Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

G protein-coupled opioid receptors undergo desensitization after prolonged agonist exposure. Recent in vitro studies of μ-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 PI3Kγ in MOR desensitization in mice and isolated sensory neurons. The tail-withdrawal nociception assay evidenced a compromised morphine-induced tolerance of PI3Kγ-deficient mice compared to wild-type animals. Consistent with a role of PI3Kγ in MOR signaling, PI3Kγ 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 PI3Kγ-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 PI3Kγ-deficient DRG. Our results uncover PI3Kγ as an essential modulator of long-term MOR desensitization and tolerance development induced by chronic opioid treatment in sensory neurons.