Title
Curative-like analgesia in a neuropathic pain model : parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT(1A) receptor agonist
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Amsterdam ,
Subject
Pharmacology. Therapy
Source (journal)
European journal of pharmacology. - Amsterdam
Volume/pages
568(2007) :1-3 , p. 134-141
ISSN
0014-2999
ISI
000248154800016
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
High-efficacy activation of central 5-HT1A receptors by means of the recently discovered, selective 5-HT1A receptor ligand, F 13640 [(3- chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(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 infraorbital 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 0.0410-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 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. © 2007 Elsevier B.V. All rights reserved.
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