Examination of the Novel Sigma‐1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti‐Allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma‐1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti‐allodynic efficacy of SI 1/28, a recently reported ben-zylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423‐fold more selective for S1R over the sigma‐2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomo-tor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose‐dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42– 28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose‐dependent antinociception against visceral noci-ception and anti‐allodynia against CCI‐induced neuropathic pain. SI 1/28 demonstrated no impair-ment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.