Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ-AKT-nNOS-NO signaling pathwayReportar como inadecuado

Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ-AKT-nNOS-NO signaling pathway - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Pain

, 8:10

First Online: 08 February 2012Received: 03 August 2011Accepted: 08 February 2012


BackgroundIn addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors KORs inhibits inflammatory pain. Moreover, peripheral μ-opioid receptor MOR activation are able to direct block PGE2-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE2-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.

ResultsLocal 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%.

ConclusionsThe 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.

AbbreviationsPGE2Prostaglandin E2

PI3Kγphosphoinositide 3-kinase gamma

KORκ-opioid receptor

MORμ-opioid receptor

DORδ-opioid receptor

NONitric oxide

nNOSneuronal nitric oxide synthase

WTwild type

KATPdeficient mice: -: ATP-sensitive potassium channels

CFAComplete Freund-s Adjuvant.

Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-8-10 contains supplementary material, which is available to authorized users.

Thiago M Cunha, Guilherme R Souza contributed equally to this work.

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Autor: Thiago M Cunha - Guilherme R Souza - Andressa C Domingues - Eleonora U Carreira - Celina M Lotufo - Mani I Funez - Wal


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