Spinorphin Ameliorates Nitroglycerin-Induced Migraine-Like Responses and Trigeminovascular Neuroinflammation Potentially Through Opioid Receptor-Mediated Mechanisms.

Enhancement of endogenous opioid signaling through inhibition of enkephalin degradation has emerged as a potential strategy for pain control, yet its role in migraine remains unclear. This study investigated whether spinorphin, an endogenous inhibitor of multiple enkephalinases, attenuates trigeminovascular activation and migraine-like responses in experimental migraine. Migraine-like pain was induced in male Wistar rats by nitroglycerin. The effects of spinorphin were evaluated using periorbital and plantar von Frey tests, followed by assessment of c-Fos levels in the trigeminal nucleus caudalis (TNC), calcitonin gene-related peptide (CGRP) levels in the trigeminal ganglion (TG) and TNC, and meningeal mast cell degranulation. Opioid receptor involvement was examined using nalmefene. In complementary ex vivo hemiskull preparations, capsaicin-evoked CGRP release was quantified, and the interaction between spinorphin and sumatriptan was investigated. Spinorphin dose-dependently alleviated cephalic and extracephalic mechanical hypersensitivity, reduced c-Fos levels, decreased CGRP concentrations in the TG and TNC, and inhibited meningeal mast cell degranulation. These protective effects were markedly attenuated by nalmefene, supporting the involvement of opioid receptor-mediated mechanisms. In ex vivo preparations, spinorphin selectively reduced capsaicin-induced CGRP levels in the superfusates without affecting basal CGRP levels, and this effect was abolished by nalmefene. Moreover, spinorphin enhanced the inhibitory effect of sumatriptan on capsaicin-stimulated CGRP levels. Spinorphin attenuates behavioral, neurochemical, and neuroinflammatory features of experimental migraine, at least partly through mechanisms involving endogenous opioid signaling. These findings suggest enkephalinase inhibition as a promising therapeutic approach for migraine and support further investigation of spinorphin as a potential adjunct to established antimigraine therapies.