期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：10
页码：3680-3685
DOI：10.1073/pnas.0308382101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ([IMG]f1.gif" BORDER="0">). 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 [IMG]f1.gif" BORDER="0"> 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 [IMG]f1.gif" BORDER="0">) fully restored persistent hypernociception, as did injection of PGE2. Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade of acute and persistent hypernociception by opening [IMG]f1.gif" BORDER="0"> via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/NO/cGMP/PKG/[IMG]f1.gif" BORDER="0"> pathway constitute a previously undescribed well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases.
