title: Tramadol and dihydroetorphine produce synergistic analgesic effect and postpones acute opiate tolerance in rats.
abstract: The present study investigated whether a co-application of tramadol (TRA) and dihydroetorphine (DHE) would exert a synergy in analgesic effect and delay acute tolerance development. Intraperitoneal injection of TRA (in mg) and subcutaneous injection of DHE (in ng) were delivered in fixed proportions (1:6.25, 1:12.5, 1:25, 1:50, 1:100, and 1:200). The effect of analgesia was accessed by tail-flick test and analyzed with isobolographic analysis. For test of acute tolerance, six successive injections of either TRA (20 mg/kg) alone, DHE (1 000 ng/kg) alone, or a combination of TRA (20 mg/kg) and DHE (250 ng/kg) were administered. We found that (1) except for 1 mg : 6.25 ng and 1 mg : 50 ng, combinations, all the other ratios produced a significant synergy in their analgesic effect; (2) the effect of analgesia induced by repeated TRA plus DHE injections lasted significantly longer, indicating a slower onset of acute tolerance. These results indicate that TRA and DHE injections in certain dose ratios can induce synergistic analgesia, which is resistant against the development of acute tolerance.
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, School of Basic Medicine, Peking University, Beijing 100083, China.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Ming
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ji-Sheng
authors.initials: JS
authors.lastname: Han
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004357:Drug Synergism; D004361:Drug Tolerance / Q000502:physiology*; D005048:Etorphine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D005048:Etorphine; C034765:18,19-dihydroetorphine