Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with κ₃ analgesia

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially κ₃ in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose-response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for κ₃ and μ receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated κ₁ mechanisms of action. We did not detect any involvement of the 5 receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with κ₃ receptors and to a lesser extent with κ₁ as well as its activity as partial μ receptor agonist.