Autonomic dysreflexia is a potentially life-threatening complication of spinal cord injury (SCI) that is characterized by episodic hypertension (high blood pressure) due to sudden, massive discharge of the sympathetic neurons in the injured spinal cord. The sympathetic neurons enable the 'fight or flight' response of an individual (e.g. more blood flow to the muscles). The reason the sympathetic neurons are so sensitive is that descending inhibitory pathways from higher brain centers are interrupted as a result of the SCI. In spinal injured patients, autonomic dysreflexia is frequently triggered by distension of, or activity within pelvic viscera (bladder or bowel). Therefore, distension of the bladder or bowel sends a signal via sensory neurons to the sacral spinal cord (the lower back). From here, the signal is relayed to thoracic and lumbar sympathetic neurons (chest region of the cord) by relay neurons. Because there is no modulating influence from the higher brain, the action of the sympathetic neurons is unopposed. As a result, the sudden increase in their activity following visceral stimulation causes a sudden rise in blood pressure (up to 200 mmHg) that can cause potentially fatal brain or spinal hemorrhage, seizures, as well as severe headache, shivering, sweating and anxiety. Unfortunately, little is known about the anatomical or functional relationships between the visceral sensory neurons, the spinal relay neurons, and the sympathetic neurons. We propose to use a variety of histological and physiological techniques in a well-defined rat model of autonomic dysreflexia to discover the anatomical connections between these three types of neurons that are critical for the development of autonomic dysreflexia. It is currently not known how visceral sensory information entering the lumbosacral spinal cord is relayed to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the thoracolumbar cord. Since nociceptive afferent sprouting after SCI is NGF-dependent and is correlated with the incidence of autonomic dysreflexia, we have injected temperature sensitive adenoviruses (Adts) encoding nerve growth factor (NGFAdts) into thoracic, lumbar and sacral spinal cord to trigger sprouting to determine which regions are critical for eliciting autonomic dysreflexia. Overexpression of NGFAdts only in the T13/L1 and L6/S 1 segments produced significant increases in arterial blood pressure evoked by colorectal distension versus injured controls injected with GFPAdts. This suggests that following spinal transection, pelvic visceral information is relayed from its input site in the lumbosacral dorsal horn to the IML via unidentified projection pathways. This proposal has 4 goals. Firstly, we will use anterograde tracing of biotinylated dextran amine (BDA) from the L6/S 1 cord, and retrograde transsynaptic tracing of pseudorabies virus (PRV) from sympathetic pre-vertebral ganglia to identify the neural pathways that transmit visceral information from lumbosacral to thoracic cord after SCI. Secondly, since NGFAdts exacerbate dysreflexia, we will establish whether this correlates with increased pathway sprouting. Thirdly, since it is possible that NGF-independent afferents play a role in autonomic dysreflexia, we will inject Adts encoding other growth factors, FGF-2, NT-3, BDNF and GDNF, into multiple levels of the lumbosacral cord. We will also assess their direct influence on lumbar propriospinal neurons by injecting them in the distal thoracic cord. Finally, based on our recent evidence, we will inject chemorepulsive semaphorin3aAdts after injury into the lumbosacral spinal cord in an attempt to thwart early sprouting events and minimize dysreflexia, as well as establish whether chronic injections are capable of inducing retraction of established sprouts. This information will form the basis for developing potential treatments for this common and debilitating complication of SCI.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZNS1-SRB-R (06))
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Kleitman, Naomi
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University of Kentucky
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Eldahan, Khalid C; Rabchevsky, Alexander G (2018) Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management. Auton Neurosci 209:59-70
Rabchevsky, Alexander G; Patel, Samir P; Lyttle, Travis S et al. (2012) Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. Front Physiol 3:329
Rabchevsky, A G; Patel, S P; Duale, H et al. (2011) Gabapentin for spasticity and autonomic dysreflexia after severe spinal cord injury. Spinal Cord 49:99-105
Derbenev, Andrei V; Duale, Hanad; Rabchevsky, Alexander G et al. (2010) Electrophysiological characteristics of identified kidney-related neurons in adult rat spinal cord slices. Neurosci Lett 474:168-72
Duale, Hanad; Lyttle, Travis S; Smith, Bret N et al. (2010) Noxious colorectal distention in spinalized rats reduces pseudorabies virus labeling of sympathetic neurons. J Neurotrauma 27:1369-78
Duale, Hanad; Hou, Shaoping; Derbenev, Andrei V et al. (2009) Spinal cord injury reduces the efficacy of pseudorabies virus labeling of sympathetic preganglionic neurons. J Neuropathol Exp Neurol 68:168-78
Hou, S; Duale, H; Rabchevsky, A G (2009) Intraspinal sprouting of unmyelinated pelvic afferents after complete spinal cord injury is correlated with autonomic dysreflexia induced by visceral pain. Neuroscience 159:369-79
Hou, Shaoping; Duale, Hanad; Cameron, Adrian A et al. (2008) Plasticity of lumbosacral propriospinal neurons is associated with the development of autonomic dysreflexia after thoracic spinal cord transection. J Comp Neurol 509:382-99
Onifer, Stephen M; Rabchevsky, Alexander G; Scheff, Stephen W (2007) Rat models of traumatic spinal cord injury to assess motor recovery. ILAR J 48:385-95
Rabchevsky, Alexander G (2006) Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury. Prog Brain Res 152:265-74

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