Contribution of spinal inhibitory receptors in heterosegmental antinociception induced by noxious stimulation

Noxious (i.e. painful) stimulation in the rat induces profound heterosegmental antinociception as demonstrated by the ability of either thermal stimulation (50 degrees C water) or subdermal capsaicin injection in the hindpaw to attenuate the nociceptive trigeminal jaw-opening reflex. Importantly, noxious stimulus-induced antinociception (NSIA) is mediated by endogenous opioids (as well as other neurotransmitters) in nucleus accumbens, as indicated by the ability of intra-accumbens administration of mu- or delta-opioid receptor antagonists to block NSIA. Although noxious peripheral stimulation is known to release excitatory neurotransmitters such as glutamate at the level of the spinal cord, the present study was designed to test the hypothesis that NSIA depends on further activation of spinal inhibitory receptors. This hypothesis was based on findings that inhibition of spinal processing (e.g. intrathecal local anaesthetic administration) also produces heterosegmental antinociception mediated by endogenous opioids in nucleus accumbens. Thus, to reconcile the paradoxical findings that both spinal excitation and inhibition appear to activate the same nucleus accumbens opioid-mediated antinociceptive mechanism, we investigated whether spinal administration of antagonists for inhibitory receptors would block the antinociceptive effect of subdermal capsaicin. We report that spinal administration of selective antagonists for mu-opioid (Cys2, Tyr3, Orn5, Pen7amide), kappa-opioid (nor-binaltorphimine), GABA-A (bicuculline), GABA-B (CGP 35348) and glycine (strychnine) receptors significantly reduced NSIA. The selective delta-opioid receptor antagonist naltrindole had no significant effect. These results, together with our previous findings, suggest that peripheral noxious stimuli release endogenous opioids, GABA and glycine in the spinal cord which, in turn, inhibit tonic pronociceptive spinal activity to produce heterosegmental antinociception mediated in nucleus accumbens.