Comprehensive analysis of neurobehavior associated with histomorphological alterations in a chronic constrictive nerve injury model through use of the CatWalk XT system

Abstract

Object Neuropathic pain is debilitating, and when chronic, it significantly affects the patient physically, psychologically, and socially. The neurobehavior of animals used as a model for chronic constriction injury seems analogous to the neurobehavior of humans with neuropathic pain. However, no data depicting the severity of histomorphological alterations of the nervous system associated with graded changes in neurobehavior are available. To determine the severity of histomorphological alteration related to neurobehavior, the authors created a model of chronic constrictive injury of varying intensity in rats and used the CatWalk XT system to evaluate neurobehavior. Methods A total of 60 Sprague-Dawley rats, weighing 250–300 g each, were randomly assigned to 1 of 5 groups that would receive sham surgery or 1, 2, 3, or 4 ligatures of 3-0 chromic gut loosely ligated around the left sciatic nerve. Neurobehavior was assessed by CatWalk XT, thermal hyperalgesia, and mechanic allodynia before injury and periodically after injury. The nerve tissue from skin to dorsal spinal cord was obtained for histomorphological analysis 1 week after injury, and brain evoked potentials were analyzed 4 weeks after injury. Results. Significant differences in expression of nerve growth factor existed in skin, and the differences were associated with the intensity of nerve injury. After injury, expression of cluster of differentiation 68 and tumor necrosis factor–α was increased, and expression of S100 protein in the middle of the injured nerve was decreased. Increased expression of synaptophysin in the dorsal root ganglion and dorsal spinal cord correlated with the intensity of injury. The amplitude of sensory evoked potential increased with greater severity of nerve damage. Mechanical allodynia and thermal hyperalgesia did not differ significantly among treatment groups at various time points. CatWalk XT gait analysis indicated significant differences for print areas, maximum contact maximum intensity, stand phase, swing phase, single stance, and regular index, with sham and/or intragroup comparisons. Conclusions. Histomorphological and electrophysiological alterations were associated with severity of nerve damage. Subtle neurobehavioral differences were detected by the CatWalk XT system but not by mechanical allodynia or thermal hyperalgesia. Thus, the CatWalk XT system should be a useful tool for monitoring changes in neuropathic pain, especially subtle alterations.

Intrathecal Injection of Dual Zipper Kinase shRNA Alleviating the Neuropathic Pain in a Chronic Constrictive Nerve Injury Model

“…The characteristic findings of increased intensity of chronic constrictive injury (CCI) paralleled the severity of inflammatory response in the dorsal root ganglion cells published in our group [24]. In general, DLK is most abundantly expressed in nerve tissue and is especially distributed in neurons [13].…”

“…The intensity of nerve injury was correlated to the inflammatory response over the dorsal root ganglion and somatosensory cortex, as well as the severity of nerve degeneration and the works of [24,30]. Upon nerve axotomy, the injured nerve showed up-regulation of DLK over the neuron and dorsal root ganglion and decreased nerve degeneration was attenuated by the DLK gene knockdown [13,14,17].…”

“…The physiology and structural remodeling the learning circulatory of the hippocampus were noted when subjected to stress or chronic pain [32]. In our previous publication, the severity of chronic constriction injury was highly correlated with the intensity of inflammatory response in the hippocampus and attenuation of the neuropathic pain caused the decreased expression of the inflammatory response in the hippocampus [24,30]. As known, deletion of DLK in the neuron is essential for the improvement of the neuropathic pain or attenuation of nerve degeneration after nerve injury, but there was no mention of DLK distribution in the hippocampus [18,33].…”

Gait analysis in a mouse model resembling Leigh disease

“…Major advantage of this paradigm is the objectivity of the system reducing inter-and intra-observer variability. The automated CatWalk gait analysis method is also applied in models involving other types of pain and peripheral nerve damage and movement disorders like Parkinson's disease [21][22][23]. Abnormal gait was described in mice exhibiting (cerebellar) ataxia, by using paw print area, contact area, base of support of the hindpaws, stand, swing and step regularity [24][25][26].…”

A pharmacological and transcriptomic approach to exploring novel pain targets

“…While gait analysis has previously been utilised to quantify pain-related behaviours in other rodent models of inflammatory and neuropathic pain 297,298 , gait abnormalities have not previously been assessed in rodent models of burn injury. Here, the chapter provides for the first time a detailed characterisation of gait analysis following a unilateral burn-injury in mice using the CatWalk XT.…”