Role of the Intraspinal Plasticity in Automatic Dysreflexia

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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 (eg. more blood flow to the muscles). The reason the sympathetic neurons are so sensitive is that descending inhibitory pathways ITom higher brain centers are interrupted as a result of the SCI. In spinal injured patients, autonomic dysreflexia is ITequently 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 ITom 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 neuron 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 (NGF Adts) into thoracic, lumbar and sacral spinal cord to trigger sprouting to determine which regions are critical for eliciting autonomic dysreflexia. Over expression ofNGFAdts only in the T13/Ll and L6/Sl segments produced significant increases in arterial blood pressure evoked by colorectal distension versus injured controls injected with GFP Adts. This suggests that following spinal transection, pelvic visceral information is relayed ITom 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 ofbiotinylated dextran amine (BDA) ITom the L6/Sl cord, and retrograde transynaptic tracing of pseudorabies virus (PRV) from sympathetic pre-vertebral ganglia to identify the neural pathways that transmits visceral information ITom lumbosacral to thoracic cord after SCI. Secondly, since NGF Adts exacerbate dysreflexia, we will establish whether this correlates with increased pathway sprouting. Thirdly, since it is possible that NGF-independent afferents playa 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 debilitatin!! comDlicationof SCI.
Effective start/end date8/2/044/30/11


  • National Institute of Neurological Disorders & Stroke: $1,659,849.00


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