Region‐dependent attenuation of μ opioid receptor‐mediated G‐protein activation in mouse CNS as a function of morphine tolerance

Abstract

Background and purpose: Chronic morphine administration produces tolerance in vivo and attenuation of m 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-stimulatedand 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 ED 50 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 [ 35 S]GTPgS 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 [35 S]GTPgS binding was significantly decreased in most regions examined in morphine pellet þ 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.

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

“…Receptor desensitization in specific brain regions, including brain stem nuclei, has been previously observed autoradiographically using DAMGO-stimulated [ 35 S]GTPγS in chronic morphine tolerance mouse and rat models (54,55), with similar results in membrane-binding studies from morphine-tolerant mouse brain stem (56). In our study, morphine-tolerant control WT mE7M-B6 mice exhibited reduced morphine-stimulated G protein coupling in the brain stem following chronic morphine treatment, consistent with previous observations.…”

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

“…Overall, these studies demonstrate that OR desensitization is not only agonist-dependent but also neuron-or region-dependent. Furthermore, a recent study by Sim-Selley et al (2007), showed the degree of OR desensitization increases in some brain regions and becomes significant in others when the dose of long-term morphine administration was increased. Although this may be somewhat expected, this study drives home the effect of dose and duration of exposure on the long-term adaptive events that occur after prolonged drug usage across different neuronal populations.…”

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

“…Ultimately, the specific molecular mechanisms governing morphine tolerance have not been fully elucidated, and the possibility that mechanisms of morphine tolerance vary depending on the specific brain and spinal cord region requires further investigation (51).…”