New Strategy for Treating Visceral Pain: Enhancing Opioid Antinociception by Sigma-1 Receptor Inhibition

J Pain. 2026 May 27:106329. doi: 10.1016/j.jpain.2026.106329. Online ahead of print.

ABSTRACT

Visceral pain remains a major clinical challenge, often resistant to conventional analgesics. Sigma-1 receptor (σ1R) antagonists enhance opioid antinociception in somatic and neuropathic pain, yet their role in visceral nociception remains unclear. Here we investigated whether σ1R blockade potentiates the antinociceptive effects of µ-opioid agonists in a well-established model of capsaicin-induced visceral pain in mice. To this end, female wild-type (WT) and σ1R-knockout (σ1R-KO) mice received intracolonic capsaicin (0.1%). Visceral pain-related behaviors and referred mechanical hyperalgesia were quantified after subcutaneous administration of morphine, oxycodone, or fentanyl, alone or combined with selective σ1R antagonists (S1RA, NE-100, BD-1063, BD-1047). Opioid specificity was assessed using naloxone, and σ1R dependence using σ1R-KO mice and the σ1R agonist PRE-084. We found that σ1R-KO mice and WT animals treated with σ1R antagonists exhibited reduced spontaneous visceral pain. Morphine, oxycodone, and fentanyl produced dose-dependent inhibition of both pain-related behaviors and referred hyperalgesia. Genetic deletion or pharmacological inhibition of σ1R significantly potentiated these opioid-induced antinociceptive effects, especially at sub-antinociceptive opioid doses. This potentiation was absent in σ1R-KO mice, confirming receptor specificity. Naloxone fully reversed both the antinociceptive effects of all opioids and the potentiation induced by σ1R antagonists, whereas PRE-084 did not modify opioid efficacy. Taken together, these findings demonstrate that genetic deletion or pharmacological inhibition of σ1R significantly enhances µ-opioid-induced antinociception in visceral nociception. This interaction is σ1R-dependent and requires opioid receptor activation. σ1R blockade emerges as a promising adjuvant strategy to improve opioid efficacy against visceral pain while potentially allowing lower opioid doses. PERSPECTIVE: This study demonstrates that sigma-1 receptor antagonism enhances µ-opioid-mediated antinociception in visceral nociception at sub-antinociceptive opioid doses. These findings suggest that antagonizing the sigma-1 receptor may represent a clinically relevant adjuvant strategy to shift opioid dose-response relationships toward increased apparent potency, potentially allowing reduction of opioid dose requirements in visceral pain conditions.

PMID:42208747 | DOI:10.1016/j.jpain.2026.106329