Effects of picenadol (LY150720) and its stereoisomers on electric shock titration in the squirrel monkey.

Abstract

The mixed-action opioid picenadol (LY150720) is a racemic mixture whose resolution results in a stereoselective separation of agonist and antagonist activity. The effects of picenadol, its dextrorotatory isomer (LY136596) and morphine were studied alone and in combination with naloxone in squirrel monkeys responding under a schedule of electric shock titration. Shock intensity was scheduled to increase at 15-sec intervals in 30 steps from 0 to 5.5 mA. Completion of a fixed ratio 5-response requirement terminated the shock for a 15-sec time-out period after which shock resumed at the next lower intensity. Picenadol (0.1-17.5 mg/kg), the d-isomer (0.3-3.0 mg/kg) and morphine (0.3-5.6 mg/kg) produced dose-related increases in the intensity at which monkeys maintained the shock without decreasing responding in the presence of shock. Shock intensity increases produced by picenadol occurred over a broader dose range than with either the d-isomer or morphine. Increases in shock intensity produced by picenadol, the d-isomer and morphine were blocked by naloxone (0.001-1.0 mg/kg), although the effects of picenadol were less susceptible to antagonism. The effects of the levorotatory isomer of picenadol (LY136595) were also examined alone and in combination with morphine. The l-isomer (0.1-10.0 mg/kg) did not alter shock intensity when administered alone; however, in combination with morphine it produced a dose-dependent antagonism of the effects of morphine. The l-isomer was less potent than naloxone in this respect. These data support previous suggestions that the antinociceptive properties of picenadol arise from mu agonist actions of the dextrorotatory isomer and that the levorotatory isomer acts to limit the efficacy of the racemate.

• Authors: R B Carter, L A Dykstra
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 234 Issue 2 Pg. 299-306 (Aug 1985) ISSN: 0022-3565 [Print] United States
• PMID: 4020674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Analgesics
• Narcotic Antagonists
• Piperidines
• Naloxone
• Morphine
• picenadol

Topics

• Analgesics (pharmacology)
• Animals
• Dose-Response Relationship, Drug
• Electroshock
• Male
• Morphine (pharmacology)
• Naloxone (pharmacology)
• Narcotic Antagonists (pharmacology)
• Piperidines (pharmacology)
• Saimiri
• Stereoisomerism