Effect of continuous spinal remifentanil infusion on behaviour and spinal glutamate release evoked by subcutaneous formalin in the rat

Abstract

Injection of formalin into the hind paw of the rat evokes a biphasic nociceptive behavioural response, which is considered to be an animal model of postoperative pain in humans. The initial response (phase 1) is caused by activation of peripheral nociceptors and is followed by a second phase attributed to ongoing activity in primary afferents and increased sensitivity of dorsal horn neurones. The latter effect is thought to result from glutamate-mediated N-methyl-D-aspartate receptor activation. In studies to date it has been difficult to discriminate mechanisms underlying phase 1 and phase 2 events because of the long-lasting half-times of intrathecally administered opioids. To further understanding of the opioid pharmacology of the two different phases of the formalin test, we have studied behavioural activity and spinal glutamate release after intrathecal administration of remifentanil, a new short-lasting mu opioid. Intrathecal remifentanil 3 micrograms microliter-1 min-1 delivered during phase 1 inhibited behavioural response during phase 1 (100%), but did not abolish subsequent phase 2 behavioural activity completely (67 (12) %). Intrathecal remifentanil administered separately in phase 1 and phase 2 revealed a similar ED50 (0.2 microgram microliter-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 supramaximal doses of intrathecal remifentanil sufficient to inhibit phase 1 activity still permitted sufficient glutamate release to allow spinal facilitation. Incomplete suppression of spinal excitatory neurotransmitter release by intrathecal opioids is consistent with spinal wind-up that is triggered during phase 1 and results in phase 2 afferent drive. This might reflect one of the mechanisms underlying post-operative pain.