Mechanisms of Autonomic Dysreflexia Following Spinal Cord Injury

A common result of injury to the brain or the spinal cord is the appearance of functional deficits or paralysis that are generally irreversible due to the inability of nerve cells within the brain or spinal cord of mammals to regrow or regenerate after injury. Following complete spinal cord injury, noxious stimulation of cutaneuous or visceral sensory nerves below the injury site can create exaggerated spinal and sympathetic reflexes leading to a condition termed autonomic dysreflexia that elicits potentially life-threatening episodic hypertension. Paradoxically, sprouting of regenerating sensory fibers into the injured spinal cord occurs concomitantto the development of autonomic dysreflexia, and nerve growth factor (NGF), in particular, stimulates fiber sprouting and magnifies spinal sympathetic reflexes that promote dysreflexia. To directly address the pathophysiological mechanisms involved in autonomic dysreflexia, we will first transect the spinal cords of anesthetized adult rats. We will then immediately inject recombinant adenoviruses encoding NGF cDNA, as well as other growth-promoting proteins or a potent growth inhibitor, into the spinal cord below the injury to transfect and genetically modify endogenous cells in an attempt to increase or abolish the central sprouting of sensory fibers below the injury. We will then correlate this altered axonal sprouting with autonomic dysreflexia as measured by increased arterial blood pressure following colorectal distention. Importantly, the combined physiological and morphological data will help establish whether autonomic dysreflexia is regulated at the level of the spinal cord interneurons or in the peripheral sensory or autonomic systems. We believe that the established injury model and gene delivery paradigm presented in this proposal will provide important mechanistic information regarding a potentially lifethreatening condition following acute spinal cord injury in humans, as well as a potential therapeutic intervention for its alleviation. Importantly, we will be able to manipulate the spinal cord microenvironment by modifying endogenous cells to enhance and/or inhibit regeneration of injured neurons following injury. In this regard, the methodologies we will employ may also be used to address a multitude of questions regarding the mechanisms that govern successful and/or abortive regeneration. in the injured spinal cord.