PI3Kγ Integrates CAMP and Akt Signalling of the μ-opioid Receptor

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2014 Mar 25

PMID 24654606

Citations 7

Authors

Sreedhar Madishetti

Nadine Schneble

Christian Konig

Emilio Hirsch

Stefan Schulz

Jorg P Muller

Reinhard Wetzker

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: 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.

Experimental Approach: 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.

Key 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 And Implications: 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.

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