Antihyperalgesic effects of cizolirtine in diabetic rats: behavioral and biochemical studies.
Although clinically well controlled at the metabolic level, type I diabetes resulting from an insufficient insulin secretion remains the cause of severe complications. In particular, diabetes can be associated with neuropathic pain which fails to be treated by classical analgesics. In this study, we investigated the efficacy of a novel non opioid analgesic, cizolirtine, to reduce mechanical hyperalgesia associated with streptozotocin (STZ)-induced diabetes, in the rat. Cizolirtine was compared to paroxetine, an antidepressant drug with proven efficacy to relieve painful diabetic neuropathy. Under acute conditions, cizolirtine (30 and 80 mg/kgi.p.) significantly increased paw withdrawal and vocalization thresholds in the paw pressure test in diabetic rats displaying mechanical hyperalgesia. The antihyperalgesic effects of cizolirtine persisted under chronic treatment conditions, since pre-diabetes thresholds were recovered after a two week-treatment with the drug (3 mg/kg/day, s.c.). In this respect, cizolirtine was as efficient as paroxetine (5 mg/kg per day, s.c.) which, however, was inactive under acute treatment conditions. Measurements of the spinal release of calcitonin gene-related peptide (CGRP) through intrathecal perfusion under halothane-anesthesia showed that acute administration of cizolirtine (80 mg/kg, i.p.) significantly diminished (-36%) the peptide outflow in diabetic rats suffering from neuropathic pain. This effect as well as the antihyperalgesic effect of cizolirtine were prevented by the alpha(2)-adrenoreceptor antagonist idazoxan (2 mg/kg, i.p.). These data suggest that the antihyperalgesic effect of cizolirtine in diabetic rats suffering from neuropathic pain implies an alpha(2)-adrenoceptor-dependent presynaptic inhibition of CGRP-containing primary afferent fibers.
INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris cedex 13, France. aubel@ext.jussieu.fr
Bertrand
B
Aubel
Valérie
V
Kayser
Annie
A
Mauborgne
Antonio
A
Farré
Michel
M
Hamon
Sylvie
S
Bourgoin
D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004347:Drug Interactions; D038321:Glycemic Index / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D017374:Paroxetine / Q000494:pharmacology; D011720:Pyrazoles / Q000627:therapeutic use*; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D011720:Pyrazoles; D017374:Paroxetine; D013311:Streptozocin; D015740:Calcitonin Gene-Related Peptide; C075798:cizolirtine; D019329:Idazoxan