Subgroups among μ‐opioid receptor agonists distinguished by ATP‐sensitive K+ channel‐acting drugs

Abstract

1 We evaluated the effects of the i.e.v. administration of different K+ channel blockers (gliquidone, 4‐aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several μ‐opioid receptor agonists in a tail flick test in mice. 2 The s.c. administration of all agonists of μ‐opioid receptors tested (morphine, 1–16 mg kg−1; methadone, 1–6 mg kg−1; buprenorphine, 0.04–0.64 mg kg−1; fentanyl, 0.02–0.32 mg kg−1 and levorphanol, 0.2–3.2 mg kg−1) elicited a dose‐dependent antinociceptive effect. 3 The ATP‐sensitive K+ channel blocker, gliquidone (0.06–16 μg per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and methadone. In contrast, gliquidone (0.25–160 μg per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4 Cromakalim (4–64 μg per mouse, i.c.v.), an opener of ATP‐sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5 The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 μg per mouse) or 4‐aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any μ‐opioid receptor agonist tested. 6 These results suggest that the opening of ATP‐sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among μ‐opioid receptor agonists, each inducing antinociception through different effector mechanisms. 1995 British Pharmacological Society