Clinical relevance of chronic neuropathic pain phenotypes in mice: A comprehensive behavioral analysis

Despite a large number of preclinical studies performed each year, the safe and effective therapeutic interventions for chronic pain are scant. Therefore, it appears that pre-clinical modeling requires a systematically organized behavioral test paradigm to quantify the response of animals for a specific pain state. The present study, therefore, conceptualized a test battery to evaluate the behavioral changes in mice following neuropathic pain. We employed sciatic nerve chronic constriction injury (CCI) in C57BL/6 J mice to model chronic pain state. Mice were monitored for thermal hyperalgesia and grip strength for 30 days. Subsequently, mice underwent a behavioral test battery consisting of the nociceptive threshold, the affective and cognitive functions and motor coordination, and strength. Our results showed that CCI mice are insensitive to thermal stimuli. However, nerve-injured mice showed significant changes in neuromuscular coordination, basal anxiety, and hedonic state. Such impaired neuromuscular coordination is indicative of disability rather than the actual pain phenotype. While using the digital gait analysis, our study revealed rationales for the insensitivity of CCI mice to thermal stimuli. Our results suggest that the predictive validity of the CCI model necessitates a comprehensive behavioral test battery to select the clinically relevant and measurable phenotype to quantify chronic neuropathic pain.