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Peripheral Analgesic Blockade of Hypernociception: Activation of Arginine/NO/cGMP/Protein Kinase G/ATP-Sensitive K+ Channel Pathway

Sachs, Daniela ; Cunha, Fernando Q. ; Ferreira, Sérgio H.

Proceedings of the National Academy of Sciences - PNAS, 2004-03, Vol.101 (10), p.3680-3685 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Peripheral Analgesic Blockade of Hypernociception: Activation of Arginine/NO/cGMP/Protein Kinase G/ATP-Sensitive K+ Channel Pathway
Autor: Sachs, Daniela ; Cunha, Fernando Q. ; Ferreira, Sérgio H.
Assuntos: Adenosine Triphosphate - metabolism ; Analgesics ; Analgesics - pharmacology ; Animals ; Arginine - metabolism ; Behavioral neuroscience ; Biological Sciences ; Carbazoles - pharmacology ; Cyclic GMP - metabolism ; Cyclic GMP-Dependent Protein Kinases - metabolism ; Dinoprostone - pharmacology ; Indoles - pharmacology ; Inhibitor drugs ; Injections ; Male ; Morphine ; Nitric oxide ; Nitric Oxide - metabolism ; Nociceptors ; Nociceptors - drug effects ; Nociceptors - metabolism ; omega-N-Methylarginine - pharmacology ; Oxadiazoles - pharmacology ; Oxides ; Pain ; Pharmacology ; Potassium Channels - metabolism ; Pretreatment ; Prostaglandins ; Quinoxalines - pharmacology ; Rats ; Rats, Wistar ; Signal Transduction
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2004-03, Vol.101 (10), p.3680-3685
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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To whom correspondence should be addressed. E-mail: shferrei@fmrp.usp.br.
Contributed by Sérgio H. Ferreira, December 16, 2003
Abbreviations: 8-Br-cGMP, 8-bromoguanosine cGMP; COX, cyclooxygenase; i.pl., intraplantar; \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{K}}_{{\mathrm{ATP}}}^{+}\end{equation*}\end{document}, ATP-sensitive K+ channel; L-NMMA, NG-monomethyl-l-arginine acetate; ODQ, 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PGE2, prostaglandin E2; SNAP, S-nitroso-N-acetyl-dl-penicilamine; PKG, protein kinase G.
Descrição: The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K+ channels ( K ATP+). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-N-acetyl-D,L-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K ATP+ opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E2 ( PGE2, 100 ng) into the rat paw for 14 days. After cessation of PGE2 injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. In this phase, glibenclamide (which specifically closes K ATP+) fully restored persistent hypernociception, as did injection of PGE2. Thus, the activation of the arginine/NO/cGMP pathway causes direct block-ade of acute and persistent hypernociception by opening K ATP+ via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/ NO/ cGMP/ PKG/ K ATP+ pathway constitute a previously undescribed well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Peripheral Analgesic Blockade of Hypernociception: Activation of Arginine/NO/cGMP/Protein Kinase G/ATP-Sensitive K+ Channel Pathway

Sachs, Daniela ; Cunha, Fernando Q. ; Ferreira, Sérgio H.

United States: National Academy of Sciences

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