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.