Expression of melatonin receptors in trigeminal and sphenopalatine ganglia: potential targets for primary headache disorders

BACKGROUND: Primary headache disorders such as migraine and cluster headache exhibit circadian and circannual variations in attack onset. Melatonin plays a central role in regulating biological rhythms and likely influences the timing of headache attacks. Recent evidence suggests melatonin may be a promising treatment for migraine and cluster headache; however, underlying mechanisms need to be elucidated. Because of the importance of the trigeminovascular system (TVS) and trigeminal-parasympathetic ganglia in these disorders, we proposed that melatonin receptors (MT1 and MT2) are expressed in these pathways. METHODS: The trigeminal ganglion (TG), sphenopalatine ganglion (SPG), dorsal root ganglion (DRG), basilar artery, dura mater and hypothalamus were dissected from adult male and female rats. RT-qPCR and immunohistochemistry were used to assess the expression of mRNA and protein, respectively, for melatonin MT1 and MT2 receptors. RESULTS: Immunohistochemical analysis showed MT1 and MT2 were differentially expressed in the TG, SPG and DRG. MT1 was widely distributed in the cytoplasm and nuclei of neurons and satellite glial cells (SGCs) in the TG, while MT2 localized mainly in the cytoplasm of neurons and Aδ-fibers. Both MT1 and MT2 co-localized with CGRP and the CGRP receptor component RAMP1. MT2 immunoreactivity was also found in Aδ-fibers throughout the dura mater and was co-expressed with Contactin-associated protein 1(CASPR) at the paranodal regions of Aδ-fibers. No significant sex differences were found in receptor expression in the TG, although mRNA levels of MT1 were approximately twice as high as those for MT2. In SPG, both receptors co-localized with the neuropeptides VIP and PACAP. In cerebral arteries, only MT1 was detected, and it was localized mainly in endothelial and smooth muscle cells. CONCLUSIONS: This study demonstrates that MT1 and MT2 receptors are expressed in the TVS and SPG, key components involved in migraine and cluster headache. Melatonin receptor co-localization with neuropeptides involved in autonomic and sensory neuronal regulation supports a potential mechanism by which melatonin influences headache onset and progression. Together, these findings support a role for melatonin influences in primary headache pathophysiology and point to its potential for novel headache treatment.