Recovery Sleep Does Not Mitigate the Effects of Prior Sleep Loss on Paclitaxel-Induced Mechanical Hypersensitivity in Sprague-Dawley Rats

Abstract

Society has a rapidly growing accumulative sleep debt due to employment obligations and lifestyle choices that limit sleep opportunities. The degree to which poor sleep may set the stage for adverse symptom outcomes among more than 1.7 million persons who will be diagnosed with cancer is not entirely understood. Paclitaxel (PAC), a commonly used chemotherapy agent, is associated with painful, debilitating peripheral neuropathy of the hands and feet, which may persist long after adjuvant therapy is completed. The aims of this preclinical study were to determine the accumulative and sustained effects of sleep restriction on PAC-induced mechanical sensitivity in animals and whether there are male–female differences in mechanical sensitivity in PAC-injected animals. Sixty-two adult Sprague-Dawley rats (n = 31 females) were assigned to three cycles of intraperitoneal injections of PAC (1 mg/kg) versus vehicle (VEH; 1 ml/kg) every other day at light onset for 7 days, followed by seven drug-free days and to sleep restriction versus unperturbed sleep. Sleep restriction involved gentle handling to maintain wakefulness during the first 6 hr of lights on immediately following an injection; otherwise, sleep was unperturbed. Mechanical sensitivity was assessed via von Frey filaments, using the up–down method. Mechanical sensitivity data were Log10 transformed to meet the assumption of normality for repeated measures analysis of variance. Chronic sleep restriction of the PAC-injected animals resulted in significantly increased mechanical sensitivity that progressively worsened despite sleep recovery opportunities. If these relationships hold in humans, targeted sleep interventions employed during a PAC protocol may improve pain outcomes.

<p>KDR inferred haplotype is associated with upper limb dysfunction in breast cancer survivors of mixed ancestry</p>

“…In the bivariate analyses of clinical and demographic data, only participants’ age at consent was significantly associated with both shoulder pain and shoulder disability following breast cancer treatment. This association is consistent with previous reports on age and persistent pain following breast cancer treatment12,60,61 . The bivariate regression models for shoulder pain or disability explained only 5.2% and 2.5% of the variance in pain or disability category membership, respectively (Tables 3 and 4).…”

A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity

“…On protocol Days 8-14, the 7-day intercycle/recovery period, rats were not injected, but they did undergo VFH testing. We repeated this 14-day cycle twice to more closely model a clinical chemotherapy protocol that a cancer patient might undergo (Kozachik et al, 2015). VFH testing occurred through Day 42.…”

“…PAC preparation and administration. We developed the PAC protocol in our lab to model the human experience of undergoing chemotherapy and used it in a companion study (Kozachik et al, 2015). Briefly, PAC (Henry Schein, NY) was supplied in multiuse vials at a concentration of 6 mg/ml.…”

“…Among the few rodent studies of PAC-induced mechanical hypersensitivity that tested sex differences, results were mixed. In two studies that employed male and female Sprague Dawley (SD) rats, authors reported no sex differences in PAC-induced mechanical hypersensitivity (Hwang, Kim, Kim, Kwon, & Kim, 2012; Kozachik, Opp, & Page, 2015). However, in a study of 10 inbred mouse strains, authors reported that male mice, as compared to female mice, demonstrated significantly greater PAC-induced mechanical hypersensitivity and that the DBA/2J strain demonstrated an amplified mechanical hypersensitivity response to PAC (4 mg/kg, accumulative), whereas the C57BL/6J strain demonstrated resilience against the effects of PAC until Day 21 post-PAC injections (Smith, Crager, & Mogil, 2004).…”