Modulation of mu opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase gamma.
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.
König
C
C
Department of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
Gavrilova-Ruch
O
O
von Banchet
G Segond
GS
Bauer
R
R
Grün
M
M
Hirsch
E
E
Rubio
I
I
Schulz
S
S
Heinemann
S H
SH
Schaible
H G
HG
Wetzker
R
R
D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured / Q000201:enzymology / Q000502:physiology; D058541:Class II Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004361:Drug Tolerance / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D009294:Narcotics; D017450:Receptors, Opioid, mu; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D009020:Morphine; D058541:Class II Phosphatidylinositol 3-Kinases