Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway

Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully el...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-03, Vol.107 (9), p.4442-4447
Main Authors: Cunha, Thiago M, Roman-Campos, Danilo, Lotufo, Celina M, Duarte, Hugo L, Souza, Guilherme R, Verri, Jr, Waldiceu A, Funez, Mani I, Dias, Quintino M, Schivo, Ieda R, Domingues, Andressa C, Sachs, Daniela, Chiavegatto, Silvana, Teixeira, Mauro M, Hothersall, John S, Cruz, Jader S, Cunha, Fernando Q, Ferreira, Sergio H
Format: Article
Language:English
Subjects:
Analgesics, Opioid - administration & dosage
Analgesics, Opioid - therapeutic use
Animals
KATP Channels - metabolism
Male
Mice
Mice, Inbred C57BL
Morphine - administration & dosage
Morphine - therapeutic use
Nitric Oxide - metabolism
Nitric Oxide Synthase Type I - metabolism
Pain - drug therapy
Pain - enzymology
Pain - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Wistar
Signal Transduction
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Summary:Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kgamma/AKT protein kinase B (AKT) and culminated in increased activation of K(ATP) channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.
ISSN:1091-6490
DOI:10.1073/pnas.0914733107