Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in μ-opioid receptor knockout mice

Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of mu-, delta-, and kappa-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous m- opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type mu-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the d- selective opioid antagonist naltrindole or the kappa-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial delta-, mu-, and kappa-agonist, support the ideas that mu-opioid receptors mediate most of analgesic properties of buprenorphine, but that mu- and delta- and/or kappa-opioid receptors are each involved in the rewarding effects of this drug.