CGRP receptor blockade by MK-8825 alleviates allodynia in infraorbital nerve-ligated rats.

Abstract

Previous data showed that, in rats, anti-migraine drugs (triptans, olcegepant) significantly reduced mechanical allodynia induced by infraorbital nerve (ION) ligation but not that evoked by sciatic nerve (SN) ligation. Whether this also occurs with MK-8825, a novel anti-migraine drug also acting through CGRP receptor blockade (but chemically unrelated to olcegepant) was tested in the present study, which also investigated possible anti-neuroinflammatory effects of this drug. Adult male Sprague-Dawley rats underwent unilateral chronic constriction injury (CCI) to either the ION or the SN, and mechanical allodynia was assessed 2 weeks later within the ipsilateral vibrissae territory or hindpaw, respectively. Transcripts of neuroinflammatory markers were quantified by real-time quantitative RT-PCR in ipsilateral trigeminal ganglion and spinal trigeminal nucleus in CCI-ION rats. Acute as well as repeated (for 4 days) administration of MK-8825 (30-100 mg/kg, i.p.) significantly reduced CCI-ION-induced mechanical allodynia but was ineffective in CCI-SN rats. CCI-ION was associated with marked up-regulation of neuronal and glial inflammatory markers (ATF3, IL6, iNOS, COX2) in ipsilateral trigeminal ganglion but not spinal trigeminal nucleus. MK-8825-induced inhibition of iNOS mRNA up-regulation probably underlay its anti-allodynic effect because pharmacological blockade of iNOS by AMT (6 mg/kg, s.c.) mimicked this effect. These data further support the idea that CGRP receptor blockade might be a valuable approach to alleviate trigeminal, but not spinal, neuropathic pain through, at least partly, an inhibitory effect on neuropathic pain-associated increase in NO production in trigeminal ganglion.