CLONIDINE POTENTIATES THE NEUROPATHIC PAIN-RELIEVING ACTION OF MK-801WHILE PREVENTING ITS NEUROTOXIC AND HYPERACTIVITY SIDE-EFFECTS

Antagonists of NMDA glutamate receptors have been shown to alleviate n europathic pain in rats and humans. However, NMDA antagonists can caus e significant side effects ranging from behavioral disturbances to inj ury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex . We have found that alpha-2 adrenergic agonists prevent the PC/RS neu rotoxic side effects of NMDA antagonists. In the present study of adul t female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a t hermal stimulus, we evaluated the ability of the NMDA antagonist, MK-8 01, to alleviate neuropathic pain either by itself or when administere d together with the alpha-2 adrenergic agonist, clonidine. We found th at MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyp eractivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve lig ation. However, the relief at this dose was very transient, and no neu ropathic pain-relieving effect was observed at a lower dose (0.025 mg/ kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that preven ts the cerebrocortical neurotoxic effects of MK-801, decreased sensiti vity to the thermal stimulus equally under all conditions (ligated, sh am ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ine ffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats recei ving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate exper iments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c .) and returned activity levels to a normal range. These findings sign ify that clonidine, which does not specifically relieve neuropathic pa in, can potentiate the neuropathic pain-relieving action of MK-801, wh ile also protecting against neurotoxicity and hyperactivity side effec ts of MK-801. The potentiation is of a sufficient magnitude that it pe rmits cutting the MK-801 dose requirement in half, thereby achieving p rolonged neuropathic pain relief while doubling the margin of safety a gainst any type of side effect that might be mediated by blockade of N MDA receptors. (C) 1998 Elsevier Science B.V.