PUTATIVE KAPPA-2 OPIOID AGONISTS ARE ANTIHYPERALGESIC IN A RAT MODEL OF INFLAMMATION

It has been demonstrated that kappa-2 opioid receptor agonists can inh ibit the current that flows through the N-methyl-D-aspartate (NMDA) su bclass of excitatory amino acid receptor. NMDA receptor antagonists ha ve been shown to be effective antihyperalgesic agents when administere d intrathecally into rats. Antihyperalgesia is defined as the ability to block enhanced sensitivity, usually produced by nerve injury or inf lammation, to nociceptive stimuli. Thus, the hypothesis was proposed t hat kappa-2 opioid receptor agonists would be antihyperalgesic when in jected intrathecally into rats with an inflamed hind paw. The kappa ag onists bremazocine and GR89,696 were effective at reversing the hypera lgesia associated with the inflamed hind paw but did not influence the sensitivity of the noninflamed hind paw to noxious heat. The kappa-1- selective agonist U69,593 had no effect on the heat sensitivity of eit her the inflamed paw or the noninflamed paw. Intrathecal injection of the mu-selective agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin or the delta-selective agonist [D-Pen(2,5)]enkephalin elevated paw withdr awal latencies to heat in both hind paws. These findings indicate that activation of presumed kappa-2 receptors in the rat spinal cord resul ts in suppression of the hyperalgesic state without influencing normal sensitivity to noxious stimuli. It is proposed that the anti-hyperalg esic effect of kappa-2 receptor activation is mediated by the ability of the opioid receptor to reduce the flow of current through the NMDA receptor ionophore.