Suppression of Voluntary Wheel Running in Rats Is Dependent on the Site of Inflammation: Evidence for Voluntary Running as a Measure of Hind Paw-Evoked Pain

Abstract

Decreased voluntary wheel running has recently been proposed as a preclinical pain measure for inflammatory pain, but whether this reflects pain evoked by use of the affected limbs is unknown. To assess the role of inflammation site as a determinant of this measure, complete Freund’s adjuvant (CFA), formalin, or equivolume vehicle was subcutaneously injected into the plantar surface of the hindpaws (bilateral) or L1 dorsum dermatome (leaving paws unaffected) of male Sprague Dawley rats. CFA-induced hindpaw mechanical allodynia (P<0.001) did not correlate with reduced voluntary wheel running. Intraplantar formalin did not attenuate voluntary running, despite eliciting robust licking/writhing/flinching behavior and hindpaw mechanical allodynia (P<0.001). Subcutaneous L1 dorsum dermatome formalin, but not CFA, induced licking/writhing/flinching behavior (P<0.001), but neither induced hindpaw mechanical allodynia or attenuated voluntary running. That voluntary running is decreased by hindpaw, but not L1 dorsum CFA, implies that the behavior is a measure of CFA-induced pain evoked by use of the affected limbs, rather than supraspinal pain processing that is independent of inflammation site. Furthermore, the results suggest that interpretation of voluntary wheel running data cannot simply be explained by correlation with mechanical allodynia. Perspective Whether decreased voluntary running is dependent on inflammation site is unknown. We show that intraplantar, but not L1 dorsum, CFA suppressed voluntary running and formalin induced licking/writhing/flinching behavior but no effect on voluntary running. These data suggest that suppressed voluntary running by CFA likely reflects pain evoked by use of the affected limbs.

Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats

“…Results from our pain-evoked experiments are consistent with previous studies showing that depression of wheel running recovers faster than reversal of evoked hypersensitivity (Cobos et al, 2012; Grace et al, 2014). This difference between pain-depressed and pain-evoked measures of nociception highlights one of the advantages of wheel running as a measure of nociception, namely that it reveals whether allodynia and hyperalgesia produce a functional deficit in behavior.…”

“…8), such that wheel running is almost completely inhibited in the first day after CFA administration and slowly recovers over the next 14 days. Previous studies in which access to the running wheel was limited needed bilateral injections of CFA into the hindpaws to produce a reduction in wheel running (Cobos et al, 2012; Grace et al, 2014). The sensitivity of our test is probably related to continuous access to the wheel in the rat’s home cage as opposed to assessing wheel running for 1 hr a day.…”

“…The sensitivity of our test is probably related to continuous access to the wheel in the rat’s home cage as opposed to assessing wheel running for 1 hr a day. Limiting access to the wheel for 1 hr a day via locking the wheel (Grace et al, 2014) or moving the animal to a chamber with a wheel (Cobos et al, 2012) may increase motivation to run. Moreover, testing rats outside the home cage may induce stress-induced antinociception.…”

“…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.…”

Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice

“…lactic acid and i.pl. CFA is consistent with previous studies that reported depression by these noxious stimuli of other behaviors, including liquid food consumption, locomotor activity, and wheel running in mice [8; 9; 27; 43] and burrowing, wheel running, and operant responding for electrical brain stimulation in rats [1; 15; 21; 22]. Nesting may be advantageous relative to these other behaviors as a dependent measure for studies of pain-depressed behavior for several reasons.…”