Spinal cord injury (SCI) results in a loss of normal motor and sensory function, leading to severe disability and reduced quality of life. A large proportion of individuals with SCI also suffer from neuropathic pain symptoms. The causes of abnormal pain sensations are not well understood, but can include aberrant sprouting and reorganization of injured or spared sensory afferent fibers. L1 is a cell adhesion molecule that contributes to axonal outgrowth, guidance and fasciculation in development as well as synapse formation and plasticity throughout life. In the present study, we used L1 knockout (KO) mice to determine whether this adhesion molecule contributes to sensory dysfunction after SCI. Both wild-type (WT) and KO mice developed heat hyperalgesia following contusion injury, but the KO mice recovered normal response latencies beginning at 4 weeks post-injury. Histological analyses confirmed increased sprouting of sensory fibers containing calcitonin gene related peptide (CGRP) in the deep dorsal horn of the lumbar spinal cord and increased numbers of interneurons expressing protein kinase C gamma (PKCγ) in WT mice 6 weeks after injury. In contrast, L1 KO mice had less CGRP+ fiber sprouting, but even greater numbers of PKCγ+ interneurons at the six week time point. These data demonstrate that L1 plays a role in maintenance of thermal hyperalgesia after SCI in mice, and implicate CGRP+ fiber sprouting and the upregulation of PKCγ expression as potential contributors to this response.

Following spinal cord injury (SCI), individuals lose normal sensation and often develop debilitating neuropathic pain. Basic research has helped to elucidate many of the underlying mechanisms, but unanswered questions remain concerning how sensation changes after SCI and potential negative consequences of regenerative therapies. Mouse models provide an opportunity to explore these questions using genetic markers and manipulations. However, despite the increasing use of mice in pain and sensory research, the responses to sensory stimuli after SCI are poorly characterized in this species. This study evaluated behavioral responses to mechanical and nociceptive stimuli applied to the hindlimbs and the dorsal trunk in C57BL/6 mice after mid-thoracic SCI. Adult mice were subjected to laminectomy, contusion injuries of different severities, or complete transections to test the hypothesis that the patterns of sensory pathology depend on the extent of tissue damage at the injury site. In the hind paws, hyper-responsiveness to a heat stimulus developed independent of injury severity, while mechanical sensitivity decreased, except after the most severe contusion injuries sparing less than 2% of the white matter at the injury site, when enhanced sensitivity was observed. On the trunk, mechanical and pin prick testing revealed diminished sensitivity at and below the injury level, while responses above the level of the injury were unchanged. The contrast in injury severity threshold for thermal and mechanical hypersensitivity in the hind paws suggests that these responses have different underlying mechanisms. These results establish essential baseline information for murine studies of pain and changes in sensation after SCI.

Exercise provides a number of important benefits after spinal cord injury in clinical studies and animal models. However, the amount of functional improvement in overground locomotion obtained with exercise alone has been limited thus far, for reasons that are still poorly understood. One hypothesis is that the complex network of endogenous extracellular matrix components, including chondroitin sulfate proteoglycans (CSPGs), can inhibit exercise-induced remodeling and limit plasticity of spared circuitry in the adult central nervous system. Recent animal studies have shown that chondroitinase ABC (ChABC) can enhance plasticity in the adult nervous system by cleaving glycosaminoglycan sidechains from CSPGs. In this article we review the current literature on plasticity observed with locomotor training and following degradation of CSPGs with ChABC and then present a rationale for the use of exercise combined with ChABC to promote functional recovery after spinal cord injury. We also present results of a preliminary study that tested the simplest approach for combining these treatments; use of a single intraparenchymal injection of ChABC administered to the lumbar enlargement of mice with voluntary wheel running exercise after a mid-thoracic spinal contusion injury. The results are negative, yet serve to highlight limitations in our understanding of the most effective protocols for combining these approaches. Further work is directed to identify the timing, type, and quantity of exercise and pharmacological interventions that can be used to maximize functional improvements by strengthening appropriate synaptic connections.