Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat

Abstract

Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3mg/kg, subcutaneously), olcegepant (0.3 to 0.9mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3mg/kg intravenously) plus naratriptan (0.1mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.

A systematic review of animal models for experimental neuroma

“…38 In a previous study, they also measured ground reaction forces (GRFs) 'to determine the contribution of each limb to weight support, propulsion, braking, and balance during locomotion'. The sciatic functional index (SFI) described by de Medinaceli in 1982 73 is an easy, inexpensive and reliable method still in use, 43 which evaluates the print marks of both feet. Its assessment can be hindered by the dragging of the tail and by flexion contracture or autotomy.…”

Targeting CGRP: A New Era for Migraine Treatment

“…CGRP is thought to play an important role in these neuroadaptive changes, including increase in its expression at the trigeminal primary afferent neurons [113]. Olcegepant significantly reduced mechanical allodynia induced by infraorbital nerve ligation in animal models [114]. Similarly, another CGRP-RA (a-CGRP ) produced reversal of periorbital and hind paw sensitivity to light tactile stimuli [112].…”

The Role of Different Methods of Nerve Ablation in Prevention of Neuroma

“…8,9 Calcitonin gene-related peptide is responsible for maintenance of neuropathic pain, and is an assay of mechanical allodynia. 10,11 Thus, it is expected to be increased in neuromas. Quantification of mRNA was performed using Roche Sybr Green I Supermix (Roche, Indianapolis, Ind.)…”