Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kgamma/AKT/nNOS/NO signaling pathway
In 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 mu-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.
Results:
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 PI3Kgamma/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kgamma 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 PI3Kgamma ([approximately equal to] 43%).
Conclusions:
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 PI3Kgamma/AKT signaling.
This study extends a previously study of our group suggesting that PI3Kgamma/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.
Author: Thiago M CunhaGuilherme R SouzaAndressa C DominguesCelina M LotufoMani I FunezWaldiceu A Verri JrFernando Q CunhaSergio H FerreiraEleonora U Carreira
Credits/Source: Molecular Pain 2012, 8:10
Published on: 2012-02-08
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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