Peripheral component in the enhanced antinociceptive effect of systemic U-69,593, a κ-opioid receptor agonist in mononeuropathic rats

Abstract

The contribution of a peripheral action of the κ-opioid receptor agonist U-69,593 ( trans-3,4-dichloro- N-methyl- N-[7-(1-pyrrolidinyl) cycloexil] benzene-acetamide methanesulfonate) in the augmented antinociceptive effect of this substance was investigated in a well-established rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Relatively low dose of systemic U-69,593 (0.75 mg/kg intravenous (i.v.)) and intraplantar (i.pl.) low doses of specific antagonists of κ-(nor-binaltorphimine) or μ-( d-Phe-Cys-Tyr- d-Trp-Orn-Thr-Pen-Thr-NH 2: CTOP) opioid receptors were used. Vocalization thresholds to paw pressure were used as a nociceptive test. The i.pl. injection of nor-binaltorphimine (10–15 μg injected into the nerve-injured hind paw) had no effect on the antinociceptive effect of U-69,593. Higher doses (20–30 μg i.pl. nor-binaltorphimine) significantly reduced the effect of U-69,593 on this paw but not on the contralateral paw, an effect which plateaued at 30 μg. By contrast, the i.pl. injection of CTOP (1 μg into the nerve-injured paw) had no effect on U-69,593 antinociception, whereas it reduced the effect of systemic morphine in these animals. The doses of nor-binaltorphimine used, injected into the contralateral paw or i.v., failed to modify the antinociceptive effects of U-69,593 on either paw. These results provide evidence for a peripheral component in the enhanced antinociceptive effect of systemic U-69,593 in this model of neuropathic pain.