[Direct involvement of the supraspinal phosphoinositide 3-kinase/phospholipase C gamma 1 pathway in the mu-opioid receptor agonist-induced supraspinal antinociception in the mouse].
Recent works have documented that the stimulation of the mu-opioid receptor (MOR) can activate phosphoinositide-specific phospholipase C (PI-PLC). Here I demonstrate that PLC beta 3 isoform activated by beta gamma subunit of G-protein (G beta gamma) in the brain may contribute to the negative modulation for supraspinal antinociception induced by morphine in mice. In immunohistochemical studies, phosphoinositide 3-kinase (PI3K) was detected in the membrane of the cell soma and the immunoreactivity of PI3K (PI3K-IR) was almost overlapped with MOR-IR and PLC gamma 1-IR in the periaqueductal gray matter (PAG) that is considered to be one of the most important sites for the expression of MOR-mediated antinociception. Morphine produced a marked increase in the protein level of membrane-bound PLC gamma 1, and this increase induced by morphine was significantly inhibited by intracerebroventricullar (i.c.v.) pretreatment with PI3K inhibitors at the dosage that suppressed the morphine-induced supraspinal antinociception. Furthermore, morphine also caused a robust increase in the number of phosphorylated-PLC gamma 1 (p-PLC gamma 1) expressing cells in the PAG. It is worthwhile to note that MOR-IR was overlapped with p-PLC gamma 1-IR in the same cells that also contained PI3K in this region. Based on these findings, the next experiment was designed to investigate whether a deletion of the PLC gamma 1 gene by i.c.v. pretreatment with antisense oligodeoxynucleotide (AS-ODN) against PLC gamma 1 could affect the antinociception induced by MOR agonists. Pretreatment with AS-ODN against PLC gamma 1 revealed a significant inhibition of supraspinal antinociception induced by MOR-agonists. In addition, the morphine-induced supraspinal antinociception was suppressed by the blockade of the G beta gamma subunit that can directly activate both PI3K and PLC gamma 1. Moreover, mice lacking the gene for inositol 1,4,5-trisphosphate (IP3)-sensitive receptors, which can modulate the release of Ca2+ from the endoplasmic reticulum, exhibited a significant inhibition of the morphine-induced antinociception. Collectively, these findings raise the possibility that the activation of the PLC pathway associated with the stimulation of PI3K and/or G beta gamma is implicated in supraspinal antinociception induced by MOR agonists in mice.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501 Japan.
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051966:Phospholipase C gamma; D017450:Receptors, Opioid, mu / Q000819:agonists*; D010738:Type C Phospholipases / Q000502:physiology*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine; D015544:Inositol 1,4,5-Trisphosphate; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D019204:GTP-Binding Proteins; D002118:Calcium