Agonists determine the pattern of G-protein activation in μ-opioid receptor-mediated supraspinal analgesia

摘要

The opioids heroin, methadone, buprenorphine, and morphine produce supraspinal antinociception in CD-1 mice that is antagonized by Cys2, Tyr3, Orn5, Pen7-amide but not by naltrindole or nor-binaltorphimine. The patterns of GTP-binding regulatory proteins (G-proteins) activation exhibited by these agonists at μ-opioid receptors were characterized. The expression of α-subunits of Gi-protein classes, Gi1, Gi2, Gi3, Go1, Go2 and Gz, and those of the Gq-protein family, Gq and G11, was reduced by administration of antisense oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs. The ODN treatments demonstrated differences in the analgesic profiles of these opioids. Though the knock-down of Gi2α or Gzα subunits diminished the analgesic effets of the four opioids, impairment of Gi3α did not modify the potency of morphine. In mice with reduced Gi1α, Go1α or G11α levels, antinociception induced by heroin and methadone was diminished, but buprenorphine and morphine showed no change in their effects. Also, antinociception induced by heroin and buprenorphine, but neither morphine nor methadone, required intact Go2α or Gqα levels. Thus, morphine, heroin, methadone, and buprenorphine showed different patterns of G-protein activation in evoking μ-opioid receptor-mediated supraspinal antinociception. Therefore, after binding identical receptors, each agonist determines the classes of GTP-binding regulatory transducer proteins to be activated. Copyright © 2001 Elsevier Science Inc.