Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway.
BACKGROUND
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 μ-opioid receptor (MOR) activation are able to direct block PGE(2)-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 PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.


RESULTS
Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-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%).


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 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.
Department of Pharmacology, School of Medicine of Ribeirão Preto University of São Paulo, Av, Bandeirantes, 3900, 14049-900, Ribeirão Preto SP, Brazil. thicunha@usp.br
Thiago M
TM
Cunha
Guilherme R
GR
Souza
Andressa C
AC
Domingues
Eleonora U
EU
Carreira
Celina M
CM
Lotufo
Mani I
MI
Funez
Waldiceu A
WA
Verri
Fernando Q
FQ
Cunha
Sergio H
SH
Ferreira
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D017473:Receptors, Opioid, kappa; D009569:Nitric Oxide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D052248:Nitric Oxide Synthase Type I; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone