σ1 Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

Background: Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (sigma(1)) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored. Methods: The authors evaluated the role of sigma(1) receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and sigma(1) receptor knockout (sigma(1)-KO) (n = 10 per group) mice, selective sigma(1) receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen). Results: The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and sigma(1)-KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in sigma(1)-KO mice (mean +/- SEM, 22 +/- 2.9) was 48% of that observed in WT animals (46 +/- 4.2). Subcutaneous administration of the sigma(1) receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 +/- 0.05 g) in WT mice. In contrast, these drugs produced no change in sigma(1)-KO mice. Thus, the effects of these drugs are specifically mediated by sigma(1) receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and sigma(1)-KO mice, whereas ketoprofen had no effect in either mouse type. Conclusion: These results suggest that sigma(1) receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value.