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Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits

KM Standifer, GC Rossi and GW Pasternak

Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Antisense oligodeoxynucleotides directed against various G protein alpha subunits differentially block the analgesic actions of mu-, delta- , and kappa-opioid agonists in mice. Intracerebroventricular administration of oligodeoxynucleotides targeting Gi alpha 2, G(o) alpha, and Gs alpha block supraspinal mu-opioid analgesia, whereas Gi alpha 2 and Gx/z alpha antisense probes block spinal mu analgesia. Although supraspinal and spinal morphine-6 beta-glucuronide (M6G) analgesia also is sensitive to these antisense treatments, its sensitivity profile differs from that of morphine, implying the existence of a different analgesic system. Gi alpha 1 and Gx/z alpha antisense probes block supraspinal M6G analgesia, whereas Gi alpha 1, Gi alpha 3, G(o) alpha, and Gx/z alpha antisense probes block spinal M6G analgesia. Spinal delta-opioid analgesia is blocked by antisense probes to all of the G protein alpha subunits tested, whereas kappa 1- opioid analgesia is sensitive to only Gq alpha. The kappa 3 agonist naloxone benzoylhydrazone produces its analgesia through supraspinal mechanisms and is blocked by Gi alpha 1, Gi alpha 3, Gs alpha, Gq alpha, and Gx/z alpha antisense oligodeoxynucleotides. Together, these results support the presence of seven different analgesic systems for these various opioid agonists.

Volume 50, Issue 2, pp. 293-298, 08/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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