Abstract
Spinal cord injury (SCI) triggers profound changes in visceral and somatic targets of sensory neurons below the level of injury. Despite this, little is known about the influence of injury to the spinal cord on sensory ganglia. One of the defining characteristics of sensory neurons is the size of their cell body: for example, nociceptors are smaller in size than mechanoreceptors or proprioceptors. In these experiments, we first used a comprehensive immunohistochemical approach to characterize the size distribution of sensory neurons after high- and low-thoracic SCI. Male Wistar rats (300 g) received a spinal cord transection (T3 or T10) or sham-injury. At 30 days post-injury, dorsal root ganglia (DRGs) and spinal cords were harvested and analyzed immunohistochemically. In a wide survey of primary afferents, only those expressing the capsaicin receptor (TRPV1) exhibited somal hypertrophy after T3 SCI. Hypertrophy only occurred caudal to SCI and was pronounced in ganglia far distal to SCI (i.e., in L4-S1 DRGs). Injury-induced hypertrophy was accompanied by a small expansion of central territory in the lumbar spinal dorsal horn and by evidence of TRPV1 upregulation. Importantly, hypertrophy of TRPV1-positive neurons was modest after T10 SCI. Given the specific effects of T3 SCI on TRPV1-positive afferents, we hypothesized that these afferents contribute to autonomic dysreflexia (AD). Rats with T3 SCI received vehicle or capsaicin via intrathecal injection at 2 or 28 days post-SCI; at 30 days, AD was assessed by recording intra-arterial blood pressure during colo-rectal distension (CRD). In both groups of capsaicin-treated animals, the severity of AD was dramatically reduced. While AD is multi-factorial in origin, TRPV1-positive afferents are clearly involved in AD elicited by CRD. These findings implicate TRPV1-positive afferents in the initiation of AD and suggest that TRPV1 may be a therapeutic target for amelioration or prevention of AD after high SCI.
Highlights
The original formulation of the neurotrophic hypothesis by Hamburger and Levi-Montalcini (1949) asserted that the survival of neurons depends on cues produced in limiting amounts in target tissues
Peptidergic (NGF-sensitive) nociceptors were identified by expression of Substance P (SP; Figure 2A), while non-peptidergic nociceptors were identified by binding of the glycoprotein isolectin B4 (IB4, from Bandeiraea simplicifolia) and the ionotropic ATP purinoceptor P2X3 (Figures 2B,C)
SPINAL CORD INJURY-INDUCED HYPERTROPHY WAS MOST PRONOUNCED IN LUMBOSACRAL SENSORY GANGLIA Since our initial observations were made in dorsal root ganglion (DRG) far distal to T3 Spinal cord injury (SCI) (Figures 1–3, L4/L5 DRG), we examined the extent of SCI-induced hypertrophy in TRPV1-positive neurons at different rostro-caudal levels (Figure 4)
Summary
The original formulation of the neurotrophic hypothesis by Hamburger and Levi-Montalcini (1949) asserted that the survival of neurons depends on cues produced in limiting amounts in target tissues. The subsequent discovery of nerve growth factor (NGF) as a survival factor for sympathetic and sensory neurons (Cohen et al, 1954) validated this hypothesis, and extended the role of neurotrophic factors beyond developmental neuronal survival: target-derived NGF and numerous other neurotrophic molecules maintain the phenotype of neurons during adulthood. This has been arguably best demonstrated in experiments on primary afferent neurons of the dorsal root ganglion (DRG), a heterogeneous population of neurons responsible for transmission of information from the periphery (somatic) and internal milieu (visceral) to the spinal cord and brainstem. Among the small dark cells, for example, there are peptidergic and non-peptidergic subtypes, which happen to be sensitive to different neurotrophic factors
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