PERIPHERAL COMPONENT IN THE ENHANCED ANTINOCICEPTIVE EFFECT OF SYSTEMIC U-69,593, A KAPPA-OPIOID RECEPTOR AGONIST IN MONONEUROPATHIC RATS

The contribution of a peripheral action of the K-opioid receptor agoni st U-69,593 (trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloex il] benzene-acetamide methanesulfonate) in the augmented antinocicepti ve effect of this substance was investigated in a well-established rat model of peripheral unilateral neuropathy (chronic constriction of th e common sciatic nerve). Relatively low dose of systemic U-69,593 (0.7 5 mg/kg intravenous (i.v.)) and intraplantar (i.pl.) low doses of spec ific antagonists of kappa-(nor-binaltorphimine) or mu-(D-Phe-Cys-Tyr-D -Trp-Orn-Thr-Pen-Thr-NH2: CTOP) opioid receptors were used. Vocalizati on thresholds to paw pressure were used as a nociceptive test. The i.p l. injection of nor-binaltorphimine (10-15 mu g injected into the nerv e-injured hind paw) had no effect on the antinociceptive effect of U-6 9,593. Higher doses (20-30 mu g i.pl. nor-binaltorphimine) significant ly reduced the effect of U-69,593 on this paw hut not on the contralat eral paw, an effect which plateaued at 30 mu g. By contrast, the i.pl. injection of CTOP (1 mu g into the nerve-injured paw) had no effect o n U-69,593 antinociception, whereas it reduced the effect of systemic morphine in these animals. The doses of nor-binaltorphimine used, inje cted into the contralateral paw or i.v., failed to modify the antinoci ceptive effects of U-69,593 on either paw. These results provide evide nce for a peripheral component in the enhanced antinociceptive effect of systemic U-69,593 in this model of neuropathic pain. (C) 1998 Elsev ier Science B.V. All rights reserved.