Neutralizing Intraspinal Nerve Growth Factor Blocks Autonomic Dysreflexia Caused By Spinal Cord Injury

Abstract

Autonomic dysreflexia is a condition that develops after spinal cord injury in which potentially life-threatening episodic hypertension is triggered by stimulation of sensory nerves in the body below the site of injury. Central sprouting of small-diameter primary afferent fibers in the dorsal horn of the spinal cord occurs concurrently with the development of this condition. We propose a model for the development of autonomic dysreflexia in which increased nerve growth factor (NGF) in the injured cord stimulates small-diameter primary afferent fiber sprouting, thereby magnifying spinal sympathetic reflexes and promoting dysreflexia. We identified this population of afferent neurons using immunocytochemistry for calcitonin gene-related peptide. Blocking intraspinal NGF with an intrathecally-delivered neutralizing antibody to NGF prevented small-diameter afferent sprouting in rats 2 weeks after a high thoracic spinal cord transection. In the same rats, this anti-NGF antibody treatment significantly decreased (by 43%) the hypertension induced by colon stimulation. The extent of small-diameter afferent sprouting after cord transection correlated significantly with the magnitude of increases in arterial pressure during the autonomic dysreflexia. Neutralizing NGF in the spinal cord is a promising strategy to minimize the life-threatening autonomic dysreflexia that develops after spinal cord injury.

Leg sympathetic response to noxious skin stimuli is similar in high and low level human spinal cord injury

“…Although a lack of inhibition from higher centers is prerequisite to the development of AD (Curt et al, 1996), a time dependent reorganization of the neural circuitry and changes in peripheral receptor sensitivity contribute to this pathologic reflex (Krassioukov et al, 2002;Weaver et al, 2002). In animal models, plasticity has been documented in many components of the sympathetic reflex arc including small diameter primary afferents (Krenz et al, 1999;Weaver et al, 2001) and sympathetic preganglionic neurons (Krassioukov and Weaver, 1996), and these changes correspond to the emergence (Krassioukov and Weaver, 1995) and severity (Krenz et al, 1999) of AD. All of the subjects in the current study were at least 2-years post injury, placing them in a chronic state where any plastic changes in the sympathetic reflex pathways would have probably already occurred.…”

Orthostatic hypotension following spinal cord injury: understanding clinical pathophysiology

“…Factors likely to underlie orthostatic hypotension and symptoms of orthostatic 26 Reduced sympathetic tone below the lesion 6,27,28 Morphologic changes in sympathetic neurons [29][30][31] Plasticity within spinal circuits [31][32][33] Peripheral a-adrenoceptor hyper-responsiveness 34 intolerance in SCI patients are discussed below, and summarised in Table 2.…”

Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats

“…For example, sprouting of peripheral fibers has been noted after SCI [29], likely impacting nociception [33], autonomic function [28,37], and proprioception [17]. Multiple studies have begun to elucidate a role for plasticity in various neurotransmitter systems in the lumbar spinal cord after SCI and how those changes relate to changes in motor performance [14,24,32,34].…”