammation	Gepants, anti-CGRP monoclonal antibodies	Established in migraine; dental relevance investigational	Dental pain trials lacking
NMDA/glutamatergic signaling	Sustained input recruits central sensitization	Ketamine, memantine, NMDA modulators	Clinical in selected pain settings	Not routine for dental pain; side effects
KCC2/chloride regulation	Restores inhibitory tone	KCC2 enhancers/chloride-modulating strategies	Mostly preclinical	Limited clinical availability
Cannabinoid/FAAH pathways	Modulate peripheral and central pain/inflammation	CB2 agonists, FAAH inhibitors, endocannabinoid modulators	Preclinical/early clinical	Regulatory and safety considerations
Nanoparticle/local delivery	Improves local retention and reduces systemic exposure	Liposomes, PLGA, pH-responsive carriers, TRPV1 nanogels	Preclinical/early translational	Biocompatibility, release kinetics, regulation

Rather than treating these interventions as isolated targets, they can be grouped by their dominant level of action. Peripheral strategies aim to reduce the initiating nociceptive drive through source control, anti-inflammatory treatment, optimized local anesthesia, and nociceptor- or ion-channel–directed approaches, and are most applicable to dentin hypersensitivity, acute pulpitis, and the hot tooth phenotype. Neuroimmune strategies target cytokine, chemokine, inflammasome, satellite glial, microglial, and neuron–glia signaling that may sustain or amplify pain and are most relevant to persistent inflammatory and post-procedural pain. Central strategies are most relevant when clinical or experimental features support trigeminal amplification, altered inhibitory tone, or maladaptive synaptic gain, and apply particularly to referred pain, allodynia, and headache-related orofacial pain overlap. In refractory or overlapping phenotypes, biomarker-guided combination approaches may be required because peripheral, neuroimmune, central, and contextual contributors can coexist. This level-of-action framework is summarized schematically in Fig. 4.

Fig. 4.

Mechanism-guided therapeutic strategy map for odontogenic and headache-related orofacial pain. Current and investigational treatments are organized by level of action: peripheral intervention, neuroimmune modulation, central sensitization regulation, and biomarker-guided combination regimens. For each strategy, the principal site of action, core mechanism, and the clinical phenotype to which it is best matched are indicated, mirroring the targets summarized in Table 5. The map is intended to support phenotype- and biomarker-guided selection rather than uniform escalation of analgesia

For persistent or overlapping orofacial pain, non-pharmacological and communication-based approaches are valuable adjuncts to mechanism-targeted pharmacology. Pain education, a clear explanation of the diagnosis, explicit reassurance that the pain is real, avoidance of unnecessary repeated procedures, sleep optimization, stress management, graded functional restoration, and behavioral interventions can each be understood as ways to modulate the pain network, reduce fear and vigilance, and improve function. Framed mechanistically, these strategies act on the same affective-motivational and descending-modulatory pathways that shape central sensitization, and they are particularly relevant when peripheral source control alone is insufficient.

Trial design implications

A hot tooth trial could stratify patients by thermal hypersensitivity, spontaneous pain, referred pain, anesthetic failure, inflammatory biomarkers, and sensory testing. Interventions could be matched to mechanisms: prostanoid-dominant phenotypes to NSAID or mPGES-1 strategies, TRPV1-positive thermal hyperalgesia to TRPV1-guided delivery, Nav remodeling or anesthetic failure to sodium-channel-targeted adjuncts, and central sensitization phenotypes to NMDA, KCC2, or glial-focused approaches. Outcomes should include pain intensity, time to anesthesia, supplemental injection need, postoperative pain, analgesic consumption, function, sleep, quality of life, and persistence or recurrence, and should be complemented by patient-centered measures such as oral health–related quality of life, interference with eating and speaking, sleep quality, dental fear, treatment expectation, pain catastrophizing, anxiety and depressive symptoms, treatment satisfaction, and the patient’s understanding of the symptom explanation. These outcomes align trial measurement with the same patient-level contextual contributors discussed earlier, including sleep, stress, prior pain and treatment experience, expectation, and affective-motivational processing.

The onset of persistent pain after dental treatment also deserves explicit clinical framing. Endodontic therapy, extraction, restorative and prosthodontic treatment, occlusal adjustment, and repeated procedures are often necessary and appropriate, yet in susceptible patients, dental treatment can serve as a temporary starting point or a maintaining context for persistent pain rather than as evidence of technical error or ongoing local pathology [28]. When acute pain, procedural stress, diagnostic uncertainty, repeated intervention, and heightened attention to oral sensation combine with trigeminal sensitization, persistent dentoalveolar and post-procedural pain may be better explained by neuropathic, nociplastic, cognitive-affective, and behavioral mechanisms than by unresolved peripheral disease. Recognizing this distinction is essential to avoid escalating irreversible treatment in pain states that will not respond to it.

For headache-related orofacial pain, trials should incorporate classification-based screening. ICOP and ICHD-3 criteria can help distinguish true odontogenic pain from orofacial presentations of migraine, trigeminal autonomic cephalalgias, trigeminal neuralgia, persistent idiopathic facial pain, and post-traumatic trigeminal neuropathic pain [7]. This is essential because treating a headache disorder as a dental disease can lead to unnecessary procedures, while missing a true odontogenic driver may allow ongoing inflammatory input to sustain trigeminal sensitization [8].

Translational value and design considerations

Mechanism-anchored trials should include target-engagement endpoints. A drug targeting TRP channels should show TRP-related sensory or molecular effects. A glial-targeted intervention should show changes in glial or cytokine markers. A central sensitization intervention should include quantitative sensory testing, referred pain mapping, or neuroimaging when feasible. In early-phase studies, biomarker enrichment may be more informative than broad enrollment because it can identify responders and refine inclusion criteria for larger trials.

As summarized in Fig. 4, refractory or overlapping phenotypes may require biomarker-guided combinations when clinical features indicate coexisting peripheral, neuroimmune, central, and contextual contributors. Such combinations should not be applied indiscriminately; their rationale should come from phenotype, mechanism, and evidence of target engagement.

Dental pain trials should also be designed with network biology in mind. Persistent or refractory pain often reflects interacting peripheral sensitization, trigeminal ganglion and brainstem activation, glial and immune signaling, descending modulation, limbic processing, and patient-level factors such as sex, stress, sleep, prior pain, and psychological context [115, 127, 152]. We therefore propose that future dental pain trials should stratify patients by clinical phenotype, dominant mechanism, biomarker profile, and evidence of target engagement. A trial framework that measures mechanism, function, patient-centered outcomes, and durability, rather than short-term analgesia alone, can transform dental pain research into translational trigeminal pain science.

Conclusion

Odontogenic pain, particularly the hot tooth phenotype, should be understood not only as a local dental symptom but also as a clinically accessible model of trigeminal sensitization. Severe pulpal inflammation can activate peripheral nociceptors, alter ion-channel and receptor signaling, promote neuroimmune crosstalk, and amplify pain processing within trigeminal ganglion and brainstem pathways. These mechanisms help explain clinically important features of dental pain, including poor localization, referred pain, local anesthetic difficulty, persistent hypersensitivity, and overlap with headache-related orofacial pain.

The central contribution of this review is the alignment of clinical phenotypes, mechanisms, models, biomarkers, and therapeutic strategies within a single tooth-to-trigeminal framework. In this framework, the five linked review questions are answered as follows: the clinically relevant phenotype domains are dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. These phenotypes are explained by interacting peripheral, ganglionic, central, and neuroimmune mechanisms; tested through phenotype-matched models and readouts; refined through biomarkers of target engagement; and translated into mechanism-guided therapeutic and trial-design strategies. These pain states should not be studied as interchangeable entities. Each requires model selection, outcome measures, biomarkers, and therapeutic targets that reflect its dominant biology, whether peripheral inflammation, tissue acidosis, ion-channel remodeling, neuroimmune activation, central sensitization, or trigeminal convergence.

The relevance of this framework extends beyond dentistry. By linking tooth-derived nociceptive input to headache-relevant trigeminal pathways, odontogenic pain can serve as a valuable translational window into peripheral-to-central pain amplification. This perspective may help reduce diagnostic confusion between dental pain and primary headache disorders, avoid unnecessary procedures, and improve the design of mechanism-anchored clinical trials.

Future therapeutic development should move beyond short-term analgesia alone. Durable improvement will likely require biomarker-guided and mechanism-informed strategies that combine appropriate source control with targeted modulation of peripheral, neuroimmune, central, and patient-level contributors. Ultimately, the value of the tooth-to-trigeminal framework is that it helps clinicians choose more appropriate treatment rather than simply more intensive treatment. By integrating mechanisms with the patient-level context that shapes pain expression, including sleep, stress, prior experience, expectation, and affective processing, and by distinguishing true odontogenic drivers from non-odontogenic and overlapping orofacial pain, this perspective supports care that is both biologically informed and patient-centered while avoiding the cycle of unnecessary, irreversible procedures.

Electronic supplementary material

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Abbreviations

5-HT

5-hydroxytryptamine/serotonin

Aδ

A-delta fiber

AMPA

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ASIC

Acid-sensing ion channel

ATF3

Activating transcription factor 3

ATP

Adenosine triphosphate

Cav

Voltage-gated calcium channel

cAMP

Cyclic adenosine monophosphate

CB2

Cannabinoid receptor type 2

CCL2

C-C motif chemokine ligand 2

CGRP

Calcitonin gene-related peptide

cGAS

Cyclic GMP–AMP synthase

CNS

Central nervous system

COX

Cyclooxygenase

CREB

cAMP response element-binding protein

CyTOF

Cytometry by time-of-flight

DAG

Diacylglycerol

DAMP

Damage-associated molecular pattern

DNA

Deoxyribonucleic acid

ERK

Extracellular signal-regulated kinase

FAAH

Fatty acid amide hydrolase

GCaMP

Genetically encoded calcium indicator

GFAP

Glial fibrillary acidic protein

GPCR

G protein-coupled receptor

Iba1

Ionized calcium-binding adaptor molecule 1

ICHD-3

International Classification of Headache Disorders, 3rd edition

ICOP

International Classification of Orofacial Pain

IFN-γ

Interferon gamma

IL

Interleukin

IL-1β

Interleukin-1 beta

IL-6

Interleukin-6

KCC2

Potassium-chloride cotransporter 2

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

mGluR

Metabotropic glutamate receptor

mPGES-1

Microsomal prostaglandin E synthase-1

Nav

Voltage-gated sodium channel

NF-κB

Nuclear factor kappa B

NGF

Nerve growth factor

NK1

Neurokinin 1 receptor

NLRP3

NOD-like receptor family pyrin domain-containing 3

NMDA

N-methyl-D-aspartate

NMDAR

N-methyl-D-aspartate receptor

NOS

Nitric oxide synthase

PAMP

Pathogen-associated molecular pattern

PET

Positron emission tomography

PGE2

Prostaglandin E2

PI3K

Phosphoinositide 3-kinase

PIEZO

Mechanosensitive ion channel family

PIFP

Persistent idiopathic facial pain

PKA

Protein kinase A

PKC

Protein kinase C

PLC

Phospholipase C

PRR

Pattern-recognition receptor

P2X

Purinergic P2X receptor

P2Y

Purinergic P2Y receptor

QST

Quantitative sensory testing

QX-314

Quaternary lidocaine derivative

RNA

Ribonucleic acid

RNAscope

RNA in situ hybridization platform

Src

Proto-oncogene tyrosine-protein kinase Src

STING

Stimulator of interferon genes

TLR

Toll-like receptor

TLR4

Toll-like receptor 4

TMD

Temporomandibular disorder

TNC

Trigeminal nucleus caudalis

TNF-α

Tumor necrosis factor alpha

TRP

Transient receptor potential

TRPA1

Transient receptor potential ankyrin 1

TRPC

Transient receptor potential canonical

TRPM

Transient receptor potential melastatin

TRPM8

Transient receptor potential melastatin 8

TRPV1

Transient receptor potential vanilloid 1

TRPV4

Transient receptor potential vanilloid 4

TSPO

Translocator protein

Author contributions

ECF: contributed to the conception and design of the review, performed the literature synthesis and interpretation, wrote the main manuscript text, and prepared Figures 1–4. KA, HW, SY: contributed to the conceptual development of the review, interpretation of the literature, and substantive revision of the manuscript for important intellectual content. All authors reviewed and approved the submitted version of the manuscript. All authors agree to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and documented.

Funding

This work was supported by the National Institutes of Health under award numbers R01DE034088 and R01DE033004.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.