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 STATEMENT Painful
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.