Central components of the analgesic/antihyperalgesic effect of nimesulide: studies in animal models of pain and hyperalgesia.
The analgesic action of NSAIDs has been attributed to the peripheral inhibition of prostaglandin synthesis via the blockade of the enzyme cyclo-oxygenase (COX) and prevention of bradykinin and cytokine-induced hyperalgesia via inhibition of the release of tumour necrosis factor-alpha. However, it is becoming increasingly evident that NSAIDs exert their analgesic effect through several mechanisms. Recent data suggest that significant expression of COX-2 is found in the central nervous system, where COX-2 seems to have, together with nitric oxide, an important role in spinal nociceptive transmission. Nitroglycerin is a nitric oxide donor and induces a hyperalgesic state, partially mediated by central mechanisms. Nimesulide is a preferential COX-2 inhibitor widely used to treat pain. In this study, we evaluated the analgesic effect of nimesulide in several animal models of pain, intending to provide additional information on the characteristics of the analgesic effect of nimesulide, with specific focus on a possible central component.


METHODS
Nimesulide was compared with vehicle in groups of 4-10 rats that were randomly tested with different models of pain. The experimental design also included study of the effect of nimesulide upon nitroglycerin-induced neuronal activation at central sites. Analysis of variance was used to evaluate the influence of time and treatments. Differences between groups at specific time-points were analysed by post-hoc t-test. A probability level of less than 5% was regarded as significant.


METHODS
The analgesic effect of nimesulide (or vehicle) was evaluated in male Sprague-Dawley rats. The animals underwent tail-flick and formalin tests, both performed in baseline conditions and after nitroglycerin-induced hyperalgesia. Two separate groups of rats were treated with nitroglycerin alone or nimesulide followed by nitroglycerin, and their brains were processed for immunocytochemical detection of Fos protein, a marker of neuronal activation.


RESULTS
Nimesulide showed a significant analgesic effect in both the tail-flick and the formalin tests in baseline conditions. In addition, the drug proved effective in counteracting nitroglycerin-induced hyperalgesia in both tests. Brain mapping of nuclei activated by the administration of nitroglycerin showed that nimesulide pretreatment significantly inhibited neuronal activation in several areas, namely the supraoptic nucleus, ventrolateral column of the periaqueductal grey, locus coeruleus, nucleus tractus solitarius and area postrema. We conclude that nimesulide possesses a strong analgesic and antihyperalgesic activity, the mechanisms of action of which are partly central.
D000698:Analgesia; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D016762:Genes, fos / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D005996:Nitroglycerin / Q000009:adverse effects; D009619:Nociceptors / Q000187:drug effects / Q000503:physiopathology; D010146:Pain / Q000175:diagnosis* / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D014275:Trigeminal Caudal Nucleus / Q000187:drug effects
D013449:Sulfonamides; D005996:Nitroglycerin; C012655:nimesulide