Examination of the preclinical antinociceptive efficacy of buprenorphine and its designation as full- or partial-agonist

Summary: The terminology used to characterize agonist action in preclinical studies requires careful application based on fundamental concepts of receptor theory. Especially important in this regard are the terms ‘intrinsic activity’, ‘efficacy’ and ‘full-’ or ‘partial-’ agonist. Failure to apply or interpret these terms properly can lead to erroneous prediction or perception of a compound''s clinical utility. This is illustrated here in reporting our recent antinociceptive studies with buprenorphine. Buprenorphine has been classified in some preclinical studies as a ‘partial agonist’, but there is now clear evidence using PET technology that buprenorphine can produce analgesia at less than full receptor occupancy, the definition of a ‘full agonist’, and that its analgesic effectiveness extends to cancer and neuropathic pain. We measured buprenorphine-induced antinociceptive time-course and dose-response curves in the same test (tail-dip/flick in mice) at three stimulus intensities: 48, 55, and 65°C. Buprenorphine antinociception was inversely related to stimulus intensity, producing 100% antinociception at 48°C. The dose-response curve was curvilinear (bell-shaped) at each temperature. The current results demonstrate the necessity of defining threshold criteria with the use of the term ‘full agonist’ and, more generally, highlight the importance of careful and accurate use of, and predictions based upon, the terms ‘intrinsic activity’, ‘efficacy’, and ‘full-’ or ‘partial-’ agonist. [Copyright &y& Elsevier]