Abstract
The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR) and is also implicated in the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. σ2R-/- animals developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R-/- mice and diminished in σ2R-/- mice. The analgesic effect of morphine was increased in σ2R-/- mice by treatment with S1RA. However, σ2R-/- mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55212-2 and the alfa2-adrenergic receptor agonist clonidine. These findings suggest that σ2R and σ1R have selective regulatory effects on MOR-mediated analgesia, with σ2R promoting MOR-mediated analgesia and σ1R inhibiting it. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.
Intrathecal interleukin-1β decreases sigma-1 receptor expression in spinal astrocytes in a murine model of neuropathic pain
