title: PI3Kγ integrates cAMP and Akt signalling of the μ-opioid receptor.
abstract: OBJECTIVE
  The μ-opioid receptor has been characterized as the main mediator of opioid signalling in neuronal cells. Opioid-induced pain suppression was originally proposed to be mediated by μ-opioid receptor-induced inhibitory effects on cAMP, which is known to mediate inflammatory hypernociception. Recent investigations revealed PI3Kγ and Akt (PKB) as additional elements of μ-opioid receptor signalling. Hence, we investigated the interaction between pronociceptive cAMP and antinociceptive PI3K/Akt signalling pathways.
  
  
  METHODS
  The human neuroblastoma cell line SK-N-LO and primary dorsal root ganglia (DRG) cells from mice were used to elucidate mediators of μ-opioid receptor signalling. In both cellular systems cAMP was manipulated by stimulation of adenylate cyclase and consequent effects on PI3K/Akt signalling were analysed.
  
  
  RESULTS
  Morphine stimulated Akt phosphorylation on Ser(473) and Thr(308) in a dose- and time-dependent manner indicating a functional μ-opioid receptor/Akt signalling pathway in μ-SK-N-LO cells. This effect of morphine was suppressed by the μ-opioid receptor inhibitor, naloxone, Pertussis toxin, an inhibitor of Gi heterotrimeric G-proteins, and the pan PI3K inhibitor wortmannin. cAMP-elevating agents also suppressed μ-opioid receptor-dependent stimulation of PI3Kγ lipid kinase and Akt activities in SK-N-LO cells and DRG.
  
  
  CONCLUSIONS
  The data unveil a hitherto unknown interaction of pronociceptive cAMP and antinociceptive PI3K/Akt signalling pathways in neuronal cells. PI3Kγ was identified as a mediator of the inhibitory action of cAMP on Akt in SK-N-LO cells and DRG. The data indicate that PI3Kγ has a critical role in cAMP-mediated inflammatory hypernociception and analgesic signalling via μ-opioid receptors and PI3K/Akt in neuronal cells.
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Madishetti
authors.forename: Nadine
authors.initials: N
authors.lastname: Schneble
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Jörg P
authors.initials: JP
authors.lastname: Müller
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine; D000242:Cyclic AMP; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3Kγ; cAMP; dorsal root ganglia; nociception; pain; μ-opioid receptor