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- Title
Region-dependent attenuation of μ opioid receptor-mediated G-protein activation in mouse CNS as a function of morphine tolerance.
- Authors
Sim-Selley, L. J.; Scoggins, K. L.; Cassidy, M. P.; Smith, L. A.; Dewey, W. L.; Smith, F. L.; Selley, D. E.
- Abstract
Background and purpose:Chronic morphine administration produces tolerance in vivo and attenuation of μ opioid receptor (MOR)-mediated G-protein activation measured in vitro, but the relationship between these adaptations is not clear. The present study examined MOR-mediated G-protein activation in the CNS of mice with different levels of morphine tolerance.Experimental approach:Mice were implanted with morphine pellets, with or without supplemental morphine injections, to induce differing levels of tolerance as determined by a range of MOR-mediated behaviours. MOR function was measured using agonist-stimulated [35S]guanylyl-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) and receptor binding throughout the CNS.Key results:Morphine pellet implantation produced 6-12-fold tolerance in antinociceptive assays, hypothermia and Straub tail, as measured by the ratio of morphine ED50 values between morphine-treated and control groups. Pellet implantation plus supplemental injections produced 25-50-fold tolerance in these tests. In morphine pellet-implanted mice, MOR-stimulated [35S]GTPγS binding was significantly reduced only in the nucleus tractus solitarius (NTS) and spinal cord dorsal horn in tissue sections from morphine pellet-implanted mice. In contrast, MOR-stimulated [35S]GTPγS binding was significantly decreased in most regions examined in morphine pellet+morphine injected mice, including nucleus accumbens, caudate-putamen, periaqueductal gray, parabrachial nucleus, NTS and spinal cord.Conclusions and implications:Tolerance and the regional pattern of apparent MOR desensitization were influenced positively by the level of morphine exposure. These results indicate that desensitization of MOR-mediated G-protein activity is more regionally widespread upon induction of high levels of tolerance, suggesting that this response contributes more to high than low levels of tolerance to CNS-mediated effects of morphine.British Journal of Pharmacology (2007) 151, 1324–1333; doi:10.1038/sj.bjp.0707328; published online 18 June 2007
- Subjects
MORPHINE; DRUG administration; DRUG interactions; SPINAL cord; PHARMACOLOGY
- Publication
British Journal of Pharmacology, 2007, Vol 151, Issue 8, p1324
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0707328