Increased level of neuronal phosphoinositide 3-kinase gamma by the activation of mu-opioid receptor in the mouse periaqueductal gray matter: further evidence for the implication in morphine-induced antinociception.
It has been proposed that phosphoinositide 3-kinase (PI3K), one of the phosphatidylinositol kinases, can be regulated by G-protein-coupled receptor as well as nerve growth factor-associated receptors. The aim of the present study was to investigate whether in vivo treatment with morphine, a mu-opioid receptor (MOR) agonist, could directly regulate PI3Kgamma isoform in the mouse periaqueductal gray matter (PAG). Using the polyclonal antibody recognizing a p110gamma catalytic subunit of PI3Kgamma, PI3Kgamma-like immunoreactivity (IR) was mostly seen in the membrane of the cell labeled by anti-neuron-specific nuclear protein. A single s.c. injection of morphine caused a marked increase in the number of PI3Kgamma-IR expressing cells in the PAG. Double immunolabeling assay showed that MOR-IR was mostly overlapped with PI3Kgamma-IR on the cell surface in the PAG section. Additionally, phosphorylated-phospholipase Cgamma1 (PLCgamma1-IR) was highly detected in the membrane compartment of the increased PI3Kgamma-IR-positive cells of this region. Further pharmacological evidence for the critical role of PI3Kgamma in MOR-mediated antinociceptive response was provided by the warm-plate test. The dose-response lines for antinociceptive effects of morphine were significantly shifted to the right following i.c.v. treatment with PI3K inhibitors. These findings suggested that acute treatment with morphine may directly activate the PI3Kgamma/PLCgamma1 pathway in the PAG. This effect may, at least in part, result in the expression of morphine-induced pharmacological actions including antinociception in mice.
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
M
M
Narita
S
S
Imai
M
M
Narita
A
A
Kasukawa
Y
Y
Yajima
T
T
Suzuki
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010146:Pain / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D021122:Protein Subunits / Q000276:immunology; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D021122:Protein Subunits; D017450:Receptors, Opioid, mu; D009020:Morphine; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma