5-HT1A receptors are involved in the effects of xaliproden on G-protein activation, neurotransmitter release and nociception.

Abstract

BACKGROUND AND PURPOSE:

Xaliproden (SR57746A) is a 5-HT(1A) receptor agonist and neurotrophic agent that reduces oxaliplatin-mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats.

EXPERIMENTAL APPROACH:

Xaliproden was tested on models associated with 5-HT(1A) receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT(1A) receptors was confirmed by antagonism with WAY100635.

KEY RESULTS:

Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT(1A) receptors (pK(i)= 8.84 and 9.00). In [(35)S]GTPgammaS (guanosine 5'-O-(3-[(35)S]thio)triphosphate) assays it activated both hippocampal r5-HT(1A)[pEC(50)/E(MAX) of 7.58/61% (%5-HT)] and recombinant h5-HT(1A) receptors (glioma C6-h5-HT(1A): 7.39/62%; HeLa-h5-HT(1A): 7.24/93%). In functional [(35)S]GTPgammaS autoradiography, xaliproden induced labelling in structures enriched with 5-HT(1A) receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [(3)H]WAY100635 to 5-HT(1A) receptors in mouse frontal cortex and hippocampus (ID(50): 3.5 and 3.3 mg x kg(-1), p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED(50): 1.2 and 0.7 mg x kg(-1), i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED(50): 1 and 3 mg x kg(-1), i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635.

CONCLUSIONS AND IMPLICATIONS:

These results indicate that activation of 5-HT(1A) receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT(1A) receptor activation as an anti-nociceptive strategy.

• Authors: J-C Martel, M-B Assié, L Bardin, R Depoortère, D Cussac, A Newman-Tancredi
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 158 Issue 1 Pg. 232-42 (Sep 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19508400 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Naphthalenes
• Neurotransmitter Agents
• Pyridines
• Serotonin 5-HT1 Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• GTP-Binding Proteins
• xaliproden

Topics

• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• GTP-Binding Proteins (metabolism)
• HeLa Cells
• Humans
• Male
• Mice
• Naphthalenes (pharmacology)
• Neurotransmitter Agents (metabolism)
• Pain Measurement (drug effects, methods)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (physiology)
• Serotonin 5-HT1 Receptor Agonists