title: A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity.
abstract: Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic-pituitary-adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up-down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy.
authors.affiliation: School of Nursing, Johns Hopkins University, Baltimore, MD, USA skozach1@jhu.edu.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Kozachik
authors.affiliation: School of Nursing, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gayle G
authors.initials: GG
authors.lastname: Page
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: Fischer 344; Lewis; Sprague Dawley; neuropathic pain; rats