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The Journal of Neuroscience, November 12, 2003, 23(32):10292-10301

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Cellular/Molecular
Phosphoinositide 3-Kinase Cascade Facilitates µ-Opioid Desensitization in Sensory Neurons by Altering G-Protein-Effector Interactions

Miao Tan,¹ Matthias Groszer,^2,3 Aiko M. Tan,¹ Amy Pandya,² Xin Liu,³ and Cui-Wei Xie¹

¹Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles (UCLA), Los Angeles, California 90024-1759, ²Howard Hughes Medical Institute and Department of Molecular and Medical Pharmacology, and ³Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California 90095-1735

Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. Here we investigated the role of phosphoinositide 3-kinase (PI3K) and its downstream pathways in desensitization of µ-opioid inhibition of neuronal Ca²⁺ channels. In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the µ agonist [D-Ala², N-MePhe⁴, Gly-ol⁵]-enkephalin (DAMGO). Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). A combined application of PI3K and MAPK inhibitors showed no additive effect, suggesting that these two kinases act in a common pathway to facilitate chronic desensitization. Acute DAMGO desensitization, however, was not affected by the inhibitors. Furthermore, upregulation of the PI3K-Akt pathway in mutant mice lacking phosphatase and tensin homolog, a lipid phosphatase counteracting PI3K, selectively enhanced chronic desensitization in a PI3K- and MAPK-dependent manner. Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between subunits of G-proteins and Ca²⁺ channels. DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. Such disruption could occur at the postreceptor level, because chronic DAMGO also reduced GTPS-induced PPF that was independent of receptor activation. Again, inhibition of PI3K or MAPK reduced desensitization of PPF. Our data suggest that the PI3Kcascade involving MAPK and Akt enhances µ-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions.

Key words: PI 3-kinase; Ca²⁺ channel; opioid; desensitization; Akt; PTEN

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Received June 11, 2003; revised September 16, 2003; accepted September 20, 2003.

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