Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function

Abstract

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED50 dose of morphine (3.2 mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0 mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients.

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

“…To avoid initiating exercise in this window of reduced activity, access to running wheels in our study was granted three days after CFA-injection. As such, while we did not measure running behavior immediately after injury, no differences between sham and CFA-RUN groups were observed at later time points, which appears to be consistent with studies indicating relatively brief running deficits after CFA [25; 60; 61; 115]. …”

“…In contrast to studies using exercise as a therapeutic tool, a number of studies have used voluntary running behavior as a diagnostic tool in persistent pain states [25; 43; 60; 61; 115; 127]. In studies using CFA-induced inflammation, wheel running in rodents pre-trained with running wheels is reduced for approximately 3 days post-injury [25; 60; 61].…”

“…In studies using CFA-induced inflammation, wheel running in rodents pre-trained with running wheels is reduced for approximately 3 days post-injury [25; 60; 61]. To avoid initiating exercise in this window of reduced activity, access to running wheels in our study was granted three days after CFA-injection.…”

Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

“…Running recovered on Days 2 and 3 as would be expected with the development of tolerance. Tolerance was only evident in pain-free animals because the induction of hindpaw inflammation also depressed home cage wheel running as we have reported previously (Kandasamy et al, 2017a). Wheel running gradually recovered across days so that when the morphine pellets were removed a spontaneous withdrawal-induced decrease in wheel running occurred.…”

“…We have previously shown that home cage wheel running provides an objective and clinically relevant measure of the duration and magnitude of pain in rats (Kandasamy et al, 2016; 2017a; 2017b). If depression of home cage wheel running is a measure of an abnormal physiological state as these previous studies indicate, then spontaneous opioid withdrawal should also cause depression of home cage wheel running.…”