Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat

Abstract

Background: These studies were undertaken to investigate the site and nature of the antinociceptive effect of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) and paracetamol in the central nervous system (CNS).

Methods: Different nociceptive test models were employed: the tail-flick and hot-plate tests (thermoreceptors), the writhing test (visceral chemoreceptors) the "scratching, biting, licking" (SBL) behaviour and the colorectal distension test (mechanoreceptors). Drugs were given intraperitoneally (i.p.), intracerebroventricularly (i.c.v.), intrathecally (i.t.) or as local injection via cannulae implanted stereotactically. Nerve destruction was made by local injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Whole brain and spinal cord contents 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 test, colorectal distension test), but not in two models of somatosensory pain (tail-flick and hot-plate test). The antinociceptive effect of diclofenac (i.p., i.c.v., or i.t.) was reversed by i.p. naloxone. Naloxone also reversed the effect of diclofenac injected locally into thalamic and hypothalamic areas involved in pain transmission as well as in n. paragigantocellularis or n. raphe magnus. In addition, chemical destruction of the n. raphe region attenuated the antinociceptive effect of diclofenac. Inhibition of serotonergic transmission by pretreatment with methiothepin, ritanserin, parachlorophenylalanine (PCPA) or 5,7-DHT also reduced the antinociceptive effect of diclofenac in a visceral pain model. Pretreatment with diclofenac or ibuprofen blocked pain behaviour (SBL) after activation of excitatory amino acid receptors of the NMDA type, but not pain behaviour after activation of AMPA or substance P (SP) receptors. Paracetamol inhibited hyperalgesia after both NMDA and SP. The antinociceptive effects of diclofenac, ibuprofen and paracetamol were reversed by L-arginine, but not by D-arginine.

Conclusions: The antinociceptive effect of diclofenac involves a central nervous component which may be elicited from several defined areas in the CNS. Part of the antinociceptive effect seems to be mediated by descending inhibitory opioid, serotonin and/or other neurotransmitter systems interfering with visceral pain impulse traffic at the spinal level. NSAIDs and paracetamol interfere with nociception associated with spinal NMDA receptor activation. This effect involves an inhibitory action on spinal nitric oxide (NO) mechanisms. Possibly, the supraspinal antinociceptive effect of NSAIDs may be explained by an analogous action.