title: The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K⁺ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats.
abstract: Crotalphine, a 14 amino acid peptide first isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces a peripheral long-lasting and opioid receptor-mediated antinociceptive effect in a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. In the present study, we further characterized the molecular mechanisms involved in this effect, determining the type of opioid receptor responsible for this effect and the involvement of the nitric oxide-cyclic GMP pathway and of K⁺ channels. Crotalphine (0.2 or 5 μg/kg, orally; 0.0006 μg/paw), administered on day 14 after nerve constriction, inhibited mechanical hyperalgesia and low-threshold mechanical allodynia. The effect of the peptide was antagonized by intraplantar administration of naltrindole, an antagonist of δ-opioid receptors, and partially reversed by norbinaltorphimine, an antagonist of κ-opioid receptors. The effect of crotalphine was also blocked by 7-nitroindazole, an inhibitor of the neuronal nitric oxide synthase; by 1H-(1,2,4) oxadiazolo[4,3-a]quinoxaline-1-one, an inhibitor of guanylate cyclase activation; and by glibenclamide, an ATP-sensitive K⁺ channel blocker. The results suggest that peripheral δ-opioid and κ-opioid receptors, the nitric oxide-cyclic GMP pathway, and ATP-sensitive K⁺ channels are involved in the antinociceptive effect of crotalphine. The present data point to the therapeutic potential of this peptide for the treatment of chronic neuropathic pain.
authors: Special Laboratory of Pain and Signaling, Butantan Institute, University of São Paulo, São Paulo, SP, Brazil.
authors: Vanessa P
authors: VP
authors: Gutierrez
authors: Vanessa O
authors: VO
authors: Zambelli
authors: Gisele
authors: G
authors: Picolo
authors: Marucia
authors: M
authors: Chacur
authors: Sandra C
authors: SC
authors: Sampaio
authors: Patricia
authors: P
authors: Brigatte
authors: Katsuhiro
authors: K
authors: Konno
authors: Yara
authors: Y
authors: Cury
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D054086:KATP Channels / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D009569:Nitric Oxide / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000700:Analgesics; D054086:KATP Channels; D010455:Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C533006:crotalphine; D009569:Nitric Oxide; D001120:Arginine; D006152:Cyclic GMP