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 resea...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/2/615 |
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| author | Lisa L. Wilson Shainnel O. Eans Insitar Ramadan-Siraj Maria N. Modica Giuseppe Romeo Sebastiano Intagliata Jay P. McLaughlin |
| author_facet | Lisa L. Wilson Shainnel O. Eans Insitar Ramadan-Siraj Maria N. Modica Giuseppe Romeo Sebastiano Intagliata Jay P. McLaughlin |
| author_sort | Lisa L. Wilson |
| collection | DOAJ |
| description | 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<sub>50</sub> (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. |
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| id | doaj.art-d97729e03dc2455194ca864b9d0e0e7a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:20:24Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d97729e03dc2455194ca864b9d0e0e7a2023-11-23T14:01:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123261510.3390/ijms23020615Examination 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 UseLisa L. Wilson0Shainnel O. Eans1Insitar Ramadan-Siraj2Maria N. Modica3Giuseppe Romeo4Sebastiano Intagliata5Jay P. McLaughlin6Department of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USADepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyDepartment of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USANeuropathic 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<sub>50</sub> (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.https://www.mdpi.com/1422-0067/23/2/615sigmasigma-1 receptorantagonistallodyniaanalgesianeuropathic pain |
| spellingShingle | Lisa L. Wilson Shainnel O. Eans Insitar Ramadan-Siraj Maria N. Modica Giuseppe Romeo Sebastiano Intagliata Jay P. McLaughlin 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 International Journal of Molecular Sciences sigma sigma-1 receptor antagonist allodynia analgesia neuropathic pain |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | sigma sigma-1 receptor antagonist allodynia analgesia neuropathic pain |
| url | https://www.mdpi.com/1422-0067/23/2/615 |
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