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

Background and purpose: Xaliproden (SR57746A) is a 5-HT1A 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-HT1A receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT1A receptors was confirmed by antagonism with WAY100635. Key results: Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT1A receptors (pK(i) = 8.84 and 9.00). In [S-35]GTP gamma S (guanosine 5'-O-(3-[S-35]thio)triphosphate) assays it activated both hippocampal r5-HT1A [pEC(50)/E-MAX of 7.58/61% (%5-HT)] and recombinant h5-HT1A receptors (glioma C6-h5-HT1A: 7.39/2%; HeLa-h5-HT1A: 7.24/93%). In functional [S-35]GTP gamma S autoradiography, xaliproden induced labelling in structures enriched with 5-HT1A receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [H-3] WAY100635 to 5-HT1A receptors in mouse frontal cortex and hippocampus (ID50: 3.5 and 3.3 mg.kg(-1), p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED50: 1.2 and 0.7 mg.kg(-1), i. p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED50: 1 and 3 mg.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-HT1A receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT1A receptor activation as an anti-nociceptive strategy. British Journal of Pharmacology (2009) 158, 232-242; doi:10.1111/j.1476-5381.2009.00249.x; published online 5 June 2009