Basic neuroscienceHome cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats
Introduction
In humans, pain is accompanied by functional impairment and depression of physical behavior. Pain-depressed behaviors can also be measured in rodents as a decrease in rate, frequency, or intensity in response to a noxious stimulus or pain state (Negus et al., 2006, Negus and Altarifi, 2013). Several tests of pain-depressed behaviors in rodents have been developed. These include pain-depressed reductions in feeding/drinking (Kwilasz and Negus, 2012, Stevenson et al., 2006), intracranial self-stimulation (ICSS) (Negus, 2013), overall locomotor activity (Matson et al., 2007, Stevenson et al., 2009), burrowing (Andrews et al., 2012, Rutten et al., 2014), nesting (Negus et al., 2015), and attention (Freitas et al., 2015). Although these tests mimic the effects of clinical pain in many ways, they are limited by assessment of nociception over a constrained time, assessment outside the home cage, and/or difficulty quantifying the duration and magnitude of pain.
Most of these problems can be overcome by examining pain-depressed wheel running. Wheel running is a natural behavior that is both easy to quantify and similar to the reduction in activity that occurs in chronic pain patients (Tierney et al., 2012). Previous studies suggest that depression of wheel running can be used to assess nociception, but that a relatively intense noxious stimulus is needed (i.e., inflammation of both hindpaws) (Cobos et al., 2012, Grace et al., 2014). However, these studies did not mimic the human pain condition because the animals had limited access to the running wheel, whereas human activity is not limited. We hypothesize that allowing continuous access to the running wheel in the rat's home cage will more accurately mimic the human pain condition and provide a more sensitive measure of nociception.
Female rats and mice have been shown to be more sensitive to noxious chemical, heat, and electrical stimuli than their male counterparts (Wiesenfeld-Hallin, 2005). The consequences of this greater sensitivity to pain on active behaviors are unclear. Despite the greater prevalence of chronic pain in women (Greenspan et al., 2007), we are aware of only one study of pain-depressed behavior that included female rats and this study did not analyze these data separately from male rats (Miller et al., 2011). The present study addresses this problem by assessing pain-depressed wheel running in both male and female rats.
The purpose of the present study was to continuously monitor home cage wheel running to assess inflammatory pain in the same manner that pain disrupts activity in humans. The effects of gender and duration of baseline exposure to the wheel were evaluated to provide a comprehensive analysis of the reliability and validity of home cage wheel running as a clinically relevant method to assess inflammatory pain in male and female rats.
Section snippets
Subjects
Data were collected from adult male and female Sprague-Dawley rats bred at Washington State University Vancouver (Vancouver, WA, USA). All rats were 50–90 days old (median = 71 days old) at the start of the study and randomly assigned to treatment groups. Both CFA- and saline-treated rats were included during each week of testing. Each rat was only used in one experiment and was euthanized at the end of the study. Prior to experimentation, rats were housed in pairs in a 22–24 °C colony room on a
Experiment 1: Three-day acquisition period
Wheel running was assessed 23 h a day beginning at 1000 h in naïve male and female rats. A burst of running occurred in the hour after the rat was returned to its cage, but most wheel running occurred during the dark phase (1800 h to 0600 h) of the light cycle. This running pattern was consistent across rats, although female rats were consistently more active than male rats (Fig. 2). In fact, 10 of 21 male rats did not reach the criterion of 400 revolutions/day, whereas only 3 of the 12 female rats
Discussion
The present study indicates that depression of wheel running in rats may be an appropriate model of inflammatory pain-depressed activity in humans. Although baseline wheel running is much greater in female compared to male rats, the induction of unilateral hindpaw inflammation almost completely inhibited running in male and female rats. Both male and female rats showed a day-by-day recovery of wheel running. In contrast, mechanical withdrawal thresholds remained low for both male and female
Conclusions
In summary, this is the first study to monitor pain-induced changes continuously for 3 days and longer, to examine differences in pain-depressed behavior in male and female rats, and to provide a method to assess nociception that closely mimics the effects of pain in humans. Taken together, continuous home cage monitoring of wheel running is a simple, objective, and clinically relevant method to assess nociception in the rat.
Conflict of interest statement
None of the authors declare a conflict of interest.
Acknowledgments
The authors would like to thank Courtney Miskell, Arthur Serkov, Andrea Lee, and Shauna Schoo for technical assistance. This investigation was supported in part by funds provided by medical and biological research by the State of Washington Initiative Measure No. 171 to R.K. and by NIH/NIDA DA027625 to M.M.M.
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