Antinociceptive interactions of micro- and kappa-opioid agonists in the colorectal distension assay in rats.
Interactions of opioid agonists, fentanyl and oxymorphone (micro-selective) and spiradoline and enadoline(kappa-selective), were examined for additive, sub-additive, or supra-additive antinociception in the colorectal distension (CRD) assay. Single-dose values (mg/kg, 0.006-0.016 for fentanyl, 0.25-1.26 forspiradoline, etc.) were summed to formulate theoretical additive-dose plots for comparison with actual combined-dose effects. Combined fentanyl and spiradoline yielded additive (low-dose levels) or supraadditive(high-dose levels) effects. Single and combined doses of fentanyl (0.012 mg/kg) and spiradoline(0.3 mg/kg) were tested after pretreatment with saline, beta-funaltrexamine (b-FNA, micro-selective antagonist), or nor-binaltorphimine (n-BNI, kappa-selective antagonist). Supra-additive effects of combined agonists were attenuated by either antagonist (greater with n-BNI). But paradoxical patterns of antagonism of single-dose effects occurred: the fentanyl antinociception was not antagonized by b-FNA, whereas the spiradoline antinociception was. The results indicate complex interactions of agonists in this visceral pain model and potential for combined agonists to improve pain relief with decreased side effects
Department of Pharmacology/Toxicology, Michigan State University, East Lansing, MI 48824, United States.
Shannon L
SL
Briggs
Richard H
RH
Rech
D000818:Animals; D003106:Colon / Q000187:drug effects*; D005283:Fentanyl / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012007:Rectum / Q000187:drug effects*
D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C051272:spiradoline; D005283:Fentanyl