The Interaction Between the Central Nervous System and Dental Tissues: Hypothetical Dental Interoception Inferred From Skeletal Interoception

ABSTRACT

Background

The circuit of interoception, through which the nervous system monitors internal physiological states and maintains tissue homeostasis, has been well characterized in bone. However, whether a comparable interoceptive mechanism exists in the other mineralized tissue—teeth—remains unknown.

Objectives

This review uses skeletal interoception as a comparative framework to examine whether analogous sensory‐regulatory mechanisms may operate in dental tissues. We summarize the neuroanatomical basis of dental innervation, the peripheral cellular mechanisms by which the pulp‐dentine complex and periodontal ligament‐alveolar bone complex sense and transduce local tissue states, and the reciprocal neural and effector responses that may contribute to dental homeostasis. Based on current evidence, we propose ‘dental interoception’ as a hypothetical conceptual framework for understanding neural‐cellular regulation in teeth and their supporting tissues.

Method

The literature search was conducted in the PubMed and Web of Science databases, with a focus on how dental cells sense local tissue‐state changes and communicate with the nervous system, as well as the direct regulation on odontogenesis‐related cells by the nervous system.

Results

Current evidence suggests two potential modules of dental interoception: a pulp‐dentine module that monitors intradental tissue states and supports pulp repair and reparative dentinogenesis, and a periodontal ligament‐alveolar bone module that senses tooth load and regulates occlusal adaptation and alveolar bone remodelling. These modules involve pulpal cell‐trigeminal nerve communication, reciprocal neural regulation of pulpal vascular, immune, stem‐cell and reparative responses, and periodontal mechanoreceptor‐guided remodelling. However, whether they form a complete peripheral‐central‐peripheral feedback loop remains unresolved.

Conclusion

The bidirectional regulation between the nervous system and dental tissues is fundamental for maintaining dental homeostasis. Mapping the full circuitry underlying this interaction will be essential to establish dental interoception as a coherent physiological concept.

Drawing on the established framework of skeletal interoception, we propose hypothetical dental interoception as a bidirectional communication system linking dental tissues with the central nervous system. Sensory signals from the pulp–dentine and periodontal ligament–alveolar bone complexes are transmitted through trigeminal pathways, whereas descending autonomic and neuropeptide signals regulate sensory responses, tissue repair and periodontal remodelling, thereby contributing to dental and periodontal homeostasis.

1. Introduction

The concept of interoception was first introduced by Sherrington in 1906 as a counterpart to exteroception, which refers to the sensing of stimuli from the external environment [1, 2]. Initially synonymous with visceroception—the sensing of internal signals from visceral organs—interoception is now understood in broader terms. It is defined as the overall process by which the nervous system senses, interprets and integrates physiological signals originating within the body and generates appropriate feedback responses to maintain internal homeostasis [2, 3, 4, 5]. This dynamic, bidirectional communication facilitates a continuous representation of the body's internal state, both at conscious and nonconscious levels.

Various types of interoceptive signals—including chemical, mechanical, thermal and humoral cues—can be transmitted to the central nervous system (CNS) via either neural or humoral pathways. Interoceptive receptors, including chemoreceptors, mechanoreceptors and free nerve endings associated with Aδ and C fibres, are distributed throughout peripheral tissues. Upon activation, these receptors convert stimuli into bioelectrical or molecular signals, which travel through specific afferent pathways toward the CNS. The vagus nerve is considered the principal conduit for visceral interoceptive input. In parallel, spinal afferents relay somatic interoceptive signals through the dorsal horn to higher‐order centers, such as the thalamus and hypothalamus. In addition to neural input, humoral signals, including circulating cytokines, hormones and metabolites, can influence both central processing and peripheral interoceptive responses. The CNS, in turn, can control the internal environment through either direct mechanisms, such as activation of the autonomic nervous system including the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) or indirectly pathways via the neuroendocrine system (such as the hypothalamic–pituitary–gonadal axis). These systems collectively modulate immune function, vascular tone, metabolic activity and cellular behaviour within local tissue microenvironments [2]. Thus, interoception serves as a sophisticated, integrated regulatory network that maintains systemic homeostasis at cellular, tissue and organ levels.

Although the term ‘interoception’ was formally coined in the early 20th century, the physiological principles underlying interoceptive processing in internal organs, such as the stomach and liver, had been recognized much earlier. Over time, the scope of interoception has expanded beyond visceral organs to encompass somatic tissues, including the skin, fascia, joints and skeletal muscle, reflecting a broader understanding of the body's internal sensory landscape [2, 6, 7, 8]. A notable development in this area is the emerging recognition of skeletal interoception. Traditionally considered a purely structural tissue, bone has now been recognized as an interoceptive organ, capable of sensing and regulating its internal physiological state. Accumulating evidence over the past two decades has revealed that sensory nerve fibres within bone detect alterations in intraosseous states and transmit these signals via afferent nerves, including the dorsal root ganglia (DRG) and the superficial layers of the spinal dorsal horn, to the CNS, particularly the hypothalamus [9]. The CNS then integrates and interprets these signals, ultimately orchestrating efferent responses through both autonomic and neuroendocrine outputs to maintain skeletal homeostasis [10]. These findings underscore that interoception is not confined to classical visceral organs but is a distributed physiological phenomenon that includes the musculoskeletal system, previously considered to have limited neural regulation.

Teeth and bones, the two primary mineralized tissues in the human body, share notable structural and developmental similarities. Both consist of an outer calcified matrix encasing an inner core of vascularized and innervated connective tissue—the bone marrow in bones and the dental pulp in teeth—providing an anatomical configuration supportive of interoception. The dental pulp is highly innervated by both sensory and sympathetic nerves, enabling it to detect mechanical and thermal stimuli, regulate blood flow and initiate immune responses. Studies using mandibular denervation animal models have revealed structural and functional alterations in teeth, suggesting that neural input is critical for dental tissue homeostasis. Given these anatomical, structural and physiological parallels between teeth and bones, it is plausible that teeth may also possess interoceptive functions, analogous to those of bone. However, the precise mechanisms by which the nervous system senses and regulates the dental microenvironment remain largely unexplored. Despite the wealth of literature on dental pain, pulp inflammation and neurovascular interactions, the concept of dental interoception has not yet been formally established. Building on the established concept of skeletal interoception, this review examines whether comparable sensory‐regulatory principles may be extended to dental tissues. We first summarize the neuroanatomical basis of dental innervation and then discuss how the pulp‐dentine complex and the periodontal ligament‐alveolar bone complex may detect, transduce and relay local tissue‐state information through peripheral cellular and neural mechanisms. We further consider how neural, vascular, immune and remodelling responses may feed back onto these dental tissues and contribute to dental homeostasis. By integrating evidence from neuroscience, skeletal biology and dental research, we propose ‘dental interoception’ as a hypothetical conceptual framework for understanding neural‐cellular regulation in teeth and their supporting tissues, and we highlight the key unresolved questions that should be addressed in future studies.

To develop this hypothetical framework, we conducted a focused narrative review of studies indexed in PubMed and Web of Science. The literature search focused on three interconnected topics: the anatomical and neurophysiological basis of skeletal and dental innervation; the mechanisms by which dental cells and tooth‐supporting tissues detect and transduce mechanical, chemical, inflammatory or injury‐related changes; and the ways in which neural signals regulate odontogenesis‐related, pulpal, periodontal and bone‐related cells during tissue homeostasis, repair and remodelling. We prioritized studies on skeletal interoception, dental innervation, odontoblast and dental pulp cell sensory mechanisms, periodontal ligament mechanosensation, alveolar bone remodelling, neuroimmune mediators, denervation models and neural regulation of dental or periodontal tissue repair. The evidence was organized according to the major steps of interoceptive regulation, including peripheral detection, signal transduction and afferent transmission, central or autonomic integration and effector responses. Because dental interoception has not yet been formally established as a defined physiological concept, this review was intended to synthesize available evidence into a conceptual framework rather than to provide a systematic meta‐analysis.

2. Interoception in Systemic Feedback Regulation

The internal sensory system of the human body has been investigated for centuries, particularly with advances in anatomy and neurophysiology. Interoception refers to the process by which the nervous system detects, integrates and regulates internal physiological signals, thereby providing continuous information about the functional state of the body and supporting homeostatic control. Recent studies have further shown that interoceptive regulation relies on coordinated peripheral receptors, ascending afferent pathways, central integrative circuits and descending autonomic or neuroendocrine outputs. Functionally, interoception involves detection of internal physiological changes, transduction and transmission of these signals to the central nervous system, central integration and effector responses. Peripheral interoceptors or specialized sensory cells detect changes such as mechanical stretch, tissue pressure, chemical or osmotic shifts, temperature variation, hypoxia, inflammation and tissue injury. The resulting signals are conveyed through neural, humoral or cellular pathways and integrated with autonomic, endocrine, emotional and behavioural contexts. Appropriate effector responses are then initiated through autonomic, neuroendocrine, immune, vascular and cellular pathways to restore or maintain homeostasis [2, 4, 5].

Interoception operates through an integrated regulatory system that consists of the following key steps: (1) Detection: peripheral interoceptors detect a wide range of internal stimuli, such as mechanical forces, chemical cues, temperature changes and visceral nociceptive or injury‐related signals. These receptors are located in various tissues and are specialized to sense physiological perturbations, thereby initiating signal transmission to the CNS.

(2) Signal transmission: These signals are conveyed to the CNS via distinct afferent pathways, primarily categorized into two types:

Somatosensory pathways via DRG: DRG neurons primarily transmit somatic signals such as thermosensation, nociception and tissue injury. These signals are relayed through the dorsal horn of the spinal cord to the CNS [11].

Visceral pathways via cranial and vagal sensory ganglia: The vagal afferents arise from the Nodose Ganglion (NG) and Jugular Ganglion (JG), projecting to the brainstem and transmitting visceral sensory signals [12]. Visceral sensory neurons play a crucial role in detecting chemical cues released by visceral organs and transmitting this information to the CNS through afferent pathways [13, 14, 15].

(3) Central processing and interpretation: Upon reaching the CNS, interoceptive signals are first processed in subcortical regions, particularly the nucleus tractus solitarius (NTS). Subsequent processing occurs in specific brain regions depending on the nature of the signal. For instance, the hypothalamus is predominantly responsible for integrating signals related to metabolic and autonomic regulation. The parabrachial nucleus processes nociceptive and gustatory interoceptive inputs. The thalamus and hippocampus are implicated in interpreting interoceptive signals [12, 16, 17, 18]. Higher‐order analysis may occur in the insula, a cortical hub crucial for integrating nociceptive and visceral signals and for generating a subjective awareness of internal bodily states [19]. Besides, the somatosensory cortex and prefrontal cortex (especially the ventromedial prefrontal cortex (vmPFC)) play a crucial role in coordinating multi‐modal sensory information, including visual, auditory and somatosensory inputs, thereby contributing to perception, cognition and autonomic regulation [20].

(4) Efferent signalling: Efferent interoceptive pathways enable the CNS to regulate peripheral target organs via autonomic, endocrine, cardiovascular and neuroimmune outputs. The SNS and PSNS are the key effectors in this process.

SNS regulation: preganglionic sympathetic neurons in the intermediolateral nucleus (IML) of the spinal cord relay signals to paravertebral sympathetic ganglia or to chromaffin cells in the adrenal medulla. This leads to the release of norepinephrine (NE) and epinephrine, which bind to adrenergic receptors on target tissues. These neurotransmitters also modulate local sensory neurons, promoting the release of neuropeptides such as NPY, CGRP and SP, which mediate a variety of physiological responses including vasomotor regulation, immune modulation and metabolic shifts [21].

PSNS regulation: postganglionic fibres of the PSNS release acetylcholine (ACh), which binds to muscarinic cholinergic receptors (M receptors) on target cells, triggering a range of effects including modulation of secretory and cardiovascular functions [22, 23].

(5) Effector response: Once a neurotransmitter binds to its corresponding receptor, intracellular signalling cascades are activated to restore or maintain homeostasis. A classic example is vascular regulation, in which norepinephrine modulates regional vascular tone through adrenergic receptors. In humans, intra‐arterial norepinephrine reduces forearm blood flow and venous distensibility, and α‐adrenergic receptor blockade modifies these responses, supporting α‐adrenergic control of local vascular tone [24]. α2‐adrenergic receptors also contribute to baroreflex‐induced vasoconstriction in the human leg, and α‐adrenergic mechanisms restrain skeletal muscle blood flow in humans, indicating that sympathetic neurotransmission can adjust regional blood flow according to physiological demands [25].

3. The Regulatory Roles and Mechanisms of Skeletal Interoception in Bone Homeostasis

Beyond its traditional role in structural support and locomotion through interactions with skeletal muscles, the skeletal system is highly metabolically active and undergoes continuous remodelling. Although innervation of bones has been recognized for centuries, recent research highlights a significant regulatory relationship between skeletal metabolism and the nervous system. Skeletal interoception, the process through which sensory signals from bones is detected, transmitted and interpreted, plays a critical role in maintaining bone homeostasis. This section elucidates the afferent and efferent components of skeletal interoceptive pathways and their mechanisms.

3.1. The Afferent Pathway in Skeleton Interoception

Bone should not be viewed as an inert mineralized structure, but as a highly innervated and neurochemically responsive tissue. Sensory and autonomic fibres have been described in the medullary cavity, trabecular bone, mineralized bone and perivascular regions, indicating that skeletal afferent signalling may arise from multiple anatomical compartments rather than from a single intramedullary source. Importantly, skeletal innervation is not confined to the bone marrow. The periosteum, which covers most external bone surfaces, is one of the most densely innervated and pain‐sensitive skeletal compartments, and noxious stimulation of either the periosteum or the marrow cavity can evoke bone pain [26, 27] Classical and more recent studies provide direct support for this view. Rowe et al. discussed whether bone‐associated receptors may contribute to mechanosensory perception, thereby raising the possibility that skeletal tissues are capable of providing sensory information beyond overt pain [28] Ivanusic later characterized sensory neurons innervating the rat tibia and showed that the periosteum, medullary cavity and trabecular bone are all supplied by sensory neurons with distinct size and neurochemical profiles. These findings are consistent with earlier observations that limb bones lack a substantial population of large‐diameter sensory fibres and are instead mainly supplied by small‐ and medium‐sized afferents [29]. Functionally, Morgan, Nencini, Thai and Ivanusic further demonstrated that TRPV1 activation can modulate Aδ‐ and C‐fibre bone afferent neurons, suggesting that intraosseous afferents are capable of detecting inflammatory or noxious changes within skeletal tissues [30]. Together, these studies indicate that bone contains a structured sensory system involving the periosteum, marrow cavity, trabecular bone and intraosseous afferents, rather than merely passive nerve fibres accompanying blood vessels. However, these findings should be interpreted with anatomical caution. Many physiological studies defining the properties of bone afferents were performed in appendicular long bones, whose sensory neurons are mainly associated with dorsal root ganglia [28, 30]. By contrast, craniofacial bones, including the maxilla, mandible and alveolar bone, are primarily integrated into the trigeminal sensory system through branches of the trigeminal nerve. Consistent with this distinction, calvarial periosteal afferents recorded from the trigeminal ganglion display nociceptive properties and respond to inflammatory mediators [31]. Therefore, evidence from long bones should be used to define general principles of skeletal innervation and bone–nerve communication, rather than being directly equated with dental or alveolar bone innervation. Nevertheless, these principles remain highly relevant to dental interoception because the periodontal ligament–alveolar bone complex is a specialized craniofacial skeletal module in which mechanical loading, bone remodelling, inflammation and trigeminal sensory transmission are closely coupled.

Bone homeostasis is orchestrated by complex biochemical networks that involve cellular responses to changes in the internal microenvironment, such as mechanical loading, injury and inflammation. These changes can stimulate bone cells to produce diverse signalling molecules that act as interoceptive messengers. Although a variety of mechanical, chemical and thermal cues can activate peripheral interoceptors, the precise molecular signals of skeletal afferent pathways remain incompletely characterized. Among the most well‐characterized mediators of skeletal interoception is PGE2, a key inflammatory mediator derived from arachidonic acid through the cyclooxygenase (COX) pathway. PGE2 has been extensively studied for its role in bone remodelling and is known to stimulate osteoclastic bone resorption, particularly in inflammatory bone diseases such as periodontitis and arthritis. Elevated levels of PGE2 have been correlated with decreased bone mineral density in osteoporotic animal models [32, 33, 34, 35]. PGE2 exerts its biological functions through four G protein‐coupled receptors: EP1, EP2, EP3 and EP4 [36].

Recent studies have demonstrated that osteoblast‐derived PGE2, produced in response to mechanical loading, functions as an interoceptive signal that activates EP4 receptors on peripheral sensory neurons, thereby linking skeletal microenvironmental changes to afferent neural signalling. Disruption of this signalling axis, by ablation of sensory nerves, targeted deletion of EP4 in sensory neurons or conditional knockout of COX2 in osteoblasts, drastically reduced bone volume. Conversely, pharmacological elevation of PGE2 using SW033291 significantly enhanced bone formation, an effect abolished in EP4 knockout mice [37]. Mechanistically, PGE2 signalling leads to phosphorylation of cAMP‐response element binding protein (CREB) within the hypothalamic arcuate nucleus (ARC), resulting in suppression of tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) and subsequent attenuation of SNS activity. This neuroendocrine feedback promotes osteogenesis [37, 38]. Furthermore, CREB activation induces the transcription of the small heterodimer partner‐interacting leucine zipper protein (SMILE), which binds to the promoter region of the Npy gene, repressing the expression of neuropeptide Y (NPY), a known inhibitor of bone formation [39].

In conclusion, these findings position PGE2 as a critical afferent molecule that bridges mechanical and inflammatory perturbations in bone to CNS‐regulated bone remodelling programs. Nonetheless, additional interoceptive mediators and signalling pathways likely exist and warrant further investigation to fully elucidate the complexity of neural regulation in bone homeostasis.

However, other mediators have also been implicated in bone–nerve communication. Neurotrophic factors, including NGF and GDNF‐family ligands, can activate or sensitize bone‐innervating afferents and contribute to inflammatory bone pain [27, 40]. Sensory nerve terminals in bone contain neuropeptides such as CGRP and substance P, which are associated with bone remodelling, vascular responses and neurogenic inflammation [41] Glutamatergic signalling may also participate in skeletal regulation, as glutamate‐containing fibres have been detected in bone and bone cells express functional glutamate receptors [42, 43].

Inflammation or injury further expands this mediator network. Cytokines such as IL‐1β, IL‐6 and TNF‐α can modulate both bone remodelling and nociceptive afferent excitability, whereas 5‐HT, opioid‐related pathways and endocannabinoid signalling have been implicated in skeletal metabolism, bone pain or inflammatory modulation, although their roles in physiological skeletal interoception are less clearly defined [27, 44, 45].

3.2. The Efferent Pathways in Skeletal Interoception

Following CNS integration of afferent input, efferent responses are generated to maintain or restore homeostasis. These are primarily mediated by the SNS and the PSNS, through the release of NE and ACh, respectively. In addition, NPY has emerged as a crucial efferent molecule linking central neural pathways to peripheral skeletal regulation.

3.2.1. The Efferent Pathway via NPY/Y1 Receptor

NPY, a highly conserved 36‐amino acid neuropeptide widely expressed in both the central and peripheral nervous system (PNS), plays a key regulatory role in bone metabolism through interactions with Y1 receptors on MSCs and osteoblasts [46, 47, 48]. NPY is abundantly synthesized in the hypothalamic ARC and is secreted locally by both sympathetic and sensory nerve terminals. NPY acts via two primary receptors, Y1R and Y2R. While Y1R mRNA has been detected in skeletal tissues and the nervous system, Y2R mRNA is confined to the brain.

NPY‐Y1R signalling exerts inhibitory effects on bone formation. Global or osteoblast‐specific deletion of Y1R results in increased bone mass, whereas hypothalamic deletion does not, suggesting a peripheral mechanism. In vitro, exogenous NPY impairs osteoblast mineralization and downregulates osteoblastogenic markers, including osteocalcin, bone sialoprotein (BSP) and dentine matrix protein 1 (DMP1) [49, 50, 51].

In MSCs, NPY/Y1R signalling suppressed the cAMP/PKA/CREB pathway, leading to reduced expression of osteogenic transcription factors (such as Jun) and enhanced adipogenic differentiation (such as downregulation of Tead1) [52]. Besides, NPY suppression mediated by afferent interoceptive signalling has been linked to enhanced lipolysis in adipose tissue, thereby increasing energy availability for osteogenesis [39]. For osteoclasts, global knockout of Y1R increases osteoclast surface. However, in vitro studies demonstrated that NPY inhibits the production of cAMP and RANKL induced by isoprenaline activation of the β2AR, thereby suppressing osteoclast formation [53]. In conclusion, NPY/Y1R signalling pathway simultaneously inhibits osteoblast‐mediated bone formation and osteoclast‐mediated bone resorption. However, the ultimate result is a decrease in bone mass, suggesting that the inhibitory effect on osteoblast‐mediated bone formation predominates. These findings also imply that the NPY/Y1R signalling pathway may lead to a reduction in the capacity for bone remodelling.

3.2.2. The Efferent Pathway via NE/β‐Adrenergic Receptors (βARs)

Sympathetic neurons have been identified throughout the skeletal system, including subchondral bone, bone marrow and periosteum [12, 26]. NE, released from sympathetic nerve terminals, binds to both α‐adrenergic receptors (αARs) and βARs, with β2AR being the predominant in bone [54, 55].

Genetic and pharmacological inhibition of β2AR signalling results in increased bone formation and decreased bone resorption [56, 57]. Treatment with propranolol, a βARs antagonists, enhances osteoblast differentiation, as evidenced by upregulated BMP2, Runx2, COL‐1 and osteocalcin [58]. NE also stimulates RANKL production, thereby promoting osteoclastogenesis. While sympathetic activity suppresses bone formation, whether it integrates with afferent signalling pathways remains unresolved.

3.2.3. The Efferent Pathway via ACh/ACh Receptors (AChRs)

Parasympathetic innervation of bone has been demonstrated through anatomical and pharmacological studies. ACh exerts its regulatory effects via nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). nAChRs are expressed in both osteoclasts and osteoblasts and show stage‐dependent expression patterns during osteoblast differentiation [59, 60].

Current evidence identifies osteoclasts as the primary cellular targets of ACh‐mediated bone regulation. Pharmacological activation of nAChRs in vitro, particularly through high‐dose administration of the α7nAChR‐specific agonist PNU282987, significantly promotes osteoclast apoptosis and reduces resorption [61]. In vivo, administration of donepezil, an acetylcholinesterase inhibitor, reduced osteoclast number and urinary NE levels [62]. Conversely, α7 nicotinic acetylcholine receptor (α7nAChR)‐deficient mice exhibit reduced bone mass and increased osteoclast activity [63], suggesting a counter‐regulatory role of PSNS against SNS‐mediated bone resorption. However, the effects of ACh signalling on osteoblast activity remain controversial, warranting further investigations into cell type‐specific and dose‐dependent responses. Figure 1 summarizes the bidirectional communication between bone and the CNS, including ascending sensory signalling and descending autonomic regulation of bone remodelling.

FIGURE 1.

An overview of the skeletal interoceptive circuitry. Bone‐derived sensory signals are conveyed to the CNS through afferent pathways and integrated within hypothalamic circuits. Descending autonomic and neuropeptide‐related outputs, including NE–β2AR, NPY–Y1R and ACh–nAChR signalling, subsequently regulate osteoblast and osteoclast activity to coordinate bone formation, bone resorption and skeletal homeostasis.

4. Prospective Insights into Dental Interoception

Teeth and bones are the two principal mineralized tissues in the human body and their shared developmental, structural and neurovascular features provide the rationale for extending the concept of skeletal interoception to dental tissues [37, 64]. Following this conceptual framework, dental interoception may be understood as comprising two interconnected peripheral modules: the pulp‐dentine complex and the periodontal ligament‐alveolar bone complex. The pulp‐dentine complex is primarily positioned to monitor the internal condition of the tooth, including dentinal fluid movement, pulpal pressure, thermal and chemical changes and inflammatory tissue disturbance. In response to these changes, it may generate afferent signals through communication between inner cells and sensory nerve endings and may also trigger local neurovascular, immune and reparative reactions that contribute to the maintenance of intradental homeostasis [37, 64, 65].

In parallel, the periodontal ligament‐alveolar bone complex is primarily positioned to monitor the mechanical environment of the tooth‐supporting apparatus, including occlusal loading, tooth displacement, tensile and compressive stress and the remodelling demands induced by functional or orthodontic force. In response, it may convert mechanical input into adaptive cellular and tissue responses, thereby regulating periodontal ligament turnover and alveolar bone resorption and formation to preserve tooth support and functional adaptation [66, 67, 68].

Taken together, these two modules suggest that dental interoception is not limited to the detection of pulpal injury or pain, but may instead involve a broader system for monitoring the internal state of the tooth and its supporting tissues and for coordinating local homeostatic and adaptive responses. In the following sections, we discuss in greater detail how these two systems may participate in dental interoception through distinct yet interconnected sensory, cellular and regulatory mechanisms.

4.1. The Pulp‐Dentine Complex as an Intradental Sensory and Homeostatic Module

4.1.1. Trigeminal Afferent Routes of the Pulp‐Dentine Complex

Before considering cellular transduction within the pulp‐dentine complex, it is necessary to clarify the afferent routes by which intradental signals enter the central nervous system. The pulp‐dentine complex is innervated by primary sensory neurons of the trigeminal system, with most pulpal afferent cell bodies located in the trigeminal ganglion [69, 70]. After entering the tooth together with the neurovascular bundle through the apical foramen and accessory canals, these afferent fibres ascend coronally within the pulp and give rise to a dense subodontoblastic plexus of Raschkow beneath the odontoblast layer, with terminal branches extending toward the pulp‐dentine border and, in some cases, into the inner dentine [69, 71, 72]. This anatomical organization places pulpal afferents in an appropriate position to detect changes occurring at the dentine‐pulp interface and within the pulpal microenvironment, rather than functioning merely as passive pain‐conducting elements [69, 72]. From the periphery, pulpal sensory information is conveyed centrally through the trigeminal nerve to the trigeminal sensory nuclear complex in the brainstem, particularly the spinal trigeminal nucleus, including its caudal division and is then relayed through trigeminothalamic pathways to higher‐order centers such as the thalamus and somatosensory cortex [69, 73]. This peripheral‐to‐central projection provides the neuroanatomical basis by which the central nervous system can monitor the physiological and pathological state of the pulp‐dentine complex [37, 64, 69]. Within this afferent system, pulpal nerve fibres comprise both myelinated A fibres and unmyelinated C fibres, with A‐delta fibres representing the major myelinated nociceptive population in the pulp [70, 74]. A‐delta fibres are concentrated mainly in the peripheral pulp and subodontoblastic region and are particularly suited to respond to hydrodynamic disturbances in dentinal tubules, cooling and early dentine‐pulp perturbation, typically contributing to fast, sharp, well‐localized pain [70, 74, 75]. By contrast, C fibres are distributed more deeply within the pulp and are preferentially activated under conditions of tissue injury, inflammation, increased intrapulpal pressure and hypoxia, being more closely associated with dull, lingering and poorly localized pain [70, 74]. This functional distinction indicates that different classes of pulpal afferents do not simply duplicate one another, but rather encode partially different aspects of intradental tissue disturbance, thereby supporting the view that the pulp‐dentine complex is capable of monitoring multiple internal states through structurally and functionally specialized sensory pathways [69, 75]. The significance of this peripheral sensory specialization, however, depends on how these locally encoded signals are transmitted to and processed within the central nervous system. After entering the brainstem, pulpal signals are processed within the trigeminal sensory nuclear complex, including the spinal trigeminal nucleus and its caudal subnucleus or medullary dorsal horn, before ascending through trigeminothalamic pathways toward the ventral posteromedial thalamus and somatosensory cortices. The reticular formation, parabrachial nucleus and limbic‐related circuits, may also contribute to arousal, autonomic, affective and defensive components of dental sensory experience. These established trigeminal pathways provide the neuroanatomical basis by which the CNS could monitor the state of the pulp‐dentine complex.

4.1.2. Odontoblast‐Mediated Sensory Transduction

A related question, however, is how changes within the dentine‐pulp complex are first detected at the periphery before they are relayed to these central pathways. In this context, odontoblasts are increasingly recognized as sensory transducers rather than merely dentine‐forming cells. First, their cell bodies line the dentine‐pulp interface and their processes extend into dentinal tubules, placing them at a strategic site for detecting dentinal fluid movement, mechanical deformation, thermal changes and other local disturbances [65]. Transmission electron microscopy has shown close structural relationships between nerve fibres and odontoblast processes, and although classical synapse‐like structures were not observed, this spatial arrangement permits paracrine or juxtacrine communication. The sensory capacity of odontoblasts is supported by mechanosensitive, thermosensitive and chemosensitive ion channels, including Piezo1 and multiple TRP channel subfamilies [65] [PMID:30704026]. Mechanically activated Piezo1 can facilitate calcium influx and initiate intracellular signalling cascades in odontoblast‐like cells, providing a plausible mechanism for converting dentinal deformation into cellular excitation. A key downstream pathway is the Piezo1‐ or TRP‐associated pannexin‐1–P2X3 signalling axis, in which stimulated odontoblasts release ATP through PANX1 channels and ATP activates P2X3 receptors on trigeminal afferent neurons. This mechanism supports the view that odontoblasts can transmit locally detected mechanical disturbances at the dentine‐pulp interface to nearby nerve endings and thereby contribute to afferent signalling from the pulp‐dentine complex [65]. In inflammatory pulp conditions, PIEZO expression and sensitivity may also be altered, and PIEZO1 expression has been reported to correlate with inflammatory mediators such as IL‐1β, TNF‐α and IL‐6 in irreversible pulpitis; however, whether odontoblast Piezo1 directly transduces inflammatory signals remains to be determined [69]. Glutamatergic signalling may provide an additional odontoblast‐neuron communication route, because odontoblasts contain high concentrations of glutamate and mGluR5 is detected in trigeminal ganglion neurons and pulpal axons. Especially during pulpal inflammation, increased glutamate expression in odontoblasts and upregulation of mGluR5 in adjacent pulpal axons may enhance neural excitation and peripheral sensitization. These findings place odontoblasts at the forefront of peripheral dentine‐pulp sensory transduction.

4.1.3. Pulpal Cellular and Mediator‐Based Amplification of Afferent Signalling

However, afferent signalling in the pulp is unlikely to be determined by odontoblasts alone. The dental pulp is a neurovascular, immune and stromal tissue environment in which local cells can respond to injury, inflammation and neuropeptide release and, in turn, modify the excitability of nearby sensory fibres. Other pulpal cells, including dental pulp stem cells, immune cells, vascular cells and resident stromal cells, may act as modulators or amplifiers of afferent signalling by reshaping the local inflammatory, vascular and biochemical environment surrounding pulpal nerve endings. Dental pulp stem cells may participate in this process through bidirectional communication with sensory nerves. Under inflammatory conditions, CGRP‐primed dental pulp stem cells have been shown to release mediators that increase sensory afferent activity and enhance calcium responses in trigeminal neurons, partly through CXCL1/CXCL8‐CXCR2‐related mechanisms, which can in turn stimulate neurons to release CGRP, suggesting a local positive feedback loop between neural and pulp‐derived cells [76]. This amplifying role is closely related to peripheral sensitization, in which local injury‐ or inflammation‐associated mediators lower the activation threshold and increase the responsiveness of peripheral trigeminal nociceptors. In the pulp‐dentine complex, mediators released by odontoblasts, DPSCs, immune cells, vascular cells and sensory terminals may sensitize nearby pulpal afferent endings by modulating excitatory receptors and ion channels, including TRP channels and purinergic receptors. As a result, subtle changes in dentinal fluid movement, tissue pressure, temperature, chemical composition or inflammatory status may be encoded as exaggerated afferent output, contributing to dentine hypersensitivity, pulpitis‐related hyperalgesia and persistent dental pain. This interpretation is consistent with broader models of orofacial pain plasticity, in which peripheral tissue damage and inflammation alter sensory afferent nerves and trigeminal neuronal or non‐neuronal cells, thereby increasing peripheral terminal excitability and promoting downstream nociceptive transmission [77, 78, 79]. Pulp inflammation‐related studies further support this view by showing that dental inflammatory stimuli can upregulate TRPV1 in trigeminal ganglia and alter pulpal afferent excitability, purinergic signalling and neuroimmune interactions during dental pulp injury [80, 81, 82]. In this review, peripheral sensitization is not considered equivalent to dental interoception itself, but rather as an injury‐ or inflammation‐associated amplification mechanism through which local tissue‐state changes are converted into stronger neural output. These findings suggest that DPSCs can both respond to neural signals and feed back onto sensory neurons, thereby linking peripheral sensitization‐associated afferent amplification with reparative adaptation in the injured or inflamed pulp.

Immune cells provide a second layer of modulation during pulpitis or tissue injury. Inflammatory immune‐cell infiltration and resident pulpal responses generate cytokines, chemokines, prostaglandins and other inflammatory mediators that can activate or sensitize nearby trigeminal afferent endings, increasing neuronal excitability and amplifying nociceptive input from the pulp‐dentine complex [81] Activated sensory neurons, in turn, release neuropeptides such as CGRP and substance P from their peripheral terminals, contributing to neurogenic inflammation and influencing immune‐cell recruitment, inflammatory mediator production and local tissue defence responses [76, 83]. Thus, immune cells and sensory nerves may form a reciprocal neuroimmune axis that amplifies afferent signalling under pathological conditions while also participating in tissue defence and repair.

Vascular cells may further regulate afferent signalling by shaping the neurovascular environment of the pulp. Pulpal sensory nerves are closely associated with vascular structures, and neuropeptides released from activated afferent terminals can influence vasodilation, vascular permeability and inflammatory responses, thereby altering local blood flow, tissue pressure, oxygenation and inflammatory mediator diffusion within the rigid dentine‐enclosed pulp chamber. These vascular changes are particularly relevant because increased pulpal pressure, hypoxia and inflammatory edema can preferentially activate or sensitize deeper pulpal afferents, especially C fibres [69, 84].

Besides, a soluble mediator PGE2 deserves particular attention due to its established relevance to skeletal interoception. In dental tissues, however, current evidence more directly supports PGE2 as a local inflammatory and reparative mediator rather than as an established primary interoceptive signal. PGE2‐related synthetic, transport and receptor components, including mPGES, MRP4, PGT, EP2 and EP4, have been detected in human dental pulp cells, including odontoblasts and endothelial cells. Activaton of EP2/EP4 signalling in dental pulp cells may promote angiogenesis‐ and odontogenic differentiation‐related responses, indicating that PGE2 may participate in vascular and reparative adaptation after pulp injury [85]. Thus, PGE2 may represent a plausible molecular bridge between inflammation, neurovascular regulation and tissue repair in the pulp‐dentine complex; however, whether it functions as a true dental afferent interoceptive signal analogous to its proposed role in skeletal interoception remains unresolved [37, 85, 86].

4.1.4. Neural Feedback Regulation of Pulpal Homeostasis

The preceding sections outline how the pulp‐dentine complex may generate, encode and amplify afferent signals through various crosstalks. However, interoception also requires feedback or effector mechanisms through which sensed internal states can modify peripheral tissue responses. For the pulp‐dentine complex, an analogous CNS‐mediated peripheral‐central‐peripheral feedback loop remains incompletely defined. Nevertheless, peripheral nerves clearly influence pulpal homeostasis through mechanisms that include local axon reflexes, neuropeptide release, autonomic signalling and neuroimmune interactions. These mechanisms can regulate vascular tone and permeability, inflammatory mediator production, immune‐cell recruitment and reparative cell behaviour, suggesting that pulpal nerves may serve not only as afferent conduits but also as local regulators of the pulpal microenvironment [73, 83] (PMID: 22474402; PMID: 36551174; PMID: [76]). Denervation studies provide important functional evidence for this regulatory role. Experimental sensory nerve deficiency produces structural and cellular defects in teeth, indicating that nerves contribute to tissue maintenance. In rat incisors, inferior alveolar nerve section caused disorganized tooth structure, whereas superior cervical ganglion removal, a procedure used to reduce sympathetic input to the tooth, produced only a mild reduction in dentine thickness, suggesting that sensory nerves play a particularly important role in tooth homeostasis [87]. At the cellular level, a sensory nerve‐deficient microenvironment impaired dental pulp stem cell function by increasing apoptosis and reducing proliferative capacity, and these effects were associated with downregulation of the activin B/SMAD2/3 signalling pathway enriching the current understanding of sensory nerve‐mediated regulation of pulpal stem‐cell homeostasis [87].

Denervation phenotypes mention above indicate that sensory nerves are functionally required. Mechanistic clues by showing that peripheral sensory terminals can release neuron‐derived mediators that act directly on DPSCs and odontoblasts. After pulp injury, sensory nerves can release mediators near the injury site that act directly on pulpal cells; for example, sensory nerve‐derived CGRP promotes collective DPSC migration through the CGRP‐RAMP1 axis and supports pulp repair [88]. Activated sensory neurons can also release CGRP together with Shh, and these neuron‐derived signals regulate dental pulp cell expansion, inflammatory gene expression and odontoblast‐like differentiation during injury responses [89]. In addition, CGRP receptor signalling has been implicated in intercellular communication between trigeminal ganglion neurons and odontoblasts, supporting axon‐reflex‐like local signalling within the dental pulp [83]. Collectively, these studies suggest that sensory nerves can provide local instructive signals to DPSCs and odontoblast‐lineage cells. CGRP represents a well‐supported example of sensory nerve‐derived signalling and highlights the important role of neuron‐derived mediators. However, pulpal neuropeptide signalling is broader than CGRP alone and includes multiple peptides with distinct expression patterns, injury‐ or inflammation‐related changes and insufficiently defined function. So the expression, state‐dependence and functional spectrum of these pulpal neuropeptides are therefore considered separately below.

4.1.5. Autonomic and Neuropeptide‐Mediated Modulation of Pulpal Responses

In addition to sensory nerve‐dependent local regulation, the sympathetic nervous system provides an autonomic regulatory component of the pulpal microenvironment. Classically, sympathetic fibres in the dental pulp have been associated with neurovascular structures, where they regulate vascular tone and pulpal blood flow through noradrenaline‐ and NPY‐related signalling [90]. This neurovascular role is important because changes in blood flow, vascular tone and tissue pressure can influence the biochemical and physical environment in which pulpal cells and sensory nerve endings operate.

Sympathetic regulation may also interact with pulpal inflammation. Experimental and clinical evidence indicates that sympathetic nerve fibres can sprout in chronically inflamed dental pulp and that sympathetic imbalance after unilateral sympathectomy can alter immune‐cell recruitment, including immunoglobulin‐producing cells, within the pulp [91, 92]. These findings suggest that sympathetic nerves are not limited to vascular control but may also participate in neuroimmune regulation under pathological conditions.

More recent evidence further extends this concept from neurovascular and neuroimmune regulation to direct control of pulpal stem‐cell behaviour. Norepinephrine can regulate human dental pulp stem cells through ADRA1B, shifting cellular metabolism from oxidative phosphorylation toward anaerobic glycolysis, suppressing proliferation and migration and promoting a quiescent‐like state [93]. This finding suggests that sympathetic signalling may help tune the metabolic state and functional readiness of the pulpal stem‐cell niche. However, the in vivo contribution of sympathetic signalling to tooth and pulp homeostasis remains incompletely defined. In rat incisor models, superior cervical ganglion removal, a procedure used to reduce sympathetic input to the tooth, produced only a mild reduction in dentine thickness, indicating that sympathetic denervation alone causes a relatively limited structural phenotype under the tested conditions [87]. Therefore, further studies are needed to determine when and how sympathetic activity regulates the pulp‐dentine complex in vivo, particularly with respect to injury, inflammation, vascular adaptation and stem‐cell niche remodelling. Parasympathetic/cholinergic‐related regulation may also contribute to the pulpal microenvironment and should be considered alongside sympathetic noradrenergic signalling. VIP and its receptor VPAC1 have been detected in adult human dental pulp, and caries‐associated changes in VIP levels suggest a possible role for VIP in modulating pulpal health and disease [94]. PACAP‐immunoreactive nerve fibres have also been observed around blood vessels and in the subodontoblastic and odontoblastic layers of rat and human tooth pulps, indicating that autonomic or peptide‐containing neural signals may reach vascular and odontoblast‐associated regions of the pulp [95]. At the cellular level, odontoblasts can respond to muscarinic‐cholinergic stimulation through calcium signalling, and recent evidence further indicates that human DPSCs possess cholinoceptive properties through a functional M2 muscarinic receptor that regulates a quiescence‐like cellular state [96, 97]. These findings suggest that cholinergic‐related signalling may influence odontoblast activity, vascular‐neural interactions and the pulpal stem‐cell niche. However, this evidence should be interpreted cautiously: cholinergic signalling does not necessarily prove parasympathetic origin, VIP does not show the same trend as CGRP, SP, NKA and NPY in inflamed human pulp, and functional parasympathetic vasodilator responses have not been consistently demonstrated in dental pulp [98, 99]. Therefore, parasympathetic/cholinergic‐related signalling may represent a potential but still incompletely defined component of neural regulation in the pulp‐dentine complex.

After considering sensory and autonomic regulation as neural pathway‐specific mechanisms, it is useful to examine the molecular mediators through which neural activity is translated into pulpal cellular responses. Neuropeptides are particularly relevant in this context because they are nerve‐associated signalling molecules that can link neural activation to nociception, vascular regulation, inflammation, immune‐cell recruitment and reparative responses within the pulp. Since pulpal neuropeptide signalling includes multiple peptides with distinct expression profiles, state‐dependent changes and context‐dependent effects on inflammation and repair, this mediator class should be considered separately.

Multiple neuropeptides have been detected in human dental pulp, including calcitonin gene‐related peptide (CGRP), substance P (SP), neurokinin A (NKA), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), indicating that the pulp contains a neuropeptide‐rich signalling environment rather than purely electrophysiological sensory pathways. Importantly, this neuropeptide profile is not static. In inflamed human pulp, CGRP, SP, NKA and NPY are significantly increased compared with healthy pulp, whereas VIP remains relatively stable under inflammatory conditions [98]. This differential pattern suggests that pulpal neuropeptides may reflect and modulate specific tissue states, particularly inflammation, pain and injury‐related repair.

Among these neuropeptides, CGRP has the strongest recent functional evidence in neuro‐pulpal communication. CGRP‐primed dental pulp stem cells can release mediators that enhance sensory neuron activity and sensitize trigeminal neurons, partly through CXCL1/CXCL8‐CXCR2‐related mechanisms [76]. Conversely, sensory nerve‐derived CGRP can act directly on DPSCs through RAMP1 to promote collective migration of DPSCs toward pulp injury sites and support pulp repair [88]. CGRP may also cooperate with other neuron‐derived signals such as Shh to regulate pulp cell expansion, inflammatory gene expression and odontoblast‐like differentiation after injury [89]. Together, these findings suggest that CGRP can function as a bidirectional mediator linking sensory nerve activation, DPSC behaviour, inflammatory amplification and reparative adaptation.

SP represents another neuropeptide with experimentally supported roles in pulpal inflammation and repair. SP and its receptor NK1R are expressed during DPSC odontoblastic differentiation in vitro and during reparative dentinogenesis in vivo, and SP can promote odontoblastic differentiation through NK1R signalling [100]. These findings support a role for the SP/NK1R pathway in reparative dentine formation, beyond its classical association with neurogenic inflammation and dental pain. In addition, SP‐related signalling in the pulp should not be attributed exclusively to sensory nerve terminals because SP expression has also been detected in human dental pulp fibroblasts, suggesting that local pulpal cells may participate in SP‐associated signalling networks [101].

By contrast, the functional roles of NPY, NKA and VIP in pulpal homeostasis remain less clearly defined. NPY is increased in inflamed human pulp together with CGRP, SP and NKA, and dental pulp fibroblasts express the NPY Y1 receptor but not NPY itself, suggesting that pulpal cells may respond to NPY‐containing neural signals rather than serving as a major NPY source [98, 102]. NKA is detectable in human dental pulp and is increased in inflamed pulp, consistent with its membership in the tachykinin family, but its direct effects on DPSC fate, odontoblast differentiation or reparative dentinogenesis remain insufficiently defined. VIP is also detectable in human dental pulp, but unlike CGRP, SP, NKA and NPY, it does not show the same inflammatory increase in available human pulp measurements, suggesting that its role in pulpal inflammatory regulation may be more limited or context‐dependent [98].

Overall, pulpal neuropeptides should be viewed as state‐dependent molecular mediators that connect neural activity with vascular, immune, nociceptive and reparative responses. Current evidence most strongly supports CGRP and SP as functional regulators of neuro‐pulpal communication and repair, whereas NPY, NKA and VIP are better regarded as detected or state‐associated peptides whose direct roles in pulpal stem‐cell regulation and dental homeostasis require further clarification. Figure 2 illustrates the proposed bidirectional communication between dental tissues and the CNS, encompassing sensory transduction, dentine repair, peripheral sensitisation and autonomic and neuropeptide modulation.

FIGURE 2.

The overview of hypothetical dental interoception in the pulp–dentine complex. The pulp–dentine complex may function as an intradental sensory and homeostatic module. Dentinal fluid movement, mechanical stimulation, inflammation and injury can be detected by odontoblasts, pulpal cells, vascular/immune components and sensory nerve endings. These local signals are transmitted through trigeminal pathways, while reciprocal neural, immune, vascular and stem‐cell responses contribute to sensory modulation, pulp repair and pulp–dentine homeostasis.

4.2. The Periodontal Ligament‐Alveolar Bone Complex as a Mechanosensory and Remodelling Module

Whereas the pulp‐dentine complex primarily monitors the internal state of the tooth, the periodontal ligament‐alveolar bone complex monitors the mechanical relationship between the tooth and its supporting tissues. The periodontal ligament anchors the tooth root to alveolar bone, transmits and disperses occlusal forces and provides a sensory interface through which tooth displacement and loading can be detected [66, 103]. The alveolar bone, in turn, functions as an adaptive effector tissue that remodels in response to physiological or orthodontic mechanical loading, thereby maintaining tooth support and occlusal function [67, 68]. Therefore, dental interoception should not be restricted to intradental monitoring by the pulp‐dentine complex, but should also include the tooth‐supporting apparatus as a mechanosensory and remodelling module.

4.2.1. Periodontal Sensory Innervation and Tooth‐Load Detection

The periodontal ligament is densely innervated by trigeminal sensory fibres and represents the principal neural interface between the tooth root and its supporting alveolar bone. In the maxilla and mandible, periodontal sensory fibres are conveyed mainly through branches of the superior and inferior alveolar nerves, respectively. These fibres enter the periodontal ligament through apical routes together with neurovascular bundles and, in part, through lateral channels in the alveolar bone, thereby supplying the ligament along the root surface. This anatomical organization allows the periodontal ligament to function not only as a connective tissue attachment between cementum and alveolar bone, but also as a peripheral sensory field for monitoring tooth loading and displacement.

Within the periodontal ligament, sensory terminals include free nerve endings and specialized mechanoreceptive endings, particularly Ruffini‐like endings. Free nerve endings are mainly associated with nociceptive pressure, tissue injury and inflammatory irritation, whereas Ruffini‐like periodontal mechanoreceptors are suited to detect tooth displacement, periodontal tension and compression, loading direction and occlusal force. It has been shown that periodontal afferents recorded from the inferior alveolar nerve adapt slowly to maintained tooth loads and are broadly tuned to the direction of force application, indicating that these receptors can encode both the magnitude and direction of mechanical loading [104]. Periodontal receptors are especially sensitive to low‐force tooth loading during food contact and gentle manipulation, supporting their role in tooth‐load feedback and oral sensorimotor control [66]. Consistent with this, periodontal mechanoreceptors are considered major contributors to the tactile function of natural teeth, although interocclusal tactile perception may also involve pulpal, muscular and articular receptors [103].

4.2.2. Trigeminal Pathways for Periodontal Mechanosensory Transmission

A distinctive feature of periodontal innervation is that periodontal mechanoreceptive input is represented by primary afferent neurons located in both the trigeminal ganglion and the mesencephalic trigeminal nucleus. Trigeminal ganglion‐associated periodontal afferents correspond to the conventional organization of somatosensory pathways: their peripheral terminals are located in the periodontal ligament, cell bodies reside in the trigeminal ganglion and their central projections enter the trigeminal sensory nuclear complex. By contrast, mesencephalic trigeminal nucleus‐associated afferents represent a specialized population of primary sensory neurons with centrally located cell bodies. Classical electrophysiological and anatomical studies in cats showed that neurons in both the trigeminal ganglion and the mesencephalic trigeminal nucleus respond to forces applied to the tooth and that their peripheral mechanoreceptors are located within the periodontal ligament Receptors with cell bodies in the mesencephalic trigeminal nucleus occupy a relatively restricted distribution within the periodontal ligament, whereas receptors with cell bodies in the trigeminal ganglion are distributed more broadly around the tooth root [105]. Comparative physiological and morphological studies further support the existence of distinct trigeminal ganglion‐ and mesencephalic nucleus‐associated periodontal mechanoreceptor populations [106].

These two periodontal afferent routes appear to support partially different central functions. Trigeminal ganglion‐associated periodontal afferents project centrally to the trigeminal sensory nuclear complex, including the principal sensory trigeminal nucleus and the spinal trigeminal nucleus. In this pathway, second‐order neurons can relay periodontal tactile, pressure and nociceptive information through trigeminothalamic pathways to the ventral posteromedial thalamus and then to somatosensory cortical areas. This conventional trigeminal sensory route supports conscious tooth tactile perception, occlusal contact sensation, force discrimination and periodontal pain under excessive loading, injury or inflammation. Human single‐afferent recordings further indicate that periodontal mechanoreceptors encode not only sustained force amplitude but also the rate of force application, providing a peripheral neural basis for dynamic tooth‐load perception during biting and mastication [66, 104, 107].

By contrast, mesencephalic trigeminal nucleus‐associated periodontal afferents are more closely linked to brainstem sensorimotor circuits than to a purely thalamocortical perceptual pathway. Because mesencephalic trigeminal nucleus neurons are primary afferent neurons with cell bodies located within the central nervous system, their central processes can interact with trigeminal motor and supratrigeminal circuits that regulate jaw movement. This organization is particularly suited to proprioceptive‐like tooth‐load feedback, jaw reflexes, bite‐force adjustment and masticatory sensorimotor control. Periodontal damage or tooth loss can alter mesencephalic trigeminal and trigeminal motor circuits.

4.2.3. Periodontal Cellular Modulation of Afferent Excitability

Although periodontal afferent terminals can directly detect mechanical deformation within the ligament, afferent signalling is likely shaped by the surrounding periodontal cellular microenvironment. Periodontal ligament fibroblasts are central candidates for this peripheral signal‐converting role because they are abundant in the periodontal ligament and are directly exposed to tensile and compressive forces during occlusion and orthodontic tooth movement. Recent evidence shows that compression force activates PIEZO1 on human periodontal ligament fibroblasts and induces ATP release through intracellular Ca²⁺‐dependent exocytosis and ATP‐permeable channels [108]. This finding suggests that periodontal ligament fibroblasts can translate mechanical deformation into extracellular purinergic signals. Because ATP is a well‐established excitatory mediator for sensory afferents, PIEZO1‐dependent ATP release provides a plausible mechanism through which mechanically stressed periodontal ligament fibroblasts may communicate with nearby trigeminal sensory terminals and contribute to periodontal afferent signalling.

Neurotrophic signalling provides another route through which periodontal ligament fibroblasts may influence afferent neurons. During orthodontic tooth movement, nerve growth factor is increased in the periodontium, mainly in periodontal fibroblast‐rich regions and can be retrogradely transported to the trigeminal ganglion. Neutralization of nerve growth factor attenuates tooth mechanical hyperalgesia, while nerve growth factor and ASIC3 are increased in trigeminal neurons under orthodontic force, suggesting that periodontal fibroblast‐derived neurotrophic signalling may sensitize trigeminal afferents during mechanical loading [109]. Thus, periodontal ligament fibroblasts may not only generate acute purinergic signals in response to compression, but also modulate trigeminal neuronal excitability through neurotrophic pathways under sustained mechanical stress.

Emerging evidence further suggests that periodontal ligament fibroblasts may communicate with sensory neurons through neuropeptide‐related signalling. Under mechanical stress, periodontal ligament fibroblasts can function as a non‐neuronal source of substance P and modulate sensory neuron activation; conversely, substance P can act on fibroblasts and influence inflammatory responses [110]. This bidirectional substance P signalling suggests that periodontal ligament fibroblasts and sensory neurons may form a local neurocellular communication axis during mechanical stress. However, because this evidence is mainly derived from mechanically stressed or orthodontic contexts, it should be regarded as an emerging mechanism rather than an established physiological afferent pathway.

Immune and vascular components may further shape periodontal afferent signalling by modifying the inflammatory and neurovascular environment surrounding sensory terminals. Orthodontic or excessive mechanical force can produce compression and tension zones within the periodontal ligament, leading to vascular disturbance, hypoxia, immune‐cell recruitment and the local release of inflammatory mediators such as cytokines, prostaglandins, chemokines and neurogenic mediators [109, 110, 111]. These mediators may sensitize local trigeminal afferents and contribute to periodontal pain or mechanical hyperalgesia under inflammatory or overloaded conditions. Therefore, immune and vascular cells are best viewed as amplifiers or modulators of periodontal afferent excitability rather than primary mechanotransductive cells. Together, these findings suggest that periodontal afferent signalling may involve both direct neural mechanosensation and cell‐mediated modulation of sensory terminals. However, whether these local signals constitute a defined physiological code in vivo remains unclear.

4.2.4. Mechanotransductive Regulation of Periodontal and Alveolar Bone Remodelling

The periodontal ligament‐alveolar bone complex must also generate adaptive tissue responses to changes in mechanical input. Functional evidence for this effector role comes from unloading and occlusal hypofunction models. In rats, occlusal hypofunction alters proteoglycan content in the periodontal ligament, indicating that the extracellular matrix of the ligament is sensitive to the level of functional loading [112]. Three‐dimensional micro‐computed tomography analysis further showed that occlusal hypofunction narrows the periodontal ligament space and reduces both periodontal ligament volume and the volumetric ratio of alveolar bone proper to total tissue, suggesting that reduced mechanical input induces atrophic changes in the periodontal ligament and alveolar bone proper [113]. These loss‐of‐mechanical‐input phenotypes indicate that periodontal tissues require continuous functional loading to maintain their extracellular matrix organization, ligament volume and alveolar bone structure.

At the cellular level, periodontal ligament cells provide local mechanotransductive machinery through which mechanical loading can be converted into remodelling signals. Mechanosensitive ion channels are central to this conversion. In orthodontic tooth movement models, Piezo1 is activated by orthodontic force and is mainly expressed in periodontal ligament cells throughout the tooth movement period. Pharmacological inhibition of Piezo1 reduces the rate of orthodontic tooth movement and impairs new alveolar bone formation on the tension side, indicating that Piezo1 activity is required for adaptive periodontal remodelling under mechanical loading. Mechanistically, Piezo1 inhibition reduces osteogenesis‐associated transcription factors such as RUNX2 and Osterix and alters the RANKL/OPG axis, suggesting that Piezo1 helps coordinate both osteogenic and osteoclastogenic responses during mechanically induced periodontal remodelling [68].

This mechanosensitive regulation also extends to periodontal ligament stem/progenitor populations. Lepr‐expressing periodontal ligament stem cells have been identified as a unique in vivo multipotent PDLSC population that contributes to periodontal homeostasis through Piezo1‐mediated mechanosensing. In this study, ablation of Lepr+ PDLSCs disrupted periodontal homeostasis, while hyper‐loading and unloading of occlusal forces modulated Lepr+ PDLSC activation. Conditional Piezo1 deficiency demonstrated that Piezo1 mediates the mechanosensing of Lepr+ PDLSCs, and pharmacological activation of Piezo1 with Yoda1 promoted periodontal tissue growth through induction of Lepr+ cells [114]. These findings indicate that the periodontal ligament contains mechanosensitive stem/progenitor populations that can translate changes in occlusal loading into adaptive cellular responses.

Downstream of local mechanotransduction, the remodelling output of the periodontal ligament‐alveolar bone complex is executed through coordinated osteoclastogenic and osteogenic responses. Orthodontic tooth movement requires osteoclast‐mediated bone resorption on the compression side and compensatory bone formation on the tension side. A key molecular axis in this process is RANKL/RANK/OPG signalling. Genetic deletion of RANKL in periodontal ligament and bone‐lining cells greatly reduces osteoclastogenesis in response to mechanical force and prevents orthodontic tooth movement, demonstrating that RANKL produced by these cells provides a major driving force for force‐induced tooth movement and osteoclastogenesis [115]. Thus, periodontal mechanical input is converted into adaptive remodelling output through local mechanotransduction in periodontal ligament cells and stem/progenitor cells, followed by RANKL‐dependent activation of osteoclastogenic remodelling and coupled bone formation. Figure 3 summarizes periodontal mechanotransduction and tissue remodelling on the compression and tension sides of the periodontal ligament.

FIGURE 3.

The overview of periodontal ligament–alveolar bone module in dental interoception. Mechanical loading activates distinct responses on the compression and tension sides, involving PDL fibroblast mechanotransduction, Lepr⁺ PDLSC activation, Piezo1‐mediated Ca²⁺ signalling, ATP–P2X3 sensory communication and neuropeptide‐associated cellular modulation. Together, these mechanisms couple compression‐side bone resorption with tension‐side bone formation to support periodontal adaptation and tooth stability.

4.3. Therapeutic Implications and Unresolved Questions

Clinically, the concept of dental interoception reframes dental repair as restoration of functional tissue regulation rather than replacement of mineralized structure alone. If the pulp‐dentine complex and the periodontal ligament‐alveolar bone complex are viewed as sensory‐regulatory modules, future dental therapies should aim not only to restore tissue form and mechanical strength, but also to preserve or rebuild neural, vascular, immune and cellular regulatory functions [116, 117].

For the pulp‐dentine complex, this perspective is particularly relevant to vital pulp therapy and functional pulp regeneration. Static restorative materials can restore structural integrity, wear resistance and aesthetics, but they cannot fully reproduce the dynamic sensory, vascular, immune and reparative functions of the living dentine‐pulp complex. DPSCs are attractive for regenerative strategies because they possess odontogenic potential and can express neurotrophic and immunomodulatory factors that support neural survival, neurite outgrowth, vascular formation, tissue repair and immune regulation. Dental pulp cell sheets have also been shown to enhance facial nerve regeneration through local neurotrophic factor delivery, supporting the broader concept that dental pulp‐derived cells can contribute to neural repair [117]. Moreover, neuropeptide‐related pathways may participate in reparative dentinogenesis, as shown by the involvement of SP/NK1R signalling in DPSC odontoblastic differentiation and reparative dentine formation. Therefore, a vital‐pulp‐vital‐tooth strategy should aim to restore not only odontoblast‐like hard‐tissue formation, but also pulpal innervation, vascularization, immune surveillance and neural‐cellular communication. However, current evidence still does not fully define how nerve‐derived signals regulate DPSC fate, odontoblast differentiation and reparative dentinogenesis as an integrated physiological circuit [100].

For the periodontal ligament‐alveolar bone complex orthodontic tooth movement provides a clinically established model of force‐induced periodontal adaptation. Orthodontic force produces mechanical compression and tension within the periodontal ligament and induces inflammatory reactions, inflammatory mediator release, osteoclastogenesis, osteogenesis and extracellular matrix remodelling [68, 111]. From the perspective of dental interoception, orthodontic treatment can therefore be understood not simply as mechanical displacement of teeth, but as clinical manipulation of a mechanosensory‐remodelling system. Mechanotransductive pathways in periodontal ligament cells may provide targets for optimizing this response, because Piezo1 is activated by orthodontic force in periodontal ligament cells and contributes to the rate of orthodontic tooth movement and new alveolar bone formation on the tension side. Inhibition of Piezo1 alters osteogenesis‐associated transcription factors and the RANKL/OPG axis, indicating that periodontal mechanotransduction is linked to both osteogenic and osteoclastogenic remodelling responses. These findings suggest that future orthodontic strategies may benefit from regulating periodontal mechanotransduction to improve physiological remodelling while minimizing pain, excessive inflammation, root resorption and periodontal breakdown. Such strategies should not aim merely to accelerate tooth movement, but to refine the quality, timing and safety of force‐induced remodelling.

Dental interoception may also have implications for periodontitis, particularly through neuroimmune regulation. Periodontitis is not only a microbial and immune‐mediated inflammatory disease, but may also involve neurogenic inflammatory mechanisms in which sensory nerves, neuropeptides, immune cells and bone‐resorptive pathways interact [118, 119]. A systematic review of neurogenic inflammation in periodontitis identified SP, CGRP, VIP, NKA and NPY as candidate neuropeptides associated with periodontal disease activity, although the included studies showed heterogeneity and the overall evidence quality was moderate to low. Experimental evidence further indicates that SP can aggravate ligature‐induced periodontitis in mice by enhancing inflammatory responses, osteoclast activation and alveolar bone loss. These findings suggest that neural signals in periodontal disease are not uniformly protective or harmful; rather, their effects depend on disease stage, concentration, receptor distribution and tissue context. Therefore, future periodontal therapies should aim to restore neuroimmune balance rather than broadly suppress or enhance neural activity [118, 119].

Several translational challenges must be resolved before dental interoception can be established as a clinically useful framework. First, it remains necessary to distinguish primary dental interoceptive signals from secondary inflammatory amplifiers, especially for ATP, NGF, PGE2, cytokines, chemokines and neuropeptides. Second, the central integration of pulpal and periodontal states within trigeminal, thalamic, cortical, autonomic and limbic networks remains poorly defined; Third, it remains unclear whether local neural‐cellular crosstalk in dental tissues is integrated into a true peripheral‐central‐peripheral feedback loop capable of regulating dental and periodontal homeostasis. Future studies should combine cell‐type‐specific manipulation, circuit tracing, neural activity recording, single‐cell or spatial profiling and peripheral tissue‐response mapping to determine whether dental and periodontal signals can drive centrally mediated feedback regulation of oral tissue homeostasis. Because neuropeptides can exert both inflammatory and reparative effects depending on concentration, disease stage and tissue context, future therapies should aim to restore neural homeostasis rather than broadly suppress or enhance neural activity [120]. Dental implants provide another clinically meaningful comparison because conventional osseointegrated implants lack an intervening periodontal ligament and therefore cannot fully reproduce the proprioceptive‐like feedback of natural teeth [121]. This limitation underscores the importance of periodontal sensory pathways for natural tooth function and suggests that sensory restoration may be an important goal for future regenerative or implant‐based therapies.

Several questions must be resolved before dental interoception can be established as a coherent physiological concept. First, it remains unclear which dental mediators are primary interoceptive signals and which are secondary inflammatory amplifiers, especially for ATP, glutamate, PGE2, cytokines, chemokines and neuropeptides in the pulp‐dentine complex. Second, it remains unclear which central regions encode dental and periodontal states and whether pulpal and periodontal inputs are integrated within the trigeminal sensory nuclei, VPM thalamus, somatosensory cortex, parabrachial nucleus, hypothalamus or limbic structures. Third, it remains to be demonstrated whether local neural‐cellular crosstalk in dental tissues is integrated into a true peripheral‐central‐peripheral feedback loop analogous to skeletal interoception. Future studies should combine circuit tracing, cell‐type‐specific neural manipulation, neural activity recording and peripheral tissue‐response mapping to determine whether dental and periodontal signals can drive centrally mediated feedback regulation of dental homeostasis.

5. Conclusion

This review proposes dental interoception as a hypothetical framework for understanding how the nervous system may monitor and regulate the internal state of teeth and their supporting tissues. Building on the relatively well‐characterized concept of skeletal interoception, we summarized evidence that dental tissues are not merely passive targets of neural input, but are embedded within bidirectional neural–cellular networks involving sensory afferents, autonomic fibres, vascular cells, immune cells, stem/progenitor cells, odontoblast‐lineage cells, periodontal ligament cells and alveolar bone cells. In this context, dental homeostasis may depend not only on local cellular responses, but also on coordinated communication between peripheral dental tissues and the nervous system.

Current evidence supports two potential peripheral modules of dental interoception. The pulp–dentine complex may function as an intradental sensory and homeostatic module that detects dentinal fluid movement, pulpal pressure, thermal and chemical changes, inflammation and injury‐related disturbance. Odontoblasts, dental pulp stem cells, immune cells, vascular cells and sensory nerve terminals may participate in this process through ion channels, purinergic signalling, glutamatergic signalling, prostaglandins, cytokines, chemokines and neuropeptides. In parallel, the periodontal ligament–alveolar bone complex may represent a mechanosensory and remodelling module that monitors tooth loading, displacement, occlusal force, periodontal tension and compression and remodelling demands. Periodontal mechanoreceptors, trigeminal afferent pathways, periodontal ligament cells and alveolar bone remodelling responses together provide a plausible basis for linking mechanical state detection to adaptive tissue remodelling.

Nevertheless, the concept of dental interoception remains incompletely established. Several critical questions must be resolved before it can be defined as a coherent physiological system. (1) It remains unclear which dental mediators act as primary interoceptive signals and which mainly serve as secondary inflammatory or reparative amplifiers. (2) The central circuits that encode pulpal and periodontal tissue states remain insufficiently mapped, particularly with respect to whether dental inputs are integrated within trigeminal sensory nuclei, the thalamus, somatosensory cortex, parabrachial nucleus, hypothalamus, limbic structures or autonomic regulatory centers. (3) It remains to be demonstrated whether dental neural–cellular crosstalk is integrated into a true peripheral–central–peripheral feedback loop, rather than being limited to local axon reflexes, autocrine signalling or paracrine regulation. Future studies combining circuit tracing, cell‐type‐specific neural manipulation, neural activity recording and peripheral tissue‐response mapping will be essential to determine whether dental and periodontal signals can drive centrally mediated feedback regulation of dental homeostasis. Establishing this circuitry would provide a stronger biological foundation for dental interoception and may open new perspectives for understanding dental pain, pulp repair, periodontal adaptation, tooth‐supporting tissue remodelling and regenerative dental therapies.

Author Contributions

Fang Zheng: conceptualization. Da Huang: writing – original draft, writing – review and editing, methodology, conceptualization, software. Ce Shi: writing – review and editing. Hao Guo: visualization, validation. Cangwei Liu: writing – review and editing. Weihang Guan: conceptualization.

Funding

This work was supported by National Natural Science Foundation of China, 82270959, 81970903; Department of Finance of Jilin Province, JCSZ2025678‐1, JCSZ2023421‐34; Fundamental Research Funds for the Central Universities.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.