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.

Lisa L Wilson,Jay P Mclaughlin,Insitar Ramadan-Siraj,Maria N Modica,Shainnel O Eans,Giuseppe Romeo,Sebastiano Intagliata

doi:10.3390/ijms23020615

Abstract

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 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 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.

Highlights

Chronic neuropathic pain is a common cause for decreased quality of life and disability in the United States [1]
Third line treatment of neuropathic pain with opioids may produce adverse effects including tolerance, constipation, substance abuse and respiratory depression which can result in death [5,6]
We recently identified SI 1/13, a selective benzylpiperazine-based sigma-1 receptor (S1R) antagonist with a sigma-2 receptor (S2R)/S1R selectivity ratio of 886 that demonstrated efficacy against chronic constrictive nerve injury (CCI)-induced neuropathic pain and formalin-induced inflammatory pain without impairing locomotor activity [22]

Summary

Introduction

Chronic neuropathic pain is a common cause for decreased quality of life and disability in the United States [1]. Chronic pain may be caused by disease or lesions within Aβ, Aδ and C fibers as well as central neurons found in the somatosensory system [2]. First and second line pharmacological treatments for this type of pain include antiepileptics and antidepressants, respectively [3,4], but these medications possess adverse effects including sedation, dizziness, and impaired locomotion [2], presenting a significant risk of falling and while operating machinery, lowering patient compliance. Third line treatment of neuropathic pain with opioids may produce adverse effects including tolerance, constipation, substance abuse and respiratory depression which can result in death [5,6]. The established treatments for chronic pain have been limited efficacy in approximately 50% of patients [4]. There is a clear need to find more effective analgesic therapeutic options with fewer liabilities to treat chronic pain [7]

Methods

Results

Conclusion