Compounds with dual glutaminase inhibition and Nrf2 activation activities enhance morphine analgesia and reduce pain sensitization in chemotherapy-induced peripheral neuropathy mouse model

Chemotherapy-induced peripheral neuropathy (CIPN) affects millions of patients, substantially impacting their quality of life. However, there are limited effective treatments available for alleviating CIPN. Therefore, discovering new approaches to manage neuropathic pain is in high clinical demand. Compound 968 (C968) and CU1015, both identified as glutaminase inhibitors with applications in cancer therapy, have shown promise in enhancing the anticancer activities of chemotherapy drugs in previous studies. However, their potential impact on CIPN has not been fully elucidated. This study aims to determine effects of C968 and CU1015 on pain and morphine-mediated analgesia in the CIPN mouse model. The CD-1 male and female mice received 4 doses of paclitaxel (intraperitoneal injection) to induce CIPN. Following CIPN development, mice were treated with C968 or CU1015 (intrathecal injection) 24 hours prior to morphine administration. To assess the impact of C968 or CU1015 on CIPN development, mice were treated with these compounds while concurrently receiving paclitaxel injections. The mechanical threshold was measured using the von Frey filaments. We found that C968 or CU1015 enhanced morphine analgesia in CIPN mice. C968 or CU1015 also attenuated the development of CIPN in male, but not in female mice, at the dose tested. This potential sex difference may be linked to the activation of pain-related signal transduction pathways involving ERK and AKT in the spinal cord. These findings suggest that compounds with dual glutaminase inhibition and Nrf2 activation activities could be a novel approach for treating CIPN. Significance Statement: This study demonstrates that compounds with dual glutaminase inhibition and Nrf2 activation activities could be a promising therapeutic target for managing neuropathic pain.