title: Role of the peripheral heme oxygenase-carbon monoxide pathway on the nociceptive response of rats to the formalin test: evidence for a cGMP signaling pathway.
abstract: The aim of the present study was to investigate the role of the peripheral heme oxygenase (HO)-carbon monoxide (CO) pathway on nociceptive response of rats to the formalin experimental model of pain. Animals were handled and adapted to the experimental environment for a few days before the formalin test was applied. For the formalin test, 50 microl of a 1% formalin solution was used and injected subcutaneously in the dorsal surface of the right hind paw. Following injections, animals were observed for 1 h, and flinching behavior was measured as the nociceptive response. Twenty minutes before the test rats were pretreated with podal injections with the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is known to induce the HO pathway. Control animals were treated with vehicles. We observed a significant increase on nociceptive response of rats treated with ZnDPBG, and a drastic reduction of flinching nociceptive behavioral response in the heme-lysinate and CO treated animals. Among the three different HO products, CO seems to account for the heme-lysinate effect because the injection of the gas attenuated the flinching response whereas biliverdine and deferoxanine (an iron chelator) failed to cause any significant change. Furthermore, CO seems to act via cGMP, since methylene blue (a soluble guanylate cyclase inhibitor) prevented the reduction of the flinching nociceptive behavioral response caused by heme-lysinate. These findings strongly indicate that CO is the HO pathway product that plays an antinociceptive role during the formalin test, acting via cGMP.
authors.affiliation: Department of Physiology, Medical School of Ribeirão Preto, and Dental School of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: Carlos G O
authors.initials: CG
authors.lastname: Nascimento
authors.forename: Luiz G S
authors.initials: LG
authors.lastname: Branco
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000494:pharmacology; D002248:Carbon Monoxide / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology; D003905:Deuteroporphyrins / Q000494:pharmacology; D006418:Heme / Q000031:analogs & derivatives / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D003905:Deuteroporphyrins; D007502:Iron Chelating Agents; C106087:heme lysinate; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D006418:Heme; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP; D003676:Deferoxamine; D008239:Lysine; D001664:Biliverdine