The noradrenergic component contributing to spinal fentanyl-induced antinociception is supraspinally mediated.

1. Male Sprague-Dawley rats were fitted with intrathecal (i.t.) and intracerebroventricular (i.c.v.) catheters. Fentanyl was injected either i.t. or i.c.v., and the antinociceptive efficacy of fentanyl was evaluated using the tail-flick analgesiometric assay. 2. Fentanyl dose-dependently elevated tail-flick latency (TFL) following i.c.v. or i.t. administration. The antinociceptive effects of fentanyl were reversed by naltrexone. 3. Experiments were also designed to evaluate the effects of serotonin and alpha-adrenoceptor antagonists on i.t. or i.c.v. fentanyl-induced elevations in TFL. 4. Phentolamine administered i.t. reversed both the spinal and supraspinal antinociceptive effects of fentanyl, whereas i.t. methysergide did not significantly alter the i.t. or i.c.v. effects of the mu agonist. 5. These data suggest that fentanyl-induced antinociception does not rely on local serotonergic neuronal activation. Due to the highly lipophilic nature of fentanyl, it is possible that the noradrenergic component contributing to spinal fentanyl-induced analgesia is supraspinally-mediated.