Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice

Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (sigma 1R) is known to be a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Conversely, relatively little is known about sigma 2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of sigma 1R and sigma 2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model. In agreement with previous reports, we find that sigma 1R ligands given intrathecally (IT) produce relief of SNI-induced mechanical hypersensitivity. We also find that the putative sigma 2R/Tmem97 agonists DKR-1005, DKR-1051, and UKH-1114 (K-i similar to 46 nM) lead to relief of SNI-induced mechanical hypersensitivity, peaking at 48 h after dosing when given IT. This effect is blocked by the putative sigma 2R/Tmem97 antagonist SAS-0132. Systemic administration of UKH-1114 (10 mg/kg) relieves SNI-induced mechanical hypersensitivity for 48 h with a peak magnitude of effect equivalent to 100 mg/kg gabapentin and without producing any motor impairment. Finally, we find that the TMEM97 gene is expressed in mouse and human dorsal root ganglion (DRG) including populations of neurons that are involved in pain; however, the gene is also likely expressed in non-neuronal cells that may contribute to the observed behavioral effects. Our results show robust antineuropathic pain effects of sigma 1R and sigma 2R/Tmem97 ligands, demonstrate that sigma 2R/Tmem97 is a novel neuropathic pain target, and identify UKH-1114 as a lead molecule for further development.