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

• Published in: International journal of molecular sciences Vol. 23; no. 2; p. 615
• Main Authors: Wilson, Lisa L, Eans, Shainnel O, Ramadan-Siraj, Insitar, Modica, Maria N, Romeo, Giuseppe, Intagliata, Sebastiano, McLaughlin, Jay P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.01.2022; MDPI
• Subjects: Acids; allodynia; analgesia; Analgesics - administration & dosage; Analgesics - pharmacology; Analgesics - therapeutic use; Anesthesia; Animals; antagonist; Chronic pain; Clinical trials; Disease Models, Animal; Hyperalgesia - complications; Hyperalgesia - drug therapy; Inflammation; Inflammation - complications; Inflammation - pathology; Locomotor activity; Male; Mice; Mice, Inbred C57BL; Morphine; Narcotics; neuropathic pain; Nociception; Pain; Pain perception; Place preference conditioning; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; Side effects; sigma; Sigma-1 Receptor; Therapeutic targets; Time Factors; Viscera - pathology; sigma; allodynia; neuropathic pain; analgesia; sigma-1 receptor; antagonist; sedation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23020615

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 benzylpiperazine 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 locomotor 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 ED (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 nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment 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.