LAUSR

While clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) targeting β2-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. In contrast, glucocorticoid receptor AS-ODN, prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also a risk factor for CIPN, early life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding, NLB) and stress-resilient (produced by neonatal handling, NH) phenotypes in adults. While NLB significantly enhanced CIPN only in female adults, NH significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the two major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.