Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches
Abstract
:1. Introduction
2. Methods
2.1. Search Strategy
2.2. Study Selection Criteria
3. CGRP in Peripheral and Central Sensitization
- Peripheral sensitization. Peripheral injury of the muscles, joints, or nerves of the jaw and head triggers pain signals in the trigeminal nerve from the primary afferent fibers (mostly C fiber and A delta fibers). Local tissue inflammation releases cytokines and pro-inflammatory mediators, including CGRP, that perpetuate and increase the pain response. Peripheral sensitization lowers the depolarization threshold, so that normal stimulation is now perceived as painful (primary allodynia) and painful stimuli result in higher pain perception (primary hyperalgesia or “hyperalgesic priming”) [16,17].
- Central sensitization. Sustained peripheral pain signaling leads to central sensitization, characterized by increased excitability of central pain pathways [18] https://www.iasp-pain.org/resources/terminology/ (Accessed on 25 February 2023) [18,19]. At first, this sensitization is activity-dependent and consists primarily of lowered depolarization thresholds. This characterizes the phase of acute pain. However, if it persists for a longer period of time (i.e., beyond the normal healing process), it evolves into an activity-independent phenomenon through neuroplastic adaptation [14]. In this scenario, the CGRP released in the trigeminal ganglion engages with adjacent neurons and satellite glial cells, causing the continuation of peripheral sensitization and facilitating central sensitization of the second-order neurons [13]. This identifies a shift to a chronic pain phase. Central sensitization is the physiological hallmark of chronic pain syndromes and is responsible for the clinical symptoms of secondary hyperalgesia (defined as the increased pain response derived from a normally painful stimulus (Terminology | International Association for the Study of Pain. International Association for the Study of Pain (IASP). https://www.iasp-pain.org/resources/terminology/ (Accessed on 25 February 2023) [18]) and secondary allodynia (defined as pain response derived from a stimulus that is not normally perceived as painful [19].
- Spinal cord, where CGRP is released from primary sensory neurons in the dorsal horn of the spinal cord and cerebral gray matter, where it contributes to pain transmission and modulation [21];
- Brainstem: CGRP-containing fibers and terminals have been identified in various brainstem nuclei involved in pain processing, including the periaqueductal gray (PAG) and the nucleus tractus solitarius (NTS);
- Hypothalamus: CGRP has been detected in certain hypothalamic nuclei, such as the paraventricular nucleus (PVN) and the supraoptic nucleus (SON), involved in the regulation of autonomic functions and pain modulation [21];
- Thalamus: neurons expressing CGRP in the parvocellular sub-parafascicular nucleus have been observed in the thalamus [25].
4. CGRP and Migraine
- Ergotamine derivatives and triptans, drugs approved for the acute treatment of migraine [38], mainly stimulate 5-HT1B/1D receptors. As 5-HT1B receptor is localized on smooth muscle cells of cerebral, meningeal and coronary arteries, and 5-HT1D is mainly expressed in the trigeminal ganglion, these drugs result in a strong vasoconstriction of the cranial arteries [39]. They also indirectly act on decreasing the release of CGRP, thus reducing trigeminal activation and vasodilation [35].
- Ditans, 5-HT1F receptor agonists (lasmiditan) are newly Food and Drug Administration (FDA)-approved drugs for the acute treatment of migraine [40]. 5- HT1F receptors are located on terminals and cell bodies of the trigeminal ganglion neurons, acting at the peripheral nervous system and central nervous system. It can modulate CGRP from trigeminal ganglion neurons by potentially blocking its release and inhibiting the development of central sensitization [40]. Contrary to the effect of ergotamine derivates and triptans, activation of 5- HT1F does not induce vasodilation but rather causes vasoconstriction [40].
- CGRP receptors are localized on smooth muscles cells of meningeal and cerebral blood vessels. As a result, the release of CGRP by the activated meningeal C-fibers causes blood vessels to dilate [37]. Direct blockade of CGRP signaling with gepants [41], and with monoclonal antibodies directed against the molecule or its receptor attenuated the cutaneous mechanical hypersensitivity [42] and nitroglycerin-induced trigeminal hyperalgesia in animal models of migraine-like pain [43]. They have been FDA-approved as an effective treatment in preventive migraine [44]. Although the exact mechanism and site of action of CGRP in pain are still unclear and many mechanisms of action have been proposed [45], the meningeal blood vessels and their vasodilation are a primary target to prevent or inhibit pain signals [23].
- Topiramate inhibits nitric oxide and proton mediated CGRP secretion in a time- and concentration-dependent fashion from sensory trigeminal neurons [46].
- Botulinum toxin-A (BoNT) at doses between 150 Units and 195 Units, repeated every 12 weeks, is listed among the FDA-approved therapies for prevention of chronic migraine [38]. Among the several hypotheses on mechanism of action, one of these supports that BoNT attenuates the release of local transmitters such as CGRP from trigeminal neurons [47]. This further supports the pivotal role of CGRP reduction to its mechanism of action [48].
5. CGRP and TMDs
- CGRP receptors are widely distributed through the trigeminovascular system [71].
- The inflammatory response from peripheral injury stimulates the expression of CGRP in the trigeminal ganglion and central relay centers [13].
- Biomolecular CRGP release in the trigeminal ganglion stimulates the release of pro-inflammatory mediators via supporting cells in a paracrine fashion [72].
- The resulting “inflammatory soup” in the ganglion (a sterile ganglionitis) is permissive of cross-excitation of all branches of the trigeminal nerve [73].
6. CGRP, Traumatic Headaches and TMD
- Direct jaw trauma;
- Sports injuries;
- Motor vehicle accidents;
- Whiplash associated injuries;
- Hyperextension injuries;
- Strain from repetitive or continuous muscle activation;
- Bruxism and other parafunctional behaviors.
7. Treatment Considerations
8. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Preclinical Studies | ||
---|---|---|
Author | Model | Findings |
Cady et al. [15] | TMJ capsule | Injection of CGRP in the TMJ capsule stimulated the expression of proteins associated with peripheral and central sensitization in neuronal and glial cells in animal models. |
Fiorentino et al. [64] | Osteoarthritis in a mouse model | CGRP-induced neuroinflammation contributed to histopathological modifications of the articular tissues (i.e., cartilage), leading to osteoarthritis in a mouse model. |
Lai et al. [65] | TMJ of mouse model | Inhibition of CGRP-mediated neuroinflammation curbed the progression of TMJ damage. |
Akerman et al. [59] | Rat model of myofascial TMD-like inflammation | Models of TMD-like inflammation resulted in neuronal activation and sensitization of dural trigeminal neurons, similar to migraine-like manifestation. Pre-administration of CGRP receptor antagonist effectively prevented these neuronal responses. |
Brouxhon et al. [66] | TMJ of mouse model | The overexpression of CGRP in mouse models of TMJ led to the manifestation of joint anomalies and articular pathology; conversely, in a scenario of joint inflammation, the overexpression of CGRP inhibitory peptide partially led to improvement of joint pathology. |
Shu et al. [67] | Myogenic TMD mice model | The presence of pre-existing myogenic TMD lesions caused increased central CGRP release and enhanced migraine hypersensitivity in animal models. |
Damico et al. [68] | Acute and chronic arthritis model | Both acute and chronic arthritis were associated with significant increases in CRGP expression in the trigeminal ganglion in animal models. |
Suttle et al. [69] | Mouse model | In naïve mouse models, the local injection of CGRP in masseters and/or TMD induced acute pain. Conversely, blockage of CGRP receptor decreased TMD pain. |
Romero-Reyes et al. [70] | Mouse model of acute masseter pain | Selective CGRP receptor antagonist, MK-8825, was found to significantly reduce spontaneous orofacial pain behaviors in a mouse model of acute masseter pain injected with CFA. This study also supported the role of CGRP as an important neurotransmitter involved in TMD pain, although not through an inflammatory mechanism. |
Clinical studies | ||
Sato et al. [44] | TMJ pain vs. healthy control | Human subjects exhibited a significantly higher level of CGRP in deranged TMJ joints vs. healthy controls, with CGRP levels that are positively correlated with pain intensity scores. |
Intervention | Scientific Basis | Description |
---|---|---|
Self-management training | Systematic reviews of behavioral therapies | Nutritional and dietary intervention Preventive medicine counseling Habit-reversal Mindfulness-based stress reduction Meditation and relaxation |
Intra-oral splints | Systematic reviews of intra-oral splints | Full coverage stabilization at night Repositioning splints at night Immediate quick splints short-term Anterior bite plane short-term |
Medications | Systematic reviews of medications | Migraine medication NSAIDs Acetaminophen Tricyclic medications Muscle relaxants |
Physical therapies | Systematic review evidence of therapeutic exercises | Therapeutic exercises Mobilization |
Nutritional Supplement | Scientific Rigor | N Participants | Findings |
---|---|---|---|
Coenzyme Q10 | Double-blind placebo-controlled RCT [92] | 45 female adults with migraine | Significant reduction in frequency (p = 0.018), headache intensity (p = 0.001) and duration (p = 0.012) compared to controls |
Open-label match-controlled trial [90] | 80 adults with migraine | Significant reduction in frequency of monthly attacks (p < 0.001) and headache severity (p < 0.001) compared to controls | |
Crossover double-blind placebo-controlled RCT [91] | 120 children and adolescents with migraine | Greater improvement in migraine frequency in the initial 1–4 weeks | |
Double-blind RCT [100] | 42 adults with migraine | Significant decrease in attack frequency, headache-days and responder rate (47.6% vs. 14.4% in controls) | |
Nano-curcumin and coenzyme Q10 | Double-blind placebo-controlled RCT [93] | 100 adults with migraine | Significant reduction in headache frequency, severity and duration in participants treated with nano-curcumin and coenzyme Q10 (p < 0.001) |
L-carnitine and coenzyme Q10 | Double-blind placebo-controlled RCT [94] | 56 adults with migraine | Significant reduction in headache intensity (p < 0.001), duration (p < 0.001), frequency (p < 0.001) and headache diary results (p < 0.001) |
L-carnitine, magnesium and magnesium-L-carnitine | Single-blind RCT | 133 adults with migraine | Magnesium supplementation achieved significantly higher reduction in headache frequency compared to the other groups (p = 0.008); significant reduction in migraine symptoms in all study groups with no difference among them |
Curcumin | Double-blind placebo-controlled RCT [95] | 44 female adults with migraine | Significant reduction in headache intensity (p = 0.001) and duration (p = 0.007); no significant reduction in headache frequency (p = 0.052) |
Vitamin D | Double-blind placebo-controlled RCT [96,101] | 80 adults with migraine | Significant reduction in migraine disability (p = 0.016), headache duration, intensity and frequency (p < 0.05) compared to controls |
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Sangalli, L.; Eli, B.; Mehrotra, S.; Sabagh, S.; Fricton, J. Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches. Int. J. Mol. Sci. 2023, 24, 12200. https://doi.org/10.3390/ijms241512200
Sangalli L, Eli B, Mehrotra S, Sabagh S, Fricton J. Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches. International Journal of Molecular Sciences. 2023; 24(15):12200. https://doi.org/10.3390/ijms241512200
Chicago/Turabian StyleSangalli, Linda, Bradley Eli, Sachi Mehrotra, Suzan Sabagh, and James Fricton. 2023. "Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches" International Journal of Molecular Sciences 24, no. 15: 12200. https://doi.org/10.3390/ijms241512200