Decreased spinal morphine/clonidine antinociceptive synergism in morphine-tolerant mice |
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| Institution: | 1. The Brain and Mind Institute, University of Western Ontario, London, ON, Canada;2. McGill Vision Research, Department of Ophthalmology, McGill University, Montreal, Canada;3. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK;4. School of Computing, University of Kent, Chatham Maritime, UK;5. Department of Clinical Neurosciences, The University of Cambridge, Cambridge, UK;6. School of Psychology, University of Birmingham, Birmingham, UK |
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| Abstract: | The antinociceptive interactions between spinally administered opioids and the alpha2 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 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 alpha2 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 decreased interaction than did mu opioid receptors. |
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