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

• Published in: Journal of neurochemistry Vol. 129; no. 3; pp. 484 - 494
• Main Authors: Vidal‐Torres, Alba, Fernández‐Pastor, Begoña, Carceller, Alicia, Vela, José Miguel, Merlos, Manuel, Zamanillo, Daniel
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2014
• Subjects: Animals; Behavior, Animal - drug effects; concentric microdialysis; glutamate; Male; Microdialysis; Morpholines - pharmacology; Neuralgia - chemically induced; Neuralgia - metabolism; Neurochemistry; Neurotransmitter Agents - metabolism; Neurotransmitters; noradrenaline; Pain; Pain Measurement; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptors, sigma - antagonists & inhibitors; Rodents; S1RA; Sigma-1 Receptor; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; concentric microdialysis; noradrenaline; sigma-1 receptor; S1RA; spinal cord; glutamate
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12648

We have previously shown that the selective sigma‐1 receptor (σ1R) 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 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