On deriving the dose-effect relation of an unknown second component: an example using buprenorphine preclinical data.
Buprenorphine, like many other drugs, displays a biphasic dose-response relation ('hormesis'), viz., its antinociceptive effect in some preclinical models increases up to some dose level (often achieving 100% effect) and decreases at high-doses. A decreasing component was evident in the tail-flick tests described here, occurring in both the mouse and the rat. While the mechanism of dose-related decline in antinociceptive effect, when observed, might be related to nociceptin/orphanin-FQ, the precise mechanism remains unknown. Regardless of the mechanism, the values of this dose-related decline yield data that can be used to calculate the dose-effect relation of the decreasing (unknown second) component. The calculation, which uses the same concept of dose equivalence that underlies additivity in isobolographic analysis, was employed here from tail-flick data obtained in mouse and rat. The derived dose-effect curves of the second component, though differing in efficacy between mouse and rat, displayed a very notable similarity. This novel technique offers possible insight into the dual low-dose (analgesic), high-dose (addiction medication) uses of buprenorphine.
Tallarida
Ronald J
RJ
Department of Pharmacology, Temple University School of Medicine and Center for Substance Abuse Research, 3420 N. Broad Street, Philadelphia, PA 19140, United States. ronald.tallarida@temple.edu
Cowan
Alan
A
Raffa
Robert B
RB
D000465:Algorithms; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002047:Buprenorphine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007101:Immersion; D007279:Injections, Subcutaneous; D051379:Mice; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D013045:Species Specificity
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D002047:Buprenorphine