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Neuroscience. 2010 Aug 11;169(1):449-54. doi: 10.1016/j.neuroscience.2010.04.068. Epub 2010 May 6.

Modulation of mu opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase gamma.

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Department of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.


G protein-coupled opioid receptors undergo desensitization after prolonged agonist exposure. Recent in vitro studies of mu-opioid receptor (MOR) signaling revealed an involvement of phosphoinositide 3-kinases (PI3K) in agonist-induced MOR desensitization. Here we document a specific role of the G protein-coupled class IB isoform PI3Kgamma in MOR desensitization in mice and isolated sensory neurons. The tail-withdrawal nociception assay evidenced a compromised morphine-induced tolerance of PI3Kgamma-deficient mice compared to wild-type animals. Consistent with a role of PI3Kgamma in MOR signaling, PI3Kgamma was expressed in a subgroup of small-diameter dorsal root ganglia (DRG) along with MOR and the transient receptor potential vanilloid type 1 (TRPV1) receptor. In isolated DRG acute stimulation of MOR blocked voltage-gated calcium currents (VGCC) in both wild-type and PI3Kgamma-deficient DRG neurons. By contrast, following long-term opioid administration the attenuating effect of MOR was strongly compromised in wild-type DRG but not in PI3Kgamma-deficient DRG. Our results uncover PI3Kgamma as an essential modulator of long-term MOR desensitization and tolerance development induced by chronic opioid treatment in sensory neurons.

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