Sex differences in chemotherapy-induced neuropathic pain: mechanisms and pharmacotherapy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious side effect of cancer treatment. Studies have shown that there is significant sexual dimorphism in animal models, molecular mechanisms and drug treatment responses of CIPN-related pain. This review systematically explores these sex differences in CIPN.

Mechanistically, the pain sensitivity of female mice is mainly dependent on the IL-23/IL-17A/TRPV1 signaling axis, bidirectionally regulated by estrogen and its receptor α (ER-α). In contrast, male mice are more driven by TLR9-mediated macrophage activation and subsequent TNF/CXCL1 release. Pharmaco-therapeutically, both pre-clinical and clinical studies of duloxetine have shown that females may have better efficacy. The efficacy of κ-opioid receptor (KOR) agonist, resolvin D5 (RvD5), Mitragynine, sphingosine-1-phosphate receptor 1 (S1PR1) antagonist and adenosine A3 receptor (A3AR) agonist also varies by sex and type of chemotherapy drugs.

Sex is a crucial biological variable in CIPN, influencing drug efficacy through sex-specific neuroimmune mechanisms and hormonal regulation. These findings underscore the necessity of incorporating sex as a key variable in analgesic development and clinical practice to achieve personalized pain management in CIPN patients.