The peripheral antinociceptive effect induced by the heme oxygenase/carbon monoxide pathway is associated with ATP-sensitive K+ channels

Carbon monoxide (CO), a product of the enzyme heme oxygenase (HO), has been recognized to act as an atypical neurotransmitter or neuromodulator in the nervous system, and several lines of evidence suggest that CO may play a role through multiple mechanisms in nociceptive processing. Therefore, the aim of our study was to assess the interaction between the HO/CO pathway and ATP-sensitive K+ channels in hypernociception in response to carrageenan. The electronic von Frey and Randall Selitto tests were applied before and after intraplantar carrageenan administration. The intraplantar hemin carrageenan administration (HO substrate) into the right hindpaw elicited an antinociceptive effect, which was determined to be local because it produced no effect when injected into the contralateral paw. The administration of a HO pathway inhibitor was capable of potentiating the hypersensitivity evoked by carrageenan. Among the three different HO products, CO appears to be the one that attenuated the nociceptive response, whereas biliverdin and iron (II) sulfate failed to cause any significant changes. This blockade of the carrageenan mechanical hyperalgesia induced by the hemin was antagonized by the administration of glybenclamide, and a combination of hemin and diazoxide decreased the hyperalgesic action of carrageenan. These results also suggest that an endogenous opioid system may not be involved because naloxone did not affect the hemin-induced antinociception in the carrageenan model. Our study provides evidence that the peripheral antinociceptive effect of the HO/CO pathway may result from the activation of ATP-sensitive K+ channels.