Effects and mechanisms of opioidergic system modulation on pain and neurogenic inflammation in experimental models of migraine

The present study investigated the effect of endogenous opioid system modulation via spinorphin, a natural enkephalinase inhibitor, on migraine-related mechanisms in in-vivo and ex-vivo migraine models. In the in-vivo experimental groups, an acute migraine model was established by intraperitoneal administration of 10 mg/kg nitroglycerin (NTG). At 90 minutes after NTG injection, saline, low (0.5 mg/kg) and high (5 mg/kg) doses of spinorphin, opioid receptor antagonist nalmefene (1 mg/kg) and sumatriptan (600 μg/kg) were administered separately or together according to the groups. Capsaicin (100 nM) was applied to induce calcitonin gene-related peptide (CGRP) release in ex-vivo hemiskull preparations. The effect of spinorphin (100 μM) and other drugs tested in in-vivo groups on CGRP release in hemiskull preparations was tested. Mechanical hyperalgesia was determined by von-Frey test and the number and degranulation of meningeal mast cells were determined by toluidine-blue staining. CGRP and c-Fos levels were analyzed by ELISA. One-way ANOVA was used to analyze in-vivo data and repeated measures ANOVA was used to analyze ex-vivo data. In in-vivo experiments, spinorfin reduced the levels of NTG-induced hyperalgesia, meningeal mast cell activation, CGRP release and c-fos expression (p<0.001). Nalmefene blocked the effects of spinorphin, thus confirming that spinorphin exerts these effects by activating the endogenous opioid system (p<0.05). In ex-vivo hemiskull preparations, spinorphin reduced capsaicin-induced CGRP release (P<0.01), while nalmefene blocked the effect of spinorphin. Sumatriptan inhibited NTG-induced effects in in-vivo experiments (P<0.001) and the effect of capsaicin in ex-vivo experiments (P<0.05). Spinorphin showed antinociceptive effects in experimental migraine models by reducing CGRP and mast cell activation, components of neurogenic inflammation. These results suggest that spinorphin has promising potential to improve migraine headache by increasing the level of enkephalins, one of the opioids that are the body's natural painkillers.