Connexin and Pannexin Channels in Traumatic Spinal Cord Injury: Mechanisms of Secondary Injury and Therapeutic Opportunities

Traumatic spinal cord injury (tSCI) causes immediate mechanical damage followed by a secondary cascade of excitotoxic, oxidative, metabolic, and inflammatory events that expands tissue loss. Connexin (Cx) and pannexin (Panx) channels are increasingly recognized as potential amplifiers of this secondary injury. This focused review summarizes the structural and biophysical properties of these channels that are relevant to the injured spinal cord, their cellular localization, and the experimental evidence linking Cx43 and Panx1 activity to ATP release, calcium dysregulation, neuroinflammation, tissue loss, neuropathic pain, and functional recovery after tSCI. We also review genetic and pharmacologic studies of channel inhibition and discuss the limited but emerging evidence for Cx-mediated signaling in paralyzed skeletal muscle. Evidence is strongest for astrocytic Cx43 hemichannels, whereas the contribution of Panx1 after tSCI remains promising but less completely defined. Throughout, we distinguish findings demonstrated directly after tSCI from mechanisms inferred from other tissues or disease models and identify priorities for translational research.