Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway.
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 E(2) (PGE(2), 100 ng) into the rat paw for 14 days. After cessation of PGE(2) 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 PGE(2). Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade 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.
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil.
Daniela
D
Sachs
Fernando Q
FQ
Cunha
Sérgio H
SH
Ferreira
D000255:Adenosine Triphosphate / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D019323:omega-N-Methylarginine / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000700:Analgesics; D002227:Carbazoles; D007211:Indoles; D010069:Oxadiazoles; D015221:Potassium Channels; D011810:Quinoxalines; C073601:KT 5823; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D015232:Dinoprostone