Pharmacological characterization of ATPM [(-)-3-aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a novel mixed kappa-agonist and mu-agonist/-antagonist that attenuates morphine antinociceptive tolerance and heroin self-administration behavior.
ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.
Wang
Yu-Jun
YJ
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
Tao
Yi-Min
YM
Li
Fu-Ying
FY
Wang
Yu-Hua
YH
Xu
Xue-Jun
XJ
Chen
Jie
J
Cao
Ying-Lin
YL
Chi
Zhi-Qiang
ZQ
Neumeyer
John L
JL
Zhang
Ao
A
Liu
Jing-Gen
JG
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000009:Abdominal Muscles / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006556:Heroin Dependence / Q000188:drug therapy* / Q000523:psychology*; D006358:Hot Temperature; D008297:Male; D051379:Mice; D009019:Morphinans / Q000494:pharmacology*; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012646:Self Administration
C540166:3-aminothiazolo(5,4-b)-N-cyclopropylmethylmorphinan; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine