Decreased spinal morphine/clonidine antinociceptive synergism in morphine-tolerant mice.
The antinociceptive interactions between spinally administered opioids and the alpha 2 agonist clonidine were examined in placebo and morphine pellet-implanted mice using the tail flick test. In placebo pellet-implanted animals, coadministered morphine and clonidine produced a synergistic antinociceptive effect. In mice implanted with morphine pellets, the synergism decreased to an additive interaction. The interactions between clonidine and the mu agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO), the delta agonist D-Pen2-D-Pen5-Enkephalin (DPDPE), and the kappa agonist U50-488H were also synergistic in placebo pelleted animals. In morphine pellet treated mice the DPDPE/clonidine interaction decreased to an antagonistic interaction, the DAMGO/clonidine remained synergistic and the U50-488H/clonidine interaction decreased to additive. These results support the proposal that the morphine spinal/supraspinal synergism depends upon the interaction between spinal opioid and alpha 2 receptors and a decrease in this interaction is a mechanism involved in development of tolerance to morphine. In addition, delta and kappa receptors appeared to be more involved in the morphine/clonidine decrease interaction than did mu opioid receptors.
Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130.
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Roerig
D000595:Amino Acid Sequence; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D011957:Receptors, Opioid / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects*
D004343:Drug Implants; D011957:Receptors, Opioid; D009020:Morphine; D003000:Clonidine