Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy

Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal c ells. The current study compared the antinociceptive properties of fenflura mine with those of the tricyclic antidepressants amitriptyline and desipram ine in rat models of acute, persistent, and neuropathic pain. In a rat mode l of neuropathic pain produced by tight ligation of the L-5/L-6 spinal nerv es, i.v. bolus injection of fenfluramine resulted in a dose-dependent and l ong-lasting (>4 h) blockade of mechanical allodynia (ED50 = 3.5 mg/kg; 95% confidence interval, 2.2-5.4 mg/kg) and cold allodynia (ED50 = 2.4 mg/kg; 9 5% confidence range, 1.2-4.6 mg/kg). Fenfluramine also prevented tonic pain evoked by the s.c. injection of dilute (5%) formaldehyde solution (formali n), into the dorsal hindpaw. The i.v. administration of amitriptyline (4.7 mg/kg) or desipramine (13.5 mg/kg) at maximum tolerated doses did not block either allodynia in rats with spinal nerve ligation-induced painful neurop athy or tonic pain in the formalin test. Fenfluramine had differential effe cts on acute behavioral responses to noxious thermal (heat), chemical (5% f ormaldehyde solution), and mechanical stimuli; it completely inhibited noci ceptive behavior in the acute phase of the formaldehyde solution test and p artially inhibited licking and jumping responses in the hot-plate test but did not alter nociceptive thresholds in either the paw pressure test or the tail immersion test. Intracerebroventricular bolus injection of 240 mu-g o f fenfluramine significantly increased mechanical allodynia thresholds; how ever, the same dose administered spinally by intrathecal bolus injection wa s ineffective. The inhibitory effects of fenfluramine on mechanical allodyn ia (and tonic pain behavior in the formaldehyde solution test) were prevent ed by pretreatment with 10 mg/kg metergoline, a selective antagonist of 5-H T receptors, but not with the mu-opioid receptor antagonist naloxone. These results suggest that fenfluramine produces analgesia in the formaldehyde s olution test and the spinal nerve ligation model of neuropathic pain by pot entiating, at least in part, supraspinal 5-HT mediated processes.