PI3K integrates cAMP and Akt signalling of the μ-opioid receptor

Background and Purpose The -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 -opioid receptor-induced inhibitory effects on cAMP, which is known to mediate inflammatory hypernociception. Recent investigations revealed PI3K and Akt (PKB) as additional elements of -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 -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 Ser473 and Thr308 in a dose- and time-dependent manner indicating a functional -opioid receptor/Akt signalling pathway in -SK-N-LO cells. This effect of morphine was suppressed by the -opioid receptor inhibitor, naloxone, Pertussis toxin, an inhibitor of Gi heterotrimeric G-proteins, and the pan PI3K inhibitor wortmannin. cAMP-elevating agents also suppressed -opioid receptor-dependent stimulation of PI3K 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. PI3K was identified as a mediator of the inhibitory action of cAMP on Akt in SK-N-LO cells and DRG. The data indicate that PI3K has a critical role in cAMP-mediated inflammatory hypernociception and analgesic signalling via -opioid receptors and PI3K/Akt in neuronal cells.