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

Abstract

Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 hours compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund’s Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3 days of treatment depressed wheel running in these rats for over 6 days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal.

Anti-migraine effect of ∆9-tetrahydrocannabinol in the female rat

“…Assessment of home cage wheel running is especially useful in evaluating drug treatments because the goal is restoration of function, which requires that an effective drug reduces pain without inducing disruptive side effects. For example, high doses of morphine block mechanical allodynia induced by inflammatory pain, but do not restore depressed wheel running because of disruptive side effects (Kandasamy et al, 2017a; 2017c). Likewise, the present data show that the highest dose of THC (1.0 mg/kg) does not restore migraine-depressed wheel running, and in fact, depresses wheel running in pain-free rats.…”

Pros and Cons of Clinically Relevant Methods to Assess Pain in Rodents

“…The most significant limitation of home cage wheel running is that it is an indirect measure of pain. Any disruptive stimulus, such as illness (Taraborrelli et al, 2011) the side effects of high drug doses (Kandasamy et al, 2017a) or opioid withdrawal (Kandasamy et al, 2017c) depresses wheel running. In some conditions, such as chemotherapy-induced neuropathic pain, it is difficult to distinguish whether pain or illness is the cause of depressed wheel running.…”

Rapastinel Accelerates Loss of Withdrawal Signs after Repeated Morphine and Blunts Relapse to Conditioned Place Preference

“…The fall in withdrawal signs from day 6 to day 9 is consistent with an abundant literature on opioid withdrawal in adults which shows that withdrawal signs are typically observed for up to 8-10 days after cessation of a treatment regimen. [53][54][55] The lack of sex or age differences in the magnitude of withdrawal could reflect the increasing dose regimen of morphine and the large dose of naloxone used which resulted in high withdrawal scores. Exaggerated naloxone-precipitated withdrawal has been reported in males compared to females 56 as has the absence of sex differences.…”

“…The fall in withdrawal signs from day 6 to day 9 is consistent with an abundant literature on opioid withdrawal in adults which shows that withdrawal signs are typically observed for up to 8-10 days after cessation of a treatment regimen. 53-55…”