Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 10, Pages 3680-3685Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308382101
Keywords
-
Categories
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available