Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENTPainful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.