EFFECT OF CONTINUOUS SPINAL REMIFENTANIL INFUSION ON BEHAVIOR AND SPINAL GLUTAMATE RELEASE EVOKED BY SUBCUTANEOUS FORMALIN IN THE RAT

Injection of formalin into the hind paw of the rat evokes a biphasic n ociceptive behavioural response, which is considered to be an animal m odel of postoperative pain in humans. The initial response (phase 1) i s caused by activation of peripheral nociceptors and is followed by a second phase attributed to ongoing activity in primary afferents and i ncreased sensitivity of dorsal horn neurones. The latter effect is tho ught to result from glutamate-mediated N-methyl-D-aspartate receptor a ctivation. In studies to date it has been difficult to discriminate me chanisms underlying phase 1 and phase 2 events because of the long-las ting half-times of intrathecally administered opioids. To further unde rstanding of the opioid pharmacology of the two different phases of th e formalin test, we have studied behavioural activity and spinal gluta mate release after intrathecal administration of remifentanil, a new s hort-lasting mu opioid. Intrathecal remifentanil 3 mu g mu l(-1) min(- 1) delivered during phase 1 inhibited behavioural response during phas e 1 (100%), but did not abolish subsequent phase 2 behavioural activit y completely (67 (12) %). Intrathecal remifentanil administered separa tely in phase 1 and phase 2 revealed a similar ED50 (0.2 mu g mu l(-1) min(-1)) for inhibition of the behavioural responses. In vivo, spinal microdialysis showed incomplete reduction in glutamate concentrations in response to intrathecal remifentanil administration; this in turn inhibited phase 1 behavioural responses. Therefore we contend that sup ramaximal doses of intrathecal remifentanil sufficient to inhibit phas e 1 activity still permitted sufficient glutamate release to allow spi nal facilitation. Incomplete suppression of spinal excitatory neurotra nsmitter release by intrathecal opioids is consistent with spinal wind -up that is triggered during phase 1 and results in phase 2 afferent d rive. This might reflect one of the mechanisms underlying postoperativ e pain.