title: Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats.
abstract: We have previously shown that the selective sigma-1 receptor (σ1 R) antagonist S1RA (E-52862) inhibits neuropathic pain and activity-induced spinal sensitization in various pre-clinical pain models. In this study we characterized both the behavioral and the spinal neurochemical effects of S1RA in the rat formalin test. Systemic administration of S1RA produced a dose-related attenuation of flinching and lifting/licking behaviors in the formalin test. Neurochemical studies using concentric microdialysis in the ipsilateral dorsal horn of awake, freely moving rats revealed that the systemic S1RA-induced antinociceptive effect occurs concomitantly with an enhancement of noradrenaline levels and an attenuation of formalin-evoked glutamate release in the spinal dorsal horn. Intrathecal pre-treatment with idazoxan prevented the systemic S1RA antinociceptive effect, suggesting that the S1RA antinociception depends on the activation of spinal α2 -adrenoceptors which, in turn, could induce an inhibition of formalin-evoked glutamate release. When administered locally, intrathecal S1RA inhibited only the flinching behavior, whereas intracerebroventricularly or intraplantarly injected also attenuated the lifting/licking behavior. These results suggest that S1RA supraspinally activates the descending noradrenergic pain inhibitory system, which may explain part of its antinociceptive properties in the formalin test; however, effects at other central and peripheral sites also account for the overall effect. Formalin-induced nociceptive effect occurs concomitantly with an enhancement of glutamate (Glu) level in the dorsal horn spinal cord. The selective σ1 receptor antagonist S1RA results in inhibition of formalin-evoked Glu release, no modification of GABA levels, and enhancement of noradrenaline (NA) levels. This increased spinal NA activates spinal α2-adrenoceptors producing the attenuation of the formalin-induced pain behaviour.
authors.affiliation: Drug Discovery and Preclinical Development, Laboratorios Esteve. Parc Científic Barcelona, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Vidal-Torres
authors.forename: Begoña
authors.initials: B
authors.lastname: Fernández-Pastor
authors.forename: Alicia
authors.initials: A
authors.lastname: Carceller
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology*; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010147:Pain Measurement; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D009025:Morpholines; D018377:Neurotransmitter Agents; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine
keywords: S1RA; concentric microdialysis; glutamate; noradrenaline; sigma-1 receptor; spinal cord