NO/cGMP production is important for the endogenous peripheral control of hyperalgesia during inflammation

Various studies have demonstrated the role of the nitric oxide (NO)/cGMP pathway in pain processing. Our group has also shown that this system participates in opioid-induced antinociception during peripheral inflammation. We have previously observed that inflammation mobilizes an endogenous opioidergic system to control hyperalgesia. Here, we investigated whether the NO/cGMP pathway underlies peripheral endogenous nociception control during inflammation. In this study, a pharmacological approach was used in conjunction with the rat paw pressure test to assess the effects of intraplantar NO synthase inhibitor NG-Nitro-L-arginine (NOArg), guanylyl cyclase inhibitor methylene blue (MB), phosphodiesterase-5 inhibitor zaprinast (ZP), or NO precursor L-arginine injection on carrageenan-induced hyperalgesia, which mimics an inflammatory process, or by prostaglandin E-2 (PGE(2)), which directly sensitizes nociceptors. Intraplantar carrageenan (62.5, 125, 250 or 500 mu g) or PGE2 (0.1, 0.5 or 2 mu g) administration produced hyperalgesia, which manifested as a reduction in the rat nociceptive threshold to mechanical stimuli. NOArg (25,50 or 100 mu g/paw) and MB (125, 250 or 500 mu g/paw) induced significant and dose-dependent reductions in the nociceptive threshold of carrageenan-induced (125 mu g/paw) hyperalgesia, but not PGE(2)-induced (0.5 mu g/paw) hyperalgesia. This was a local effect because it did not produce any modifications in the contralateral paw. Both Zaprinast (100, 200 or 400 mu g/paw) and L-arginine (100, 200 or 400 mu g/paw) significantly counteracted carrageenan-induced hyperalgesia (250 mu g/paw), yielding an increase in the nociceptive threshold compared with the control. Zaprinast (200 mu g/paw) or L-arginine (400 mu g/paw) did not produce an antinociceptive effect in the contralateral paw, indicating local action. In addition, at the same dose that was able to modify carrageenan-induced hyperalgesia, neither zaprinast nor L-arginine modified PGE(2) (2 mu g) injection-induced hyperalgesia of the rat paw. Taken together, these results indicate that the L-arginine/NO/cGMP pathway functions as an endogenous modulator of peripheral inflammatory hyperalgesia. (C) 2012 Elsevier Inc. All rights reserved.