title: A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain.
abstract: Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they do with migraine.
authors.affiliation: Orofacial Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA. Electronic address: mrr7@nyu.edu.
authors.forename: Marcela
authors.initials: M
authors.lastname: Romero-Reyes
authors.affiliation: Orofacial Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pardi
authors.affiliation: Headache Group, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Akerman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005157:Facial Pain / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D007839:Functional Laterality / Q000187:drug effects; D066298:In Vitro Techniques; D008406:Masseter Muscle / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D011725:Pyridines / Q000627:therapeutic use*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D013141:Spiro Compounds / Q000627:therapeutic use*; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016207:Cytokines; C575097:MK-8825; D016761:Oncogene Proteins v-fos; D011725:Pyridines; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds; D005620:Freund's Adjuvant
keywords: Anti-CGRP; CGRP; Muscle; Nociception; Orofacial; Pain; TMDs; Trigeminal