Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia

Abstract

Inflammatory pain impacts adversely on the quality of life of patients, often resulting in motor disabilities. Therefore, we studied the effect of peripheral inflammation induced by intraplantar administration of complete Freund’s adjuvant (CFA) in mice on a particular form of voluntary locomotion, wheel running, as an index of mobility impairment produced by pain. The distance travelled over 1 h of free access to activity wheels decreased significantly in response to hindpaw inflammation, peaking 24 h after CFA administration. Recovery of voluntary wheel running by day three correlated with the ability to support weight on the inflamed limb. Inflammation-induced mechanical hypersensitivity, measured with von Frey hairs, lasted considerably longer than the impaired voluntary wheel running and is not driving, therefore, the change in voluntary behavior. The CFA-induced decrease in voluntary wheel running was dose-dependently reversed by subcutaneous (s.c.) administration of anti-inflammatory and analgesic drugs, including naproxen (10–80 mg/kg), ibuprofen (2.5–20 mg/kg), diclofenac (1.25–10 mg/kg), celecoxib (2.5–20 mg/kg), prednisolone (0.62–5 mg/kg) and morphine (0.06–0.5 mg/kg), all at much lower doses than reported in most rodent models. Furthermore, the doses that induced recovery in voluntary wheel running did not reduce CFA-induced mechanical allodynia, indicating a greater sensitivity of the former as a surrogate measure of inflammatory pain. We conclude that monitoring changes in voluntary wheel running in mice during peripheral inflammation is a simple, observer-independent objective measure of functional changes produced by inflammation, likely more aligned to the global level of pain than reflexive measures, and much more sensitive to analgesic drug effects.

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

“…This study extended previous findings by using a higher intensity noxious stimulus (5.6% vs 1.8% lactic acid, see below), and despite use of this higher intensity stimulus, both ketoprofen and morphine retained efficacy to block acid-induced depression of ICSS. These results also agree with previous studies showing painrelated and analgesic-reversible depression of other behaviors including feeding (Kwilasz and Negus, 2012;Stevenson et al, 2006), locomotion (Cobos et al, 2012;Stevenson et al, 2009), burrowing (Andrews et al, 2012), and positively reinforced operant responding (Martin et al, 2004).…”

“…The mechanisms of pain-related depression are not well understood. In preclinical studies, injury, disease, or treatment with experimental noxious stimuli can produce an analgesic-reversible depression of behaviors that include feeding (Kwilasz and Negus, 2012;Stevenson et al, 2006), locomotion (Cobos et al, 2012;Stevenson et al, 2009), burrowing (Andrews et al, 2012), and positively reinforced operant responding (Martin et al, 2004). For example, intracranial self-stimulation (ICSS) is an operant procedure in which subjects emit a learned response such as a lever press to earn pulses of electrical stimulation to brain reward areas (Carlezon and Chartoff, 2007;Olds and Milner, 1954).…”

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

“…Second, we chose a modified plantar incision (injury to the skin and underlying muscle) to model sterile tissue injury-based inflammation (16)(17)(18). Both of these models evoke strong pain-like behavior in rodents (17,19), and are widely used for preclinical mechanism-based and pharmacological studies.…”

Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues

“…However, it has been difficult to identify changes in behavior of mice that are expected to be experiencing pain. Recently, Clifford Woolf and coworkers developed a paradigm in which they observed decreased voluntary wheel running in mice following hindpaw CFA injection (16). We adapted this procedure to compare wheel-running activity of WT and PTH2R-KO mice.…”

“…Wheel-running and weight-bearing tests were adapted from Cobos et al (16). Mice were singly housed in standard rat cages for 1 wk, then telemetric running wheels (ENV-044; Med Associates) were placed in the cages continuously for 3 d followed by 1 h at the same time every day for the remainder of the experiment.…”