Curative-like analgesia in a neuropathic pain model:: Parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT1A receptor agonist

High-efficacy activation of central 5-HT1A receptors by means of the recently discovered, selective 5-HT1A receptor ligand, F 13640 L(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-1[(5-methyl-pyridin-2-ylmethyl)-amino]methyl piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's (curative-like) analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral intraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation within 24 days-, thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from I to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT1A receptors may be involved in the dynamical, dose- and time-dependent, pretreatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT1A receptor activation. (C) 2007 Elsevier B.V. All rights reserved.