Molecular and electrophysiological changes induced by skin incision: implications for the development of chronic pain

The development of chronic neuropathic pain (CNP) is a serious medical problem. Major etiological factors include damage to peripheral nerves and damage to peripheral tissue (even minor damage), particularly repeated tissue damage. Using skin incision as a model for tissue damage – one where axons are injured but remain in contact with their target tissue – we have determined that sensory neuron responses are similar, but not identical, to those evoked by injury to a peripheral nerve. Using qPCR and immunohistochemistry, we show that skin incision alters the expression of pain-related genes for ion channels, transduction channels, and regeneration growth-associated factors. In the condition of repeated tissue damage, these changes are either amplified or different from the changes evoked by single incision. Many of these effects are maintained long after the wound has healed and are resistant to standard clinical interventions, but can be modulated. Furthermore, using patch clamp electrophysiology, we have observed long-lasting altered electrophysiological characteristics in sensory neurons innervating the incised skin. Our results suggest that axonal injury responses may contribute to the development of CNP after tissue damage. This mechanism may be distinct from the sensory neuron responses to tissue damage-induced tissue inflammation, which is the current focus of treatment efforts. Repeated tissue injury is a lifelong condition for many patient communities, particularly those dealing with mobility issues. For communities such as those with spinal cord injury, traumatic brain injury, stroke, and other neurological disorders which themselves may constitute a “priming event,” our findings may represent a new consideration for the impact that tissue damage may have on the health and well-being of individuals and on developing strategies for treatment. This study is funded through the Kentucky Spinal Cord and Head Injury Research Trust, Kentucky Spinal Cord Injury Research Center Traineeship, Paralyzed Veterans of America Fellowship, and NIH.