Central analgesic effects of the non-steroidal anti-inflammatory drugs : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science in Veterinary Pharmacology at Massey University

Abstract

In addition to their well-known peripheral analgesic effects, non-steroidal anti-inflammatory drugs also exert antinociceptive actions at the central level. However, it is not clear if these central effects are spinally or supraspinally mediated nor whether cyclooxygenase inhibition or the interaction of these drugs with neurones in a different way is responsible for these central analgesic actions. This project investigated the possible central analgesic mechanisms of action of these drugs. It involved the use of in vitro neonatal rat hemisected spinal cord preparations and sheep implanted with indwelling cervical intrathecal catheters. The dorsal root of the neonatal rat hemisected spinal cord preparations was electrically stimulated in such a way to evoke excitatory postsynaptic potentials in the ipsilateral ventral root. All records from this in vivo technique were identified as artefacts and no further experiments were carried out. Conscious, unrestrained, non-lame sheep chronically implanted with indwelling cervical intrathecal catheters were submitted to mechanical noxious stimulation of the left radius. They received cumulative intrathecal doses of ketoprofen, phenylbutazone, salicylic acid and tolfenamic acid as well as repetitive intrathecal administration of normal saline without significantly affecting mechanical thresholds. The same drugs and normal saline were also given intravenously and only ketoprofen and tolfenamic acid significantly raised the nociceptive thresholds. The involvement of spinal opioidergic and α2-adrenergic mechanisms in the hypoalgesia induced by the intravenous administration of ketoprofen in sheep was investigated. The prior intrathecal administration of naloxone and atipamezole at a dose that had no effect on nociceptive thresholds and reversed the analgesia mediated by intravenous fentanyl and xylazine, respectively, almost completely reversed the antinociceptive effects mediated by intravenous ketoprofen. These studies confirm that non-steroidal anti-inflammatory drugs can produce hypoalgesia even when inflammation is absent and, although they did not have a direct effect on the spinal cord, their analgesic action appeared to be spinally mediated by opioidergic and adrenergic descending inhibitory systems.