Lisa Wilson

Title of Research: Selective Sigma Receptor Antagonists as Novel Treatments for Chronic Pain

Additional Authors: S. Eans; H. Agha; S. Intagliata; L. Toll; C. McCurdy; J. McLaughlin

Abstract:

Selective sigma-1 receptor (S1R) antagonists have gained interest as safer, efficacious treatments for neuropathic pain. Our lead compound CM304 displayed good affinity and selectivity for the S1R, and antagonism yielding potent antiallodynic and antinociceptive effects in mouse models of neuropathy and nociception without respiratory or abuse liabilities. However, CM304 is rapidly metabolized, limiting its utility against chronic pain and prompting the synthesis of, and search for, longer-acting antagonists. The current research examines two analogs of CM304, HA134 and HA163, and one novel structure, SI 1/13. In radioligand competition binding assays, the three ligands showed variable affinity and selectivity for the S1R and sigma-2 receptor (S2R). Inhibition of inflammatory and chemical pain, mechanical allodynia resulting from the chronic nerve constriction injury (CCI) neuropathic pain model, and potentially confounding adverse effects of sedation in a rotorod assay were assessed after peripheral (i.p.) administration of each compound. HA134, HA163, and SI 1/13 each produced dose-dependent antinociception in the formalin test, with ED50 (and 95% C.I.) values of 5.80 (4.62-7.32), 17.3 (12.2-25.7), and 12.7 (9.89-16.6) mg/kg, i.p., respectively. Likewise, pretreatment with each sigma-receptor antagonist dose-dependently produced antinociception in the assays of visceral nociception and CCI-induced neuropathic pain. While SI 1/13 demonstrated no impairment of locomotor activity, HA134 showed transient decreases in locomotion and HA163 demonstrated sedation only at doses higher than the ED95 dose correlating with S1R selectivity. In summary, the novel selective S1R antagonists proved efficacious in the treatment of chronic pain without producing confounding sedation.

 

About the author

Lisa WilsonMy name is Lisa Wilson.  I am currently a 4th year graduate student in Dr. Jay McLaughlin’s lab.  I graduated from Rust College in Holly Springs, MS with a B.S. in Biology. I also received a M.ED in Secondary Education from the University of Mississippi.  My long-term research interests are to develop non-opioid alternatives for the treatment of pain and addiction. My dissertation project is the Characterization of Novel, Selective Sigma Receptor Antagonists as Treatments for Chronic Pain.