Antinociception by Sigma-1 Receptor Antagonists: Central and Peripheral Effects.

There is plenty of evidence supporting the modulatory role of sigma-1 receptors (σ1Rs) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists, particularly in nonacute sensitizing conditions involving sustained afferent drive, activity-dependent plasticity/sensitization, and ultimately pain hypersensitivity, as it is the case in chronic pains of different etiology. Antinociceptive effects of σ1R antagonists both when acting alone and in combination with opioids (to enhance opioid analgesia) have been reported at both central and peripheral sites. At the central level, findings at the behavioral (animal pain models), electrophysiological (spinal wind-up recordings), neurochemical (spinal release of neurotransmitters) and molecular (NMDAR function) level supports a role for σ1R antagonists in inhibiting augmented excitability secondary to sustained afferent input. Attenuation of activity-induced plastic changes (central sensitization) following tissue injury/inflammation or nerve damage could thus underlie the central inhibitory effect of σ1R antagonists. Moreover, recent pieces of information confirm the involvement of σ1R in mechanisms regulating pain at the periphery, where σ1Rs are highly expressed, particularly in dorsal root ganglia. Indeed, local peripheral administration of σ1R antagonists reduces inflammatory hyperalgesia. Potentiation of opioid analgesia is also supported, particularly at supraspinal sites and at the periphery, where locally administered σ1R antagonists unmask opioid analgesia. Altogether, whereas σ1R activation is coupled to pain facilitation and inhibition of opioid antinociception, σ1R antagonism inhibits pain hypersensitivity and "releases the brake" enabling opioids to exert enhanced antinociceptive effects, both at the central nervous system and at the periphery.