Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway

Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE2-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (？ 43%).The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.Inflammatory pain is primarily due to the sensitization of specific classes of nociceptive neurons by the direct action of inflammatory mediators (e.g., prostaglandins). In this context, pharmacologic control of inflammatory pain in the periphery is mainly based on two principal strategies. First, the use of non-steroidal anti-inflammatory drugs (aspirin and aspirin-like drugs) inhibits cyclooxygenase-derived prostaglandin production and, consequently, reduces nociceptor sensitization [1]. This effect ultimately prevents the development of hyperalgesia (decrease in nociceptive threshold) in humans and animals. On the other hand, the second strategy is exemplified by some analgesic drugs, like opioids and dipyrone, which ar