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 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.
Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900 São Paulo, Brazil. fdqcunha@fmrp.usp.br
Thiago M
TM
Cunha
Danilo
D
Roman-Campos
Celina M
CM
Lotufo
Hugo L
HL
Duarte
Guilherme R
GR
Souza
Waldiceu A
WA
Verri
Mani I
MI
Funez
Quintino M
QM
Dias
Ieda R
IR
Schivo
Andressa C
AC
Domingues
Daniela
D
Sachs
Silvana
S
Chiavegatto
Mauro M
MM
Teixeira
John S
JS
Hothersall
Jader S
JS
Cruz
Fernando Q
FQ
Cunha
Sergio H
SH
Ferreira
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D000701:Analgesics, Opioid; D054086:KATP Channels; D009569:Nitric Oxide; D009020:Morphine; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt