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

Michot, Benoît*; Bourgoin, Sylvie; Viguier, Florent; Hamon, Michel; Kayser, Valérie

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doi: 10.1016/j.pain.2012.06.009
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Summary Calcitonin gene-related peptide receptor blockade by olcegepant reduced mechanical allodynia induced by infraorbital nerve ligation but not that caused by sciatic nerve ligation in rats.

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 0.3 mg/kg, subcutaneously), olcegepant (0.3 to 0.9 mg/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 (0.3 mg/kg intravenously) plus naratriptan (0.1 mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6 mg/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.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

INSERM, UMR_S894, CPN, Neuropsychopharmacologie, Paris, France

UPMC University Paris 06, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, UMR_S894, 91, boulevard de l’Hôpital, Paris, France

Université Paris Descartes, Centre de Psychiatrie et Neurosciences, 91 Boulevard de l’Hôpital, Paris, France

*Corresponding author at: UMR_S894 INSERM-UPMC, CPN, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91, boulevard de l’Hôpital, 75634 Paris Cedex 13, France. Tel.: +33 1 4077 9709; fax: +33 1 4077 9790.

E-mail address:bemichot@yahoo.fr

Article history: Received 2 January 2012; Received in revised form 22 May 2012; Accepted 11 June 2012.

© 2012 Lippincott Williams & Wilkins, Inc.
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