Skip to main content
NCBI home page
Pharmaceuticals logoLink to Pharmaceuticals
. 2024 Sep 12;17(9):1205. doi: 10.3390/ph17091205

Association of the Serotonin and Kynurenine Pathways as Possible Therapeutic Targets to Modulate Pain in Patients with Fibromyalgia

Alfonso Alfaro-Rodríguez 1,†, Samuel Reyes-Long 1,†, Ernesto Roldan-Valadez 1,2, Maykel González-Torres 3, Herlinda Bonilla-Jaime 4, Cindy Bandala 5, Alberto Avila-Luna 1, Antonio Bueno-Nava 1, Elizabeth Cabrera-Ruiz 1, Pedro Sanchez-Aparicio 6, Angélica González Maciel 7, Ana Lilia Dotor-Llerena 8, José Luis Cortes-Altamirano 1,9,*
Editor: Dominique Massotte
PMCID: PMC11434812  PMID: 39338367

Abstract

Fibromyalgia (FM) is a disorder characterized by widespread chronic pain, significant depression, and various neural abnormalities. Recent research suggests a reciprocal exacerbation mechanism between chronic pain and depression. In patients with FM, dysregulation of tryptophan (Trp) metabolism has been identified. Trp, an essential amino acid, serves as a precursor to serotonin (5-HT), a neuromodulator that influences mood, appetite, sleep, and pain perception through the receptors 5-HT1, 5-HT2, and 5-HT3. Additionally, Trp is involved in the kynurenine pathway, a critical route in the immune response, inflammation, and production of neuroactive substances and nicotinamide adenine dinucleotide (NAD+). The activation of this pathway by pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ), leads to the production of kynurenic acid (KYNA), which has neuroprotective properties, and quinolinic acid (QA), which is neurotoxic. These findings underscore the crucial balance between Trp metabolism, 5-HT, and kynurenine, where an imbalance can contribute to the dual burden of pain and depression in patients with FM. This review proposes a novel therapeutic approach for FM pain management, focusing on inhibiting QA synthesis while co-administering selective serotonin reuptake inhibitors to potentially increase KYNA levels, thus dampening pain perception and improving patient outcomes.

Keywords: tryptophan, 5-HT1A, 5-HT2, 5-HT3, 5-HTT, quinolinic acid, kynurenine acid

1. Introduction

Fibromyalgia (FM) is characterized by widespread and persistent pain, alongside significant fatigue and sleep disturbances. It is also closely related to a relatively high prevalence of several comorbid conditions, including irritable bowel syndrome, major depressive disorder, nervous bulimia, cataplexy, anxiety, obsessive–compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, social phobias, migraines, and joint pain [1,2]. The global prevalence of fibromyalgia is approximately 1.78%, although it varies by region, with rates of 3.3% in North America and 2.9% in Europe. Women are disproportionately affected, with a ratio of 3:1 compared to men. Among women, prevalence estimates range from 0.2% to 6%, while urban populations exhibit rates between 2.4% and 6.8%. In certain populations, prevalence can range from 0.6% to 15%, depending on the diagnostic criteria applied. Typically, fibromyalgia patients are middle-aged women (30–60 years old) with a basic level of education [3]. Given the central role of chronic pain in FM, its global prevalence is noteworthy; in the United States alone, an estimated 50 million people live with chronic pain, ranging from intermittent occurrences to debilitating conditions that prevent employment [4]. The economic impact is substantial, with medical and home care expenses reaching approximately USD 500 million annually [5]. The primary treatment for fibromyalgia to inhibit pain involves a combination of pharmacological approaches, physical therapies, psychological support, and self-management strategies. This multimodal treatment plan is designed to address the diverse symptoms experienced by patients with fibromyalgia, ultimately improving their quality of life. These observations highlight the urgent need for improved diagnostic and therapeutic approaches for FM and related disorders. A systematic literature search was conducted across databases such as PubMed, Scopus, and Web of Science. The search included studies published between 1980 and 2023, using keywords like ‘fibromyalgia’, ‘pain mechanisms’, ‘serotonin’, and ‘tryptophan’. The inclusion criteria were limited to peer-reviewed articles, clinical trials, and meta-analyses, excluding case studies and editorials. Articles were screened based on their relevance to the pathophysiological mechanisms and treatment strategies for fibromyalgia, as discussed in this manuscript.

2. Physiopathology of Fibromyalgia

The pathophysiology of fibromyalgia (FM) is multifaceted, encompassing abnormalities in the nervous and neuroendocrine systems, autonomous system dysfunctions, genetic predispositions, psychosocial factors, and environmental stressors [6,7]. FM is closely associated with dysfunction in monoamine pathways, particularly concerning serotonin. Alterations in neurotransmitter systems, such as serotonin (5-HT) and norepinephrine (NE), are implicated in mood and pain disorders. Genetic polymorphisms, such as those in the serotonin transporter (5-HTTLPR), affect serotonin signaling, increasing susceptibility to conditions like fibromyalgia and depression. Neuroinflammation and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis also contribute to exaggerated pain responses and mood disorders, linking inflammation to monoamine dysfunction. Additionally, functional imaging studies reveal that certain serotonin-related genetic variants are associated with increased activation in brain regions responsible for pain perception. These mechanisms highlight the importance of the balance between neurotransmitters, such as serotonin, norepinephrine, and dopamine, and their impact on fibromyalgia [8]. Patients with FM exhibit heightened sensitivity to various stimuli, including temperature changes and mechanical and ischemic pressures, resulting in pain responses to stimuli that would typically be nonpainful for healthy individuals [9,10,11]. The primary source of pain in FM remains elusive, but emerging evidence points to a central nervous system (CNS)-mediated increase in sensory processing, akin to that observed in neuropathic pain conditions [12].

A growing body of research underscores the complex, bidirectional relationship between pain and depression, highlighting that shared pathophysiological pathways and molecular mechanisms are crucial to both conditions [13,14,15]. Notably, the prefrontal cortex, insular cortex, anterior cingulate cortex, amygdala, hippocampus, and thalamus have been implicated in the modulation of mood and pain perception. Postmortem analyses have revealed reductions in neuronal bodies within the prefrontal cortex, hippocampus, and thalamus, indicative of diminished synaptic activity [16]. Genetic research supports these findings, showing a decrease in the expression of genes related to excitatory synapses, particularly in these brain regions [17,18]. These discoveries suggest a potential link between chronic pain and depression progression through neuroplasticity alterations, underscoring the need for integrated therapeutic strategies that address the intertwined nature of these symptoms in FM.

3. Tryptophan and Fibromyalgia

Recent studies, including Groven et al. (2021) [19], have suggested that altered tryptophan (Trp) metabolism could be crucial in the pathology of fibromyalgia (FM). Trp, an indispensable amino acid, is the precursor of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter integral to mood, appetite, and sleep regulation, and is increasingly recognized for its role in nociception [20]. Additionally, Trp is involved in the kynurenine pathway, which influences immune function, inflammation, and the biosynthesis of neuroactive compounds [21].

FM is characterized by reduced 5-HT levels and a notable decrease in the 5-HT transporter (5-HTT) within the cerebrospinal fluid of affected individuals [1,22,23,24,25]. Currently, metabolites of the kynurenine pathway, including quinolinic acid (QA) and kynurenic acid (KYNA), influence central nervous system functionality, acting as either neurotoxic or neuroprotective agents, particularly in modulating glutamatergic neurotransmission [19]. Therefore, disruptions to this metabolic pathway may manifest as pain in patients with FM.

Investigating the metabolic routes of Trp in patients with FM could elucidate its potential role in hyperalgesia, fatigue, depression, and other symptoms characteristic of this condition. The concept of a ‘cytokine storm’ triggered by tissue damage, leading to inflammation that adversely affects the brain, underscores the interconnectedness of these processes [26,27]. Such mechanisms, which are far from being isolated, play crucial roles in behavior development and can contribute to depression [28,29]. Moreover, chronic inflammation is associated with changes in neuronal structures and the metabolism of neurotransmitters related to pain, mood disorders, and cognition [29,30]. Therefore, Trp metabolism represents a critical intersection between the 5-HT and kynurenine pathways, which may influence the co-occurrence of pain and depression in patients with FM.

4. Role of Serotonin Receptors in Pain in Patients with Fibromyalgia

This section explores the potential link between serotonin (5-HT) and fibromyalgia (FM), highlighting the central role of serotonin as a monoamine neurotransmitter in the CNS that is synthesized from tryptophan (Trp). Serotonin acts as a neuromodulator in various physiological processes, including sleep, appetite, thermoregulation, hormone secretion, sexual behavior, and pain management [20,31,32,33]. The biosynthesis of 5-HT begins with the hydrolysis of Trp to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, followed by the conversion of 5-HTP to 5-HT through the action of aromatic L-amino acid decarboxylase. Trp is transported across the blood–brain barrier by a specific transporter in the raphe nuclei of the midbrain, which is projected throughout the brain [34].

The interplay between 5-HT activity and pain perception in patients with FM is intricate, and various studies indicate that disruptions to serotonin metabolism and transmission significantly impact nociception. The descending pain pathway is a complex neural system crucial for pain modulation, as it transmits signals from the brain to the spinal cord and influences pain perception. This pathway involves nociceptive transmission, where painful stimuli are conveyed from peripheral receptors to the brain for conscious perception. A key component of this modulation is serotonin, a neurotransmitter that inhibits pain signals in the spinal cord by reducing the release of substance P and regulating nociceptive responses. In conditions such as fibromyalgia, lower levels of serotonin are associated with increased pain sensitivity, underscoring the role of serotonin in pain modulation [35]. Altered nociception, a prevalent feature of FM, suggests a pivotal role for 5-HT in this pathology.

Research involving mirtazapine has demonstrated its potential in reversing chronic pain and improving the analgesic effects of morphine in FM-like mouse models. Mirtazapine works by increasing 5-HT release, activating the 5-HT1 receptor, and inhibiting the postsynaptic 5-HT2 and 5-HT3 receptors, as well as the presynaptic adrenergic α2 receptors. This action may reduce pain and enhance hypoalgesia in FM. While other medications, such as pregabalin, have been explored, mirtazapine presents a novel strategy that could offer additional benefits. Nonetheless, more studies are needed to comprehensively understand its effectiveness and potential side effects in humans [36].

4.1. 5-HT1 Receptor

Studies have shown that regulation of serotonin (5-HT) release in synapses is mediated by presynaptic autoreceptors, specifically 5-HT1A, and the serotonin transporter (5-HTT), leading to a reduction in serotonergic neuronal activity [37,38]. These presynaptic 5-HT1A metabotropic receptors, particularly within the corticolimbic system, play crucial roles in mediating antidepressive and antinociceptive effects through the reuptake of 5-HT, thus controlling its availability and the duration of its effects in the synaptic cleft [39,40,41,42]. In the context of fibromyalgia (FM), a decrease in 5-HT levels within cerebrospinal fluid, accompanied by an increase in 5-HTT activity, has been noted. This observation suggests a potential dysregulation of the serotoninergic system in FM, indicating a possible target for therapeutic intervention [43,44].

4.2. 5-HT2A Receptor

Research has increasingly indicated a link between fibromyalgia (FM) and the 5-HT2A metabotropic receptors, a critical element of pain perception and the central modulation of nociceptive pathways [45]. Genetic variations in the 5-HT2A receptor have been associated with FM, with certain genotypes correlated with heightened pain sensitivity [46]. Furthermore, decreased levels of 5-HIAA, a metabolite of 5-HT, in the serum have been linked to improved self-reported pain perception among FM patients, suggesting potential dysregulation of 5-HT [47].

The interconnection between FM and the 5-HT2A receptor in pain is intricate and is shaped by genetic variation and the deregulation of the serotonin pathway [45]. Recent findings have demonstrated that the modulation of 5-HT receptors, including 5-HT2A, may be effective in managing chronic pain in FM sufferers [36]. Cyclobenzaprine, an antagonist of the 5-HT2A receptor, has been shown to be beneficial for most sleep disorders and has shown a modest improvement in FM-related pain. This evidence supports the significant role that these receptors may play in FM [48,49,50]. Furthermore, studies suggest that downregulation of the 5-HT2A and 5-HT2C receptors could contribute to the onset of chronic hyperalgesia in FM [45,51]. These findings underscore the potential of targeting these receptors for the pharmacological treatment of pain in patients with FM, particularly those with comorbid conditions.

4.3. 5-HT3 Receptor

The role of the 5-HT3 ionotropic receptor in the nociceptive processes of fibromyalgia (FM) patients remains elusive. However, the use of antagonists such as tropisetron has shown promising results in alleviating pain in FM sufferers, whether administered orally or intravenously. Current research suggests that a 10-day oral regimen of 5 mg of tropisetron per day yields positive results. Intravenous administration for 1 to 5 days has been effective in reducing pain, particularly at higher doses. In addition to pain relief, tropisetron has been reported to ameliorate other FM-related symptoms, including sleep disturbances, anxiety, and depression [49,52].

5-HT3 antagonists can mitigate pain by blocking the release of neurotransmitters such as substance P and calcitonin gene-related peptide from nociceptors [53], which are involved in nociception and can trigger peripheral inflammatory responses. Overexpression of 5-HT3 receptors in the CNS regions responsible for pain processing implies that these antagonists could influence the central processing of sensory stimuli, offering a potential therapeutic avenue to manage the symptoms of FM.

4.4. Selective Serotonin Reuptake Inhibitors

The role of serotonin (5-HT) in pain neuromodulation underpins the rationale for the use of selective serotonin reuptake inhibitors (SSRIs) in treating fibromyalgia (FM). However, the effectiveness of SSRIs in FM treatment has yielded mixed results in controlled clinical trials (Table 1).

Table 1.

Comprehensive overview of clinical trials investigating the efficacy of serotonin reuptake inhibitors (SRIs) as analgesic agents in patients with fibromyalgia (FM). Trials vary widely in design, demographics of the patients, dosage of medications and outcomes, providing a broad perspective on the analgesic effect of SRIs in FM treatment.

Registry Number Patients Study Design Medication Dose Analgesic
Effect
NCT01288807 8 adult female patients with fibromyalgia Single group assignment, open study Milnacipran 200 mg/day
for 12 weeks		 NO
NCT00314249 1025 adult patients with fibromyalgia Randomized, multicenter, double-blind, placebo controlled Milnacipran 100 mg/day
for 12 weeks		 YES
NCT01173055 22 adult female patients with fibromyalgia Randomized, double-blind, two-way placebo controlled Milnacipran 200 mg/day
for 6 weeks		 NO
NCT01108731 37 adult fibromyalgia patients Quadruple-blind, randomized, placebo controlled Milnacipran 12.5 mg/day
for 9 weeks		 NO
NCT01077375 120 adult patients with fibromyalgia Multicenter, randomized, double-blind, placebo controlled Milnacipran 100 to 200 mg/day
for 10 weeks		 YES
NCT01829243 26 older adult patients with fibromyalgia Randomized, double-blind, two-way placebo controlled Milnacipran 12.5 mg 200 mg/day
for 13 weeks		 NO
NCT01038323 58 adult fibromyalgia patients Triple-blind, randomized, 3-way placebo controlled Milnacipran 12.5 mg/day
for 21 weeks		 YES
NCT00797797 364 adult fibromyalgia patients Multicenter, randomized, open-label, placebo controlled study Milnacipran and pregabalin Milnacipran 100 mg/day and pregabalin 300 or 450 mg/day for 11 weeks YES
NCT00673452 530 adult fibromyalgia patients Quadruple-blind, randomized, two-way placebo controlled Duloxetine 60–120 mg/day
for 12 weeks		 YES
NCT01237587 184 patients with juvenile primary fibromyalgia syndrome Multicenter, quadruple-blind, randomized, placebo-controlled, 2-way crossover Duloxetine 30/60 mg/day
for 23 weeks		 YES
NCT00965081 308 adult fibromyalgia patients Quadruple-blind, randomized, two-way placebo controlled Duloxetine 30 mg/day
for 12 weeks		 YES
NCT01552057 393 adult fibromyalgia patients Randomized, double-blind, placebo controlled Duloxetine 60 mg/day
for 15 weeks		 YES
NCT00115804 6 patients with juvenile primary fibromyalgia syndrome Pilot trial, single group assignment, open study Fluoxetine 10 to 60 mg/day
for 12 weeks		 LOWER
Open in a new tab

An evaluation of six studies encompassing 343 participants demonstrated that SSRIs were significantly more effective than placebos in achieving at least a 30% reduction in pain [54]. Although some evidence suggests that SSRIs can reduce pain in patients with FM, the overall quality of this evidence remains low. In a more recent meta-analysis, duloxetine, an SSRI, was compared with a placebo in various controlled trials. This analysis indicated that duloxetine outperformed placebo in pain relief, as measured by patient-reported outcomes such as the Fibromyalgia Impact Questionnaire and the Brief Pain Inventory. However, the exact percentage of pain reduction was not specified, and the study highlighted the need for individualized dosing of duloxetine for FM treatment, underscoring the need for customized therapeutic approaches [55]. On the other hand, the dose and duration of medication in the treatment of fibromyalgia with SSRIs can be crucial for observing effective therapeutic outcomes. An appropriate dose ensures that the drug reaches sufficient levels in the body to affect neurotransmitters, such as serotonin, involved in pain modulation. However, the effectiveness of the treatment depends not only on the dose but also on the duration of medication administration. In the early stages of treatment, the drug may not have reached a stable concentration in the body, which could explain the lack of short-term effects, as observed in studies where the medication showed a notable effect at 21 weeks but not at 9 weeks. Over time, the accumulation of the drug can improve serotonin modulation and, consequently, enhance the treatment’s effectiveness in reducing pain.

Despite the theoretical foundation for using SSRIs in FM treatment on the basis of decreased serotonin levels, the precise relationship between 5-HT modulation by these drugs and pain relief remains to be fully clarified [56,57].

  • -

    **NCT01288807**: Conducted in eight adult female patients, this open study assessed milnacipran at 200 mg daily over 12 weeks but did not report no analgesic effect.

  • -

    **NCT00314249**: This large-scale, multicenter, double-blind, placebo-controlled study involving 1025 adult FM patients evaluated milnacipran at 100 mg per day for 12 weeks and reported a positive analgesic effect.

  • -

    **NCT00115804**: A pilot trial in six patients with juvenile primary fibromyalgia syndrome treated with fluoxetine (10 to 60 mg daily for 12 weeks) reported a decrease in the analgesic effect.

  • -

    **NCT01237587**: In 184 patients with juvenile primary fibromyalgia syndrome, this quadruple-blind, placebo-controlled study assessed duloxetine (30/60 mg/day for 23 weeks) and found a positive analgesic effect.

  • -

    **NCT01552057**: A randomized, double-blind, placebo-controlled trial with 393 adult patients with FM that evaluated duloxetine at 60 mg/day for 15 weeks and reported a positive outcome.

  • -

    **NCT00797797**: This study combined milnacipran (100 mg/day) and pregabalin (300 or 450 mg/day) over 11 weeks in 364 adult FM patients and reported a positive analgesic effect.

  • -

    **NCT01108731** and **NCT01173055**: These studies, which assessed milnacipran at lower doses (12.5 mg for 9 weeks and 200 mg/day, respectively), reported no analgesic effects in their small cohorts.

  • -

    **NCT00673452**: A large trial of 530 adult FM patients evaluating duloxetine (60–120 mg/day for 12 weeks), which revealed a positive analgesic effect.

  • -

    **NCT01077375**: This multicenter study assessed milnacipran (100 to 200 mg/day for 10 weeks) in 120 adult FM patients and reported a positive analgesic effect.

  • -

    **NCT01829243**: Focusing on older adult FM patients (26 participants), this study assessed milnacipran at various doses (12.5–200 mg/day) and found no analgesic effect.

  • -

    **NCT00965081**: A quadruple-blind study with 308 adult FM patients evaluated duloxetine at 30 mg/day for 12 weeks and reported a positive effect.

  • -

    **NCT01038323**: Milnacipran at 12.5 mg/day for 21 weeks was administered to 58 adult FM patients, and a positive analgesic effect was detected.

These trials collectively highlight the variable efficacy of SSRIs in FM treatment, highlighting the importance of personalized approaches to dosage and treatment duration.

5. Role of Kynurenine in Pain in Fibromyalgia

Kynurenine, a metabolite of the amino acid tryptophan (Trp), is produced through catabolism initiated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), which catalyze the conversion of Trp into N-formyl kynurenine. This process subsequently involves several steps leading to the formation of kynurenine, a process pivotal for numerous biological functions, including immune response regulation, neurotransmission, and cellular equilibrium [21].

Dysfunction in the kynurenine pathway has been associated with various neurological and psychiatric conditions and with the development of chronic pain [58]. The metabolites produced by this pathway, quinolinic acid (QA) and kynurenic acid (KYNA), have different impacts on neuronal functions, inflammation, and oxidative stress, contributing to diseases such as Alzheimer’s disease, Parkinson’s disease, and depression, as well as modulating pain perception, especially in chronic pain scenarios [58].

KYNA is known for its antinociceptive properties through glutamate modulation in the CNS, while QA facilitates pain by acting as an excitotoxin, suggesting that its balance is critical for pain perception and processing [21].

There is a suggested link between kynurenine pathway dysfunction and altered serotonin metabolism, neuroplasticity issues, and neurological disorders of specific relevance to chronic pain due to its interaction with N-methyl-D-aspartate (NMDA) receptors, which are essential for pain signal transduction [21].

Research by Maganin et al. (2022) highlighted that peripheral nerve injury triggers IDO1 upregulation in dendritic cells (DCs), leading to increased SC kynurenine. This kynurenine is then converted by astrocytic kynurenine 3-monooxygenase (KMO) into the pronociceptive metabolite 3-hydroxykynurenine (3-HK). Furthermore, DCs expressing 3-hydroxyanthranilic acid are involved in increasing spinal cord QA, promoting pronociceptive actions by enhancing glutamatergic transmission and sustaining pain hypersensitivity [59].

While KYNA is recognized for its neuroprotective and pain-modulating effects, QA is considered neurotoxic, contributing to neuroinflammation and excitotoxicity, which are pivotal in pain signaling. In addition, cerebral IDO activity has been associated with the comorbidity of pain and depression. The role of kynurenine in major depression via glutamatergic transmission modulation suggests its potential involvement in pain processing. Positive regulation of neuronal KMO has been shown to induce depression-like behavior in neuropathic pain models in mice, indicating its potential influence on pain-related behavioral changes (Figure 1) [60,61].

Figure 1.

Figure 1

Open in a new tab

Dual roles of metabolites within the kynurenine pathway, focusing on quinolinic acid and its contrast to quinuric acid in the central nervous system. Quinuric acid, which is synthesized by astrocytes from quinolinic acid, is the result of the enzymatic action of kynurenine aminotransferase (kat). This conversion process highlights the neuroprotective properties of quinuric acid. Conversely, quinolinic acid, when processed by microglia, follows a different metabolic route involving the kynurenine monooxygenase (kmo) signaling cascade. Kmo facilitates the conversion of quinolinic acid to 3-hydroxykynurenine (3-hk). The pathway continues with the transformation of 3-hk into 3-hydroxyanthranilic acid (3-haa) by the enzyme quinureninase, eventually leading back to the formation of quinolinic acid, which is known for its neurodegenerative effects. This depiction underscores the complex interplay between neuroprotective and neurodegenerative mechanisms mediated by metabolites of the kynurenine pathway.

6. Discussion

Given the essential role of tryptophan (Trp) as a dietary amino acid and precursor in several key metabolic pathways, including those leading to serotonin (5-HT) and niacin (vitamin B3), as well as its involvement in the kynurenine pathway crucial for immune modulation and synthesis of nicotinamide adenine dinucleotide (NAD+), as an enzyme vital for cell energy production, Trp stands at the intersection of numerous studies related to cognitive function and behavior [62].

Trp is an integral part of the neuromodulation and catabolism of proteins during trauma, infection, and cancer. Studies suggest that Trp levels may be decreased in serum from patients with fibromyalgia (FM), potentially impairing immunomodulatory functions and leading to symptoms such as severe fatigue, sleep disturbances, cognitive problems, and pain [62,63].

A landmark study by King (1980) [64] on the analgesic properties of Trp in postsurgical patients revealed that Trp administration reduced recurring pain and sensory deficits, highlighting Trp’s role in neurotransmitter modulation and its potential to address pain and sensory issues through the serotonin pathway.

Recent findings indicate reduced levels of Trp and kynurenine in FM patients, suggesting a link between these metabolites and the severity of FM symptoms [36]. The rapid release of cortisol in response to emotional stress, which activates the Trp–kynurenine pathway and reduces Trp availability for 5-HT synthesis, underscores the complex interactions affecting Trp metabolism under stress and disease conditions [65].

These findings collectively suggest that altered Trp metabolism in FM affects the balance between 5-HT and kynurenine and potentially impacts the central and peripheral nervous systems. Such alterations could contribute to the pathophysiology of pain in FM, emphasizing the need for further research to fully understand these mechanisms and their implications for treatment (Figure 2).

Figure 2.

Figure 2

Open in a new tab

The impact of L-tryptophan on fibromyalgia pathology underscores its crucial role through its metabolic products, serotonin, and kynurenine. Stress conditions prompt an increase in 3,2-dioxygenase activity, which favors the kynurenine pathway over serotonin synthesis by depleting the L-tryptophan levels in the bloodstream. Consequently, in the central nervous system (CNS), decreased availability of L-tryptophan leads to decreased serotonin levels, which can cause symptoms such as depression, pain, and sleep disturbances characteristic of fibromyalgia. Concurrently, an increase in kynurenine levels results in elevated quinolinic acid within the CNS, hinting at a neurodegenerative process propelled by inflammation, cellular stress, and increased glutamatergic activity. These interconnected pathways could contribute to the chronic pain and central sensitization observed in fibromyalgia patients, indicating that modulation of L-tryptophan and kynurenine levels is a promising direction for therapeutic intervention in the treatment of fibromyalgia symptoms.

Research by Russell, Michalek, et al. and Russell, Vaeroy, et al. in 1992 [23] elucidated potential aberrations in the descending pain regulatory pathways as contributors to the painful symptoms experienced by patients with fibromyalgia (FM). These pathways, which are crucial for the inhibition of the transmission of sensory stimuli from the brainstem to the dorsal root, leverage neurotransmitters linked to pain and mood regulation, including serotonin (5-HT).

FM patients exhibit heightened pain sensitivity correlated with increased sensory input, requiring approximately 50% less stimulus intensity to elicit pain than healthy individuals [8,66]. Dysfunctions in the autonomic nervous system, which are commonly observed in FM patients, might exacerbate sensitivity and other clinical manifestations by disrupting the physiological responses essential for stress management and pain inhibition, which are mediated by growth hormone and insulin growth factor 1 (IGF-1). Although 5-HTT has been implicated in heightened pain sensitivity among FM patients [8], research by Gursoy (2002) [67] suggested that the influence of 5-HT on pain perception is not mediated by transporter-regulating genes but by those regulating metabolic enzymes and receptors such as 5-HT2A and 5-HT3, with clinical trials affirming the effectiveness of 5-HT3 antagonists in FM treatment [68].

The role of 5-HT in pain regulation varies according to the receptors engaged; for example, the 5-HT1A interaction yields antinociceptive effects, whereas 5-HT2A and 5-HT3 agonists contribute to pronociception [69]. Given this diversity, the ability of 5-HTT to regulate 5-HT levels in the synaptic cleft may not specifically inhibit pain perception. This complexity renders SSRIs alone an insufficient and reductionist treatment approach for FM, underscored by mixed clinical outcomes and the potential of inflammation as a common denominator in chronic pain and depression. Inflammation triggers the kynurenine pathway, a crucial metabolic process of Trp, leading to the production of neuroactive metabolites [70].

The kynurenine pathway, which is regulated primarily by proinflammatory cytokines such as TNF-α and IFN-γ, progresses to KYNA synthesis by astroglia and QA by microglia. The balance between neuroprotective KYNA and neurotoxic QA is pivotal, with recent studies linking diminished KYNA levels and elevated QA to chronic pain and depression pathogenesis, suggesting a potential weak effect of 5-HT on these conditions in FM [70,71,72].

Therefore, we propose targeting Trp metabolism as a treatment strategy for FM, focusing on inhibiting neurotoxic QA metabolism without excluding SSRIs. Enhancing KYNA could provide neuroprotection and analgesic benefits while indirectly increasing 5-HT levels to inhibit nociceptive signals (Figure 3). This comprehensive approach may pave the way for innovative FM treatments, fostering research into new pharmaceuticals and significantly enhancing the quality of life for FM patients by effectively managing their pain and depression.

Figure 3.

Figure 3

Open in a new tab

Proposed intervention to mitigate pain in fibromyalgia (FM) patients, which focuses on modulating the serotonin–kynurenine pathway. This strategy involves two principal components: the administration of serotonin reuptake inhibitors (SRIs) to increase the serotonin levels in the synaptic cleft and the inhibition of 3-hydroxyanthranilic acid (3-HAA) production in microglia, thereby curtailing the synthesis of quinolinic acid. These targeted actions are designed to exert beneficial effects on pain alleviation in FM sufferers. Enhancing serotonin availability through SRIs is anticipated to improve the functionality of nociceptive pathways, potentially diminishing pain perception. Additionally, serotonin elevation may ameliorate depression symptoms, which are frequently observed in FM patients, thereby tackling both the neurochemical and the psychological dimensions of the condition. Simultaneously, the proposed intervention seeks to reduce quinolinic acid—a metabolite linked to neurodegenerative effects—and increase quinuric acid, which is known for its neuroprotective properties within the central nervous system. By decreasing the presence of quinolinic acid, it is hypothesized that there would be a concomitant reduction in the pain experienced by FM patients. This dual-focused approach aims not only to alleviate the immediate symptoms of pain but also to address the underlying neurochemical imbalances associated with FM, providing a holistic treatment strategy that encompasses both the physical and the psychological aspects of the disease.

7. Conclusions

Recent studies have illuminated the altered metabolism of tryptophan (Trp) in fibromyalgia (FM) patients, revealing notably low levels of serotonin (5-HT), attributable to the predominant metabolism of Trp through the kynurenine pathway. This pathway, which is responsible for the synthesis of metabolites implicated in FM, diverts up to 95% of Trp, thus impacting 5-HT synthesis.

These findings challenge the efficacy of treatments exclusively utilizing selective serotonin reuptake inhibitors (SSRIs) for FM pain management. Thus, targeting 5-HT alone is insufficient for effective pain inhibition, and the metabolites of the kynurenine pathway should not be viewed solely as nociceptive facilitators.

8. Perspectives

This review underscores the complex interplay among neuronal, immune, and metabolic pathways in FM, which contributes to the manifestation of pain and depression. We propose a novel treatment strategy aimed at reducing symptoms by inhibiting quinolinic acid (QA) synthesis alongside SSRI administration. This approach aims to increase the availability of both 5-HT and kynurenic acid (KYNA), promoting neuroprotection and analgesia. This multifaceted treatment modality acknowledges the intricacies of Trp metabolism in FM and represents a step forward in the development of more comprehensive and effective therapeutic interventions.

Author Contributions

Conceptualization, J.L.C.-A. and A.A.-R.; methodology S.R.-L.; validation, J.L.C.-A., A.A.-R. and S.R.-L.; formal analysis, E.R.-V.; investigation, M.G.-T.; resources, C.B.; data curation, H.B.-J.; writing—original draft preparation, J.L.C.-A.; writing—review and editing, A.A.-L., A.B.-N., E.C.-R., P.S.-A. and A.G.M.; visualization, A.L.D.-L. and E.C.-R.; supervision, J.L.C.-A.; project administration, A.A.-R.; funding acquisition, J.L.C.-A., S.R.-L. and A.A.-R. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were used for the research described in this paper.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research received no external funding.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

References

  • 1.Ablin J.N., Cohen H., Buskila D. Mechanisms of disease: Genetics of fibromyalgia. Nat. Clin. Pract. Rheumatol. 2006;2:671–678. doi: 10.1038/ncprheum0349. [DOI] [PubMed] [Google Scholar]
  • 2.Hudson J.I., Mangweth B., Pope H.G., Jr., De Col C., Hausmann A., Gutweniger S., Laird N.M., Biebl W., Tsuang M.T. Family study of affective spectrum disorder. Arch. Gen. Psychiatry. 2003;60:170–177. doi: 10.1001/archpsyc.60.2.170. [DOI] [PubMed] [Google Scholar]
  • 3.Canales L.d.M.V., Berenguer I.P., García-Iturrospe E.A., Rodríguez C. Dealing with fibromyalgia in the family context: A qualitative description study. Scand. J. Prim. Health Care. 2024;42:327–337. doi: 10.1080/02813432.2024.2322103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Roughan W.H., Campos A.I., García-Marín L.M., Cuéllar-Partida G., Lupton M.K., Hickie I.B., Medland S.E., Wray N.R., Byrne E.M., Ngo T.T., et al. Comorbid chronic pain and depression: Shared risk factors and differential antidepressant effectiveness. Front. Psychiatry. 2021;12:643609. doi: 10.3389/fpsyt.2021.643609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Yong R.J., Mullins P.M., Bhattacharyya N. Prevalence of chronic pain among adults in the United States. Pain. 2022;163:328–332. doi: 10.1097/j.pain.0000000000002291. [DOI] [PubMed] [Google Scholar]
  • 6.Arnold L.M., Hudson J.I., Hess E.V., Ware A.E., Fritz D.A., Auchenbach M.B., Starck L.O., Keck P.E., Jr. Family study of fibromyalgia. Arthritis Rheum. 2004;50:944–952. doi: 10.1002/art.20042. [DOI] [PubMed] [Google Scholar]
  • 7.Hudson J.I., Arnold L.M., Keck P.E., Auchenbach M.B., Pope H.G., Jr. Family study of fibromyalgia and affective spectrum disorder. Biol. Psychiatry. 2004;56:884–891. doi: 10.1016/j.biopsych.2004.08.009. [DOI] [PubMed] [Google Scholar]
  • 8.Bradley L.A. Pathophysiology of fibromyalgia. Am. J. Med. 2009;122:22–30. doi: 10.1016/j.amjmed.2009.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Carli G., Suman A.L., Biasi G., Marcolongo R. Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain. 2002;100:259–669. doi: 10.1016/S0304-3959(02)00297-X. [DOI] [PubMed] [Google Scholar]
  • 10.David S.P., Murthy N.V., Rabiner E.A., Munafó M.R., Johnstone E.C., Jacob R., Walton R.T., Grasby P.M. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT 1A receptor binding in humans. J. Neurosci. 2005;25:2586–2590. doi: 10.1523/JNEUROSCI.3769-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Yohn C.N., Gergues M.M., Samuels B.A. The role of 5-HT receptors in depression. Mol. Brain. 2017;10:28. doi: 10.1186/s13041-017-0306-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Nielsen L.A., Henriksson K.G. Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): The role of central and peripheral sensitization and pain disinhibition. Best Pract. Res. Clin. Rheumatol. 2007;21:465–480. doi: 10.1016/j.berh.2007.03.007. [DOI] [PubMed] [Google Scholar]
  • 13.Kroenke K., Spitzer R.L., Williams J.B.W. The PHQ-9: Validity of a brief depression severity measure. J. Gen. Intern. Med. 2001;16:606–613. doi: 10.1046/j.1525-1497.2001.016009606.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.World Health Organization. [(accessed on 28 June 2024)]. Available online: https://www.who.int/news-room/fact-sheets/detail/depression.
  • 15.Rayner L., Hotopf M., Petkova H., Matcham F., Simpson A., McCracken L.M. Depression in patients with chronic pain attending a specialised pain treatment centre: Prevalence and impact on health care costs. Pain. 2016;157:1472–1479. doi: 10.1097/j.pain.0000000000000542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Kang H.J., Voleti B., Hajszan T., Rajkowska G., Stockmeier C.A., Licznerski P., Lepack A., Majik M.S., Jeong L.S., Banasr M., et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat. Med. 2012;18:1413–1417. doi: 10.1038/nm.2886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Ménard C., Hodes G.E., Russo S.J. Pathogenesis of depression: Insights from human and rodent studies. Neuroscience. 2016;321:138–162. doi: 10.1016/j.neuroscience.2015.05.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Sheng J., Liu S., Wang Y., Cui R., Zhang X. The link between depression and chronic pain: Neural mechanisms in the brain. Neural Plast. 2017;2017:9724371. doi: 10.1155/2017/9724371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Groven N., Reitan S.K., Fors E.A., Guzey I.C. Kynurenine metabolites and ratios differ between chronic fatigue syndrome, fibromyalgia, and healthy controls. Psychoneuroendocrinology. 2021;131:105287. doi: 10.1016/j.psyneuen.2021.105287. [DOI] [PubMed] [Google Scholar]
  • 20.Cortes-Altamirano J.L., Olmos-Hernandez A., Jaime H.B., Carrillo-Mora P., Bandala C., Reyes-Long S., Alfaro-Rodríguez A. Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their role in the modulation of pain response in the central nervous system. Curr. Neuropharmacol. 2018;16:210–221. doi: 10.2174/1570159X15666170911121027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Huang Y., Zhao M., Chen X., Zhang R., Le A., Hong M., Zhang Y., Jia L., Zang W., Jiang C., et al. Tryptophan metabolism in central nervous system diseases: Pathophysiology and potential therapeutic strategies. Aging Dis. 2023;14:858–878. doi: 10.14336/AD.2022.0916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Offenbaecher M., Bondy B., de Jonge S., Glatzeder K., Krüger M., Schoeps P., Ackenheil M. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999;42:2482–2488. doi: 10.1002/1529-0131(199911)42:11<2482::AID-ANR27>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  • 23.Russell I.J., Vaeroy H., Javors M., Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992;35:550–556. doi: 10.1002/art.1780350509. [DOI] [PubMed] [Google Scholar]
  • 24.Wolfe F., Russell I.J., Vipraio G., Ross K., Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J. Rheumatol. 1997;24:555–559. [PubMed] [Google Scholar]
  • 25.Yunus M.B., Dailey J.W., Aldag J.C., Masi A.T., Jobe P.C. Plasma tryptophan and other amino acids in primary fibromyalgia: A controlled study. J. Rheumatol. 1992;19:90–94. [PubMed] [Google Scholar]
  • 26.Baliki M.N., Chialvo D.R., Geha P.Y., Levy R.M., Harden R.N., Parrish T.B., Apkarian A.V. Chronic pain and the emotional brain: Specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J. Neurosci. 2006;26:12165–12173. doi: 10.1523/JNEUROSCI.3576-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Walker A.K., Kavelaars A., Heijnen C.J., Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol. Rev. 2013;66:80–101. doi: 10.1124/pr.113.008144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Campos A.C.P., Antunes G.F., Matsumoto M., Pagano R.L., Martinez R.C.R. Neuroinflammation, pain and depression: An overview of the main findings. Front. Psychol. 2020;11:1825. doi: 10.3389/fpsyg.2020.01825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Miller A.H., Raison C.L. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 2016;16:22–34. doi: 10.1038/nri.2015.5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Castro-Portuguez R., Sutphin G.L. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan. Exp. Gerontol. 2020;132:110841. doi: 10.1016/j.exger.2020.110841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Graeff F.G. Serotonergic systems. Psychiatr. Clin. N. Am. 1997;20:723–739. doi: 10.1016/S0193-953X(05)70342-7. [DOI] [PubMed] [Google Scholar]
  • 32.Lee Y.H., Choi S.J., Ji J.D., Song G.G. Candidate gene studies of fibromyalgia: A systematic review and meta-analysis. Rheumatol. Int. 2012;32:417–426. doi: 10.1007/s00296-010-1678-9. [DOI] [PubMed] [Google Scholar]
  • 33.Li M., Zhu M., Xu Q., Ding F., Tian Y., Zhang M. Sensation of TRPV1 via 5-hydroxytryptamine signaling modulates pain hypersensitivity in a 6-hydroxydopamine induced mice model of Parkinson’s disease. Biochem. Biophys. Res. Commun. 2020;521:868–873. doi: 10.1016/j.bbrc.2019.10.204. [DOI] [PubMed] [Google Scholar]
  • 34.Juhl J.H. Fibromyalgia and the serotonin pathway. Altern. Med. Rev. 1998;3:367–375. [PubMed] [Google Scholar]
  • 35.Alnigenis M.N., Barland P. Fibromyalgia syndrome and serotonin. Clin. Exp. Rheumatol. 2001;19:205–210. [PubMed] [Google Scholar]
  • 36.Neyama H., Dozono N., Uchida H., Ueda H. Mirtazapine, an α 2 antagonist-type antidepressant, reverses pain and lack of morphine analgesia in fibromyalgia-like mouse models. J. Pharmacol. Exp. Ther. 2020;375:1–9. doi: 10.1124/jpet.120.265942. [DOI] [PubMed] [Google Scholar]
  • 37.Albert P.R., Vahid-Ansari F. The 5-HT1A receptor: Signaling to behavior. Biochimie. 2019;161:34–45. doi: 10.1016/j.biochi.2018.10.015. [DOI] [PubMed] [Google Scholar]
  • 38.Sharp T., Barnes N.M. Central 5-HT receptors and their function; present and future. Neuropharmacology. 2020;177:108155. doi: 10.1016/j.neuropharm.2020.108155. [DOI] [PubMed] [Google Scholar]
  • 39.Chen Q., Heinricher M.M. Descending control mechanisms and chronic pain. Curr. Rheumatol. Rep. 2019;21:13. doi: 10.1007/s11926-019-0813-1. [DOI] [PubMed] [Google Scholar]
  • 40.Kranz G.S., Kasper S., Lanzenberger R. Reward and the serotonergic system. Neuroscience. 2010;166:1023–1035. doi: 10.1016/j.neuroscience.2010.01.036. [DOI] [PubMed] [Google Scholar]
  • 41.Smythies J., Section V. Serotonin system. Int. Rev. Neurobiol. 2005;64:217–268. doi: 10.1016/S0074-7742(05)64005-6. [DOI] [PubMed] [Google Scholar]
  • 42.Sommer C. Serotonin in pain and pain control. In: Müller C.P., Jacobs B.L., editors. Handbook of Behavioral Neuroscience. Volume 21. Elsevier; Amsterdam, The Netherlands: 2010. pp. 457–471. [DOI] [Google Scholar]
  • 43.Ablin J.N., Buskila D. Update on the genetics of the fibromyalgia syndrome. Best Pract. Res. Clin. Rheumatol. 2015;29:20–28. doi: 10.1016/j.berh.2015.04.018. [DOI] [PubMed] [Google Scholar]
  • 44.Christian B.T., Wooten D.W., Hillmer A.T., Tudorascu D.L., Converse A.K., Moore C.F., Ahlers E.O., Barnhart T.E., Kalin N.H., Barr C.S., et al. Serotonin transporter genotype affects serotonin 5-HT 1A binding in primates. J. Neurosci. 2013;33:2512–2516. doi: 10.1523/JNEUROSCI.4182-12.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Bondy B., Spaeth M., Offenbaecher M., Glatzeder K., Stratz T., Schwarz M., de Jonge S., Krüger M., Engel R.R., Färber L., et al. The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol. Dis. 1999;6:433–439. doi: 10.1006/nbdi.1999.0262. [DOI] [PubMed] [Google Scholar]
  • 46.Lautenschlager J., Bruckle W., Schnorrenberger C.C., Müller W. Measuring pressure pain of tendons and muscles in healthy probands and patients with generalized tendomyopathy (fibromy-algia syndrome) Z. Rheumatol. 1988;47:397–404. [PubMed] [Google Scholar]
  • 47.Schwarz M.J., Offenbaecher M., Neumeister A., Ackenheil M. Experimental evaluation of an altered tryptophan metabolism in fibromyalgia. Adv. Exp. Med. Biol. 2003;527:265–275. doi: 10.1007/978-1-4615-0135-0_30. [DOI] [PubMed] [Google Scholar]
  • 48.Moldofsky H., Harris H.W., Archambault W.T., Kwong T., Lederman S. Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: A double-blind randomized placebo-controlled study. J. Rheumatol. 2011;38:2653–2663. doi: 10.3899/jrheum.110194. [DOI] [PubMed] [Google Scholar]
  • 49.Stratz T., Muller W. Pain modification by the 5-HT3 receptor antagonist tropisetron in secondary fibromyalgias. Fortschr. Med. Orig. 2002;120:17–20. [PubMed] [Google Scholar]
  • 50.Tzadok R., Ablin J.N. Current and emerging pharmacotherapy for fibromyalgia. Pain Res. Manag. 2020;2020:6541798. doi: 10.1155/2020/6541798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Xue Y., Wei S.Q., Wang P.X., Wang W.Y., Liu E.Q., Traub R.J., Cao D.Y. Down-regulation of spinal 5-HT2A and 5-HT2C receptors contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress. Neuroscience. 2020;440:196–209. doi: 10.1016/j.neuroscience.2020.05.044. [DOI] [PubMed] [Google Scholar]
  • 52.Müller W., Stratz T. Results of the intravenous administration of tropisetron in fibromyalgia patients. Scand. J. Rheumatol. 2000;113:59–62. doi: 10.1080/030097400446661. [DOI] [PubMed] [Google Scholar]
  • 53.Zeitz K.P., Guy N., Malmberg A.B., Dirajlal S., Martin W.J., Sun L., Bonhaus D.W., Stucky C.L., Julius D., Basbaum A.I. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci. 2002;22:1010–1019. doi: 10.1523/JNEUROSCI.22-03-01010.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Walitt B., Urrútia G., Nishishinya M.B., Cantrell S.E., Häuser W. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst. Rev. 2015;6:CD011735. doi: 10.1002/14651858.CD011735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Migliorini F., Maffulli N., Eschweiler J., Baroncini A., Bell A., Colarossi G. Duloxetine for fibromyalgia syndrome: A systematic review and meta-analysis. J. Orthop. Surg. 2023;18:504. doi: 10.1186/s13018-023-03995-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Anderberg U.M., Marteinsdottir I., Von Knorring L. Citalopram in patients with fibromyalgia--a randomized, double-blind, placebo-controlled study. Eur. J. Pain. 2000;4:27–35. doi: 10.1053/eujp.1999.0148. [DOI] [PubMed] [Google Scholar]
  • 57.Arnold L.M., Hess E.V., Hudson J.I., Welge J.A., Berno S.E., Keck P.E., Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am. J. Med. 2002;112:191–1907. doi: 10.1016/S0002-9343(01)01089-0. [DOI] [PubMed] [Google Scholar]
  • 58.Debbag S., Yalcinkaya A., Saricaoglu F. Nociceptive improvements and kynurenine pathway alterations with diclofenac treatment in a rat model of neuropathic pain created by partial sciatic nerve ligation. Eur. Rev. Med. Pharmacol. Sci. 2023;27:4239–4247. doi: 10.26355/eurrev_202305_32334. [DOI] [PubMed] [Google Scholar]
  • 59.Maganin A.G., Souza G.R., Fonseca M.D., Lopes A.H., Guimarães R.M., Dagostin A., Cecilio N.T., Mendes A.S., Gonçalves W.A., Silva C.E., et al. Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice. J. Clin. Investig. 2022;132:e153805. doi: 10.1172/JCI153805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Chen L.M., Bao C.H., Wu Y., Liang S.H., Wang D., Wu L.Y., Huang Y., Liu H.R., Wu H.G. Tryptophan-kynurenine metabolism: A link between the gut and brain for depression in inflammatory bowel disease. J. Neuroinflamm. 2021;18:135. doi: 10.1186/s12974-021-02175-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Chojnacki C., Konrad P., Mędrek-Socha M., Kaczka A., Chojnacki M., Błońska A. Altered tryptophan metabolism in patients with recurrent functional abdominal pain. Pol. Merkur. Lek. 2022;50:5–8. [PubMed] [Google Scholar]
  • 62.Blankfield A. A brief historic overview of clinical disorders associated with tryptophan: The relevance to chronic fatigue syndrome (CFS) and fibromyalgia (FM) Int. J. Tryptophan Res. 2012;5:27–32. doi: 10.4137/IJTR.S10085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Robinson M., Turnbull S., Lee B.Y., Leonenko Z. The effects of melatonin, serotonin, tryptophan and NAS on the biophysical properties of DPPC monolayers. Biochim. Biophys. Acta Biomembr. 2020;1862:183363. doi: 10.1016/j.bbamem.2020.183363. [DOI] [PubMed] [Google Scholar]
  • 64.King R.B. Pain and tryptophan. J. Neurosurg. 1980;53:44–52. doi: 10.3171/jns.1980.53.1.0044. [DOI] [PubMed] [Google Scholar]
  • 65.Li T., Wang L., Zhang L., Li B., Wang D., Zhang L., Wang T., Fu F. Rotigotine-loaded microspheres exerts the antinociceptive effect via central dopaminergic system. Eur. J. Pharmacol. 2021;910:174443. doi: 10.1016/j.ejphar.2021.174443. [DOI] [PubMed] [Google Scholar]
  • 66.Gracely R.H., Petzke F., Wolf J.M., Clauw D.J. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343. doi: 10.1002/art.10225. [DOI] [PubMed] [Google Scholar]
  • 67.Gursoy S. Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. Clin. Rheumatol. 2002;21:194–197. doi: 10.1007/s10067-002-8284-5. [DOI] [PubMed] [Google Scholar]
  • 68.Potvin S., Larouche A., Normand E., de Souza J.B., Gaumond I., Marchand S., Grignon S. No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls. Eur. J. Pain. 2010;14:742–746. doi: 10.1016/j.ejpain.2009.12.004. [DOI] [PubMed] [Google Scholar]
  • 69.Hunt S.P., Suzuki R., Rahman W. Proceedings of the 11th World Congress on Pain: Progress in Research and Management. IASP Press; Seatle, WA, USA: 2006. Chronic pain and descending facilitation. [Google Scholar]
  • 70.Jovanovic F., Candido K.D., Knezevic N.N. The role of the kynurenine signaling pathway in different chronic pain conditions and potential use of therapeutic agents. Int. J. Mol. Sci. 2020;21:6045. doi: 10.3390/ijms21176045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Ogyu K., Kubo K., Noda Y., Iwata Y., Tsugawa S., Omura Y., Wada M., Tarumi R., Plitman E., Moriguchi S., et al. Kynurenine pathway in depression: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2018;90:16–25. doi: 10.1016/j.neubiorev.2018.03.023. [DOI] [PubMed] [Google Scholar]
  • 72.Savitz J. The kynurenine pathway: A finger in every pie. Mol. Psychiatry. 2020;25:131–147. doi: 10.1038/s41380-019-0414-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No new data were used for the research described in this paper.

Articles from Pharmaceuticals are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES