ABSTRACT
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.
Subject(s)
Class II Phosphatidylinositol 3-Kinases/physiology , Morphine/pharmacology , Narcotics/pharmacology , Receptors, Opioid, mu/drug effects , Sensory Receptor Cells/enzymology , Animals , Calcium Channels/physiology , Cells, Cultured/enzymology , Cells, Cultured/physiology , Class II Phosphatidylinositol 3-Kinases/deficiency , Class II Phosphatidylinositol 3-Kinases/genetics , Drug Tolerance/physiology , Ganglia, Spinal/cytology , Mice , Mice, Knockout , Morphine/administration & dosage , Morphine/therapeutic use , Narcotics/administration & dosage , Narcotics/therapeutic use , Nociceptors/drug effects , Nociceptors/physiology , Patch-Clamp Techniques , Rats , Rats, Wistar , Reaction Time/drug effects , Recombinant Fusion Proteins/physiology , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , TRPV Cation Channels/drug effects , TRPV Cation Channels/physiologyABSTRACT
The proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) not only promote and maintain inflammation, they also contribute to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. A large proportion of dorsal root ganglion (DRG) neurons express TNF receptors and receptor units for stimulation with IL-6. In the rat model of antigen-induced arthritis (AIA), neutralization of TNF-alpha by etanercept and infliximab reduced inflammation-evoked mechanical hyperalgesia at the inflamed knee joint. This treatment also attenuated the infiltration of macrophages into the DRGs usually observed during the acute phase of AIA. Intra-articular application of etanercept reduced the responses of C-fibers to mechanical stimulation of the inflamed joint but did not influence responses to stimulation of the normal joint. Finally, in cultured DRG neurons TNF-alpha increased the proportion of neurons that express the TRPV1 receptor and may thus contribute to the generation of inflammation-evoked thermal hyperalgesia.
