CENTRAL ANTINOCICEPTIVE EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND PARACETAMOL - EXPERIMENTAL STUDIES IN THE RAT

Background: These studies were undertaken to investigate the site and nature of the antinociceptive effect of NSAIDs (Non-Steroidal Anti-Inf lammatory Drugs) and paracetamol in the central nervous system (CNS). Methods: Different nociceptive test models were employed: the tail-fli ck and hot-plate tests (thermoreceptors), the writhing test (visceral chemoreceptors) the ''scratching, biting, licking'' (SBL) behaviour an d the colorectal distension test (mechanoreceptors). Drugs were given intraperitoneally (i.p.), intracerebroventricularly (i.c.v.), intrathe cally (i.t.) or as local injection via cannulae implanted stereotactic ally. Nerve destruction was made by local injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Whole brain and spinal cord content s of serotonin and 5-hydroxyindole acetic acid (5-HIAA) were analysed by high pressure liquid chromatography (HPLC). Results: Injections of diclofenac induced antinociception in visceral pain models (writhing t est, colorectal distension test), but not in two models of somatosenso ry pain (tail-flick and hot-plate test) The antinociceptive effect of diclofenac (i.p., i.c.v., ol i.t.) was reversed by i.p. naloxone. Nalo xone also reversed the effect of diclofenac injected locally into thal amic and hypothalamic areas involved in pain transmission as well as i n n. paragigantocellularis or n. raphe magnus. In addition, chemical d estruction of the n. raphe region attenuated the antinociceptive effec t of diclofenac. Inhibition of serotonergic transmission by pretreatme nt with methiothepin, ritanserin, parachlorophenylalanine (PCPA) or 5, 7-DHT also reduced the antinociceptive effect of diclofenac in a visce ral pain model. Pretreatment with diclofenac or ibuprofen blocked pain behaviour (SBL) after activation of excitatory amino acid receptors o f the NMDA type, but not pain behaviour after activation of AMPA or su bstance P (SP) receptors. Paracetamol inhibited hyperalgesia after bot h NMDA and SP. The antinociceptive effects of diclofenac, ibuprofen an d paracetamol were reversed by L-arginine, but not by D-arginine. Conc lusions: The antinociceptive effect of diclofenac involves a central n ervous component which may be elicited from several defined areas in t he CNS. Part of the antinociceptive effect seems to be mediated by des cending inhibitory opioid, serotonin and/or other neurotransmitter sys tems interfering with visceral pain impulse traffic at the spinal leve l. NSAIDs and paracetamol interfere with nociception associated with s pinal NMDA receptor activation. This effect involves an inhibitory act ion on spinal nitric oxide (NO) mechanisms. Possibly, the supraspinal antinoceptive effect of NSAIDs may be explained by an analogous action .