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NEUROPHARMACOLOGY

Buprenorphine Blocks - and µ-Opioid Receptor-Mediated Antinociception in the Mouse

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (H.M., A.S., R.L., H.-E.W., L.F.T.); and Pharmaceutical Research Laboratory, Toray Industries Inc., Kamakura, Japan (H.N.)

Antagonistic properties of buprenorphine for - and µ-opioid receptors were characterized in -endorphin- and [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO)-induced antinociception, respectively, with the tail-flick test in male ICR mice. -Opioid receptor agonist -endorphin (0.1–1 µg), µ-opioid receptor agonist DAMGO (0.5–20 ng), or buprenorphine (0.1–20 µg) administered i.c.v. dose dependently produced antinociception. The antinociception induced by 10 µg of buprenorphine given i.c.v. was completely blocked by the pretreatment with -funaltrexamine (-FNA) (0.3 µg i.c.v.), indicating that the buprenophine-induced antinociception is mediated by the stimulation of the µ-opioid receptor. The antinociceptive effects induced by -endorphin (1 µg i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by pretreatment with smaller doses of buprenorphine (0.001–1 µg i.c.v.), but not by a higher dose of buprenorphine (10 µg i.c.v.). -FNA at a dose (0.3 µg i.c.v.) that strongly attenuated DAMGO-induced antinociception had no effect on the antinociception produced by -endorphin (1 µg i.c.v.). However, pretreatment with buprenorphine (0.1–10 µg) in mice pretreated with this same dose of -FNA was effective in blocking -endorphin-induced antinociception. -FNA was 226-fold more effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.) than by -endorphin (1 µg i.c.v.). The antinociception induced by -opioid receptor agonist [D-Ala²]deltorphin II (10 µg i.c.v.) or ₁-opioid receptor agonist trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine methanesulfonate salt [(–)-U50,488H] (75 µg i.c.v.) was not affected by pretreatment with buprenorphine (0.1–1.0 µg i.c.v.). It is concluded that buprenorphine, at small doses, blocks -opioid receptor-mediated -endorphin-induced antinociception and µ-opioid receptor-mediated DAMGO-induced antinociception, and at high doses produces a µ-opioid receptor-mediated antinociception.

Address correspondence to: Dr. Leon F. Tseng, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ltseng{at}mcw.edu