Effects of Ketoprofen and Morphine on Pain‐Related Depression of Nestlet Shredding in Male and Female Mice

Abstract

A primary goal in the treatment of pain is restoration of behaviors that are disrupted by pain. Preclinical pain researchers have attempted to develop procedures for evaluation of pain-related functional impairment in laboratory animals. The goal of the present study was to develop and validate a simple, low cost procedure for the objective evaluation of pain-related depression of home cage behavior in mice. On test days, a 5 × 5 cm Nestlet was weighed prior to being suspended from the wire lid of the home cage of individually housed male and female ICR mice. Over the course of experimental sessions, mice removed pieces of the suspended Nestlet, and began to build a nest with the material they removed. Thus, the weight of the pieces of Nestlet that remained suspended at various time points in the session provided an indicator of the rate of this behavior. The results indicate that Nestlet shredding was stable with repeated testing, and shredding was depressed by intraperitoneal injection of lactic acid. The nonsteroidal anti-inflammatory drug ketoprofen blocked pain-related depression of shredding, but did not block depression of shredding by a non-pain stimulus, the kappa opioid receptor agonist U69,593. These findings support the validity of this procedure for assessing the expression and treatment of pain-related functional impairment in mice. In contrast, the µ-opioid receptor agonist morphine did not block pain-related depression of shredding when tested up to doses that depressed shredding in the absence of lactic acid. This finding does not support the validity of this procedure for assessing the expression and treatment of pain-related functional impairment in mice. Two observations from the morphine experiments suggest further research with this procedure is warranted. First, unlike ketoprofen, morphine disrupted shredding when administered in the absence of lactic acid. Thus, it is possible that functional impairment produced by morphine is incompatible with antinociception as defined in this procedure, and manipulations that attenuate morphine-induced functional impairment might unmask antinociception. Second, the current study includes male and female mice, and the data from each sex were pooled for the primary analyses. When the data for male and female mice were segregated, the data suggest that studies designed and powered to examine sex differences might be worthwhile. For instance, males appear to be more sensitive to morphine-induced depression of shredding than females. The findings of the present study raise questions about the ability of this procedure to contribute to improvements in predictive validity in analgesic drug development, but the findings complement previous research on pain-related functional impairment. A growing body of research indicates that drug effects in the absence of pain-stimuli and the behavioral endpoint are key determinants of the effects of established analgesic drugs in these procedures. Understanding these and other behavioral and environmental variables will be an important component of efforts to improve translation from preclinical research to clinical application.