Dynorphin Promotes Comorbid Migraine-like Pain in Female Mice with Temporomandibular Joint Disorders
Date
2020-07-16
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Abstract
Migraine is a prevailing type of neurological disorder and is frequently found coexisting with temporomandibular disorders (TMD) in the same individual, especially in the patients with myogenic TMD. Both conditions have a higher prevalence in women than in men. Despite the economic burden and health adverse effects caused by migraine and TMD, the complex pathophysiologic mechanisms underlying the coexisting of migraine and TMD are still not well studies and remain elusive.
In the present study, we first employed masseter muscle tendon ligation (MMTL) procedure to generate a myogenic TMD model in mice, later we found this MMTL injury can promote the occurrence of the nitroglycerin (NTG)-induced migraine-like hypersensitivity and prolong this hypersensitivity after the onset. We characterized this MMTL-enhanced migraine-like hypersensitivity model with measuring the mechanical head withdrawal threshold in masseter and periorbital area, gnawing dysfunction, and light-aversive behavior.
Using this MMTL-enhanced migraine-like hypersensitivity model, we found Prodynorphin (Pdyn) gene and its translated product dynorphin A (dynA) peptide in the spinal trigeminal nucleus caudalis (Sp5C) play critical role in promoting the onset of migraine post-MMTL injury in female mice, but not in male mice. The projection of Pdyn-expressing excitatory neurons inside Sp5C, from the mandibular (V3) area to the ophthalmic (V1) area, explains how the MMTL injury happened in masseter area (innervated by trigeminal nerve V3 branch) has an effect on the nociception in periorbital area (innervated by trigeminal nerve V1 branch).
In the further study, we found that instead of interacting with the traditional believed dynA receptor - kappa opioid receptor, dynA carried out its effect in the MMTL-enhanced migraine-like hypersensitivity by interacting with bradykinin receptor B2 (BKRB2) and N-methyl-D-aspartate (NMDA) receptors. BKRB2 regulates this periorbital hypersensitivity by trafficking to plasma membrane, decreasing BKRB2-neuronal NOS (nNOS) binding and subsequently increases nNOS enzyme activity, thereby promoting the production of neurotoxic nitric oxide (NO). NMDA receptors also enhances nNOS activity level, but through NMDA receptor-PSD95-nNOS complex signaling pathway.
In summary, the present study suggests that dynA peptide promotes comorbid migraine in specifically female TMD mice, but not male mice, through interacting with BKRB2 and NMDA receptors.
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Keywords
TMD, migraine, dynorphin, Sp5C