Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors

Rationale

Sigma-1 (σ₁) receptor inhibition ameliorates neuropathic pain by inhibiting central sensitization. However, it is unknown whether σ₁ receptor inhibition also decreases inflammatory hyperalgesia, or whether peripheral σ₁ receptors are involved in this process.

Objective

The purpose of this study was to determine the role of σ₁ receptors in carrageenan-induced inflammatory hyperalgesia, particularly at the inflammation site.

Results

The subcutaneous (s.c.) administration of the selective σ₁ antagonists BD-1063 and S1RA to wild-type mice dose-dependently and fully reversed inflammatory mechanical (paw pressure) and thermal (radiant heat) hyperalgesia. These antihyperalgesic effects were abolished by the s.c. administration of the σ₁ agonist PRE-084 and also by the intraplantar (i.pl.) administration of this compound in the inflamed paw, suggesting that blockade of peripheral σ₁ receptors in the inflamed site is involved in the antihyperalgesic effects induced by σ₁ antagonists. In fact, the i.pl. administration of σ₁ antagonists in the inflamed paw (but not in the contralateral paw) was sufficient to completely reverse inflammatory hyperalgesia. σ₁ knockout (σ₁-KO) mice did not develop mechanical hyperalgesia but developed thermal hypersensitivity; however, the s.c. administration of BD-1063 or S1RA had no effect on thermal hyperalgesia in σ₁-KO mice, supporting on-target mechanisms for the effects of both drugs. The antiedematous effects of σ₁ inhibition do not account for the decreased hyperalgesia, since carrageenan-induced edema was unaffected by σ₁ knockout or systemic σ₁ pharmacological antagonism.

Conclusions

σ₁ receptors play a major role in inflammatory hyperalgesia. Targeting σ₁ receptors in the inflamed tissue may be useful for the treatment of inflammatory pain.