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.
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.
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.
Benoît
B
Michot
Sylvie
S
Bourgoin
Florent
F
Viguier
Michel
M
Hamon
Valérie
V
Kayser
D051700:Activating Transcription Factor 3 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy*; D015850:Interleukin-6 / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008442:Maxillary Nerve / Q000293:injuries / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D010879:Piperazines; D010880:Piperidines / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D045442:Rotarod Performance Test; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use; D014363:Tryptamines / Q000627:therapeutic use
D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D015415:Biomarkers; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides; D015850:Interleukin-6; D010879:Piperazines; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D012333:RNA, Messenger; D018015:Receptors, Calcitonin Gene-Related Peptide; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; C106783:naratriptan; C406305:olcegepant