Involvement of the histaminergic system in the nociceptin-induced pain-related behaviors in the mouse spinal cord

Intrathecal (i.t.) injection of nociceptin elicited a behavioral response mainly consisting of biting and licking, which were eliminated by the i.t. co-administration of opioid receptor-like-1 (ORL-1) receptor antagonists. The behavioral response induced by nociceptin was characteristically similar to that by i.t.-administered histamine, and was attenuated by i.t. co-administration of the H ₁ receptor antagonists, but not by the H ₂ receptor antagonists, whereas the H ₃ receptor antagonist promoted the nociceptin-induced behavior. H ₁ receptor knockout (H ₁R-KO) mice did not show the nociceptin-induced nociceptive behavior, which was observed in wild-type mice. Pretreatment with a histamine antiserum or a histidine decarboxylase inhibitor resulted in a significant reduction of the response to nociceptin. The previous studies showed that NK ₁ receptor antagonists and a novel substance P (SP)-specific antagonist given i.t. could reduce the behavioral response to nociceptin and histamine. On the other hand, the nociceptive response induced by nociceptin, but not histamine, was completely attenuated by the i.t. co-administration of agonists for GABA _A and GABA _B receptors. In contrast, the antagonists for GABA _A and GABA _B receptors injected i.t. showed same nociceptive response with nociceptin and histamine, and their nociceptive responses were significantly blocked by the i.t. co-administration of the H ₁ receptor antagonists, but not H ₂ receptor antagonists or ORL-1 receptor antagonists. The present results suggest that the activation of the ORL-1 receptor by nociceptin may induce the disinhibition of histaminergic neuron and enhance the release of histamine, which subsequently acts on the H ₁ receptor located on the SP-containing neurons to produce the spinal cord-mediated nociceptive response.