Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats.

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.