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J Pharmacol Exp Ther. 1994 Dec;271(3):1583-90.

Selective antagonism of opioid analgesia by a sigma system.

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  • 1George Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.


(+)Pentazocine antagonizes morphine analgesia as potently as its (-)-isomer, ruling out an opioid receptor mechanism of action and suggesting, which suggests a role for sigma 1 receptors. Systemic (+) pentazocine also reverses supraspinal or spinal morphine analgesia. 1,3-Di(2-tolyl)guanidine, a sigma ligand with no appreciable opioid receptor affinity, antagonizes morphine analgesia. The actions of both (+)pentazocine and 1,3-di(2-tolyl)guanidine are reversed by haloperidol, which has high affinity for both sigma and D2 receptors, but not by the D2-selective antagonist (-)sulpiride, which lacks activity at sigma sites. The antiopioid sigma system is tonically active. Haloperidol, but not (-)sulpiride, decreases morphine ED50 almost 2-fold. The antiopioid system modulates only mu analgesia. Unlike analgesia, (+)pentazocine does not influence morphine's inhibition of gastrointestinal transit or lethality. (+)Pentazocine also antagonizes kappa 1, kappa 3 and delta analgesia through sigma mechanisms in a haloperidol-sensitive manner. (-)Sulpiride is inactive. Alone, haloperidol enhances kappa 1, kappa 3 and delta analgesia more dramatically than morphine, which indicates that the sigma system is active against all opioid analgesic systems. Sigma systems are responsible for some strain differences in kappa receptor sensitivity. Unlike CD-1 mice, BALB-C mice are relatively insensitive toward the kappa 1 agent U50,488H and the kappa 3 analgesic naloxone benzoylhydrazone. Blockade of the sigma system with haloperidol eliminates these strain differences. In conclusion, sigma 1 systems functionally antagonize opioid analgesia without affecting morphine's effects on gastrointestinal transit or lethality. The antiopioid sigma system is tonically active and is more active against kappa analgesia than mu.(ABSTRACT TRUNCATED AT 250 WORDS)

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