Diminished enteric neuromuscular transmission in the distal colon following experimental spinal cord injury.

Neurogenic bowel following spinal cord injury (SCI) leads to decreased colonic motility, remodeling of the neuromuscular compartment and results in chronic evacuation difficulties. The distal colon of the rat serves a dual role for fluid absorption and storage that is homologous to the descending colon of humans. Dysmotility of the descending colon is one component of neurogenic bowel. We investigated the integrity of the enteric neuromuscular transmission responsible for the generation of excitatory and inhibitory junction potentials (EJPs and IJPs, respectively) in the distal colon of rats. We previously demonstrated a chronic reduction in colonic enteric neurons from rats with acute and chronic high-thoracic (T3) SCI and hypothesized that neurogenic bowel following T3-SCI results from diminished enteric neuromuscular transmission. Immunohistochemical labeling for myenteric neuronal nitric oxide synthase (nNOS) and choline acetyltransferase (ChAT) neurons demonstrated a significant loss of presumptive nitric oxide (NO) and acetylcholine (ACh) immunoreactive neurons in both 3-day and 3-week injured animals. Colonic neuromuscular transmission in response to transmural electrical stimulation of the colon was significantly reduced 3-days and 3-weeks following SCI in male rats. Specifically, cholinergic-mediated excitatory junction potentials (EJPs) and nitrergic-mediated slow inhibitory junction potentials (IJPs) were significantly reduced while ATP-mediated fast IJPs remained unaffected. We conclude that a reduction in excitatory and inhibitory enteric neuromuscular transmission contributes to neurogenic bowel observed following SCI, and that these loss-of-function changes involve enteric-mediated cholinergic and nitrergic pathways.

Comparing effects of rest with or without a NK1RA on fibrosis and sensorimotor declines induced by a voluntary moderate demand task.

OBJECTIVES: Fibrosis is one contributing factor in motor dysfunction and discomfort in patients with overuse musculoskeletal disorders. We pharmacologically targeted the primary receptor for Substance P, neurokinin-1, using a specific antagonist (NK1RA) in a rat model of overuse with the goal of improving tissue fibrosis and discomfort. METHODS: Female rats performed a low repetition, high force (LRHF) grasping task for 12 weeks, or performed the task for 12 weeks before being placed on a four week rest break, with or without simultaneous NK1RA treatment. Results were compared to control rats (untreated, or treated 4 weeks with NK1RA or vehicle). RESULTS: Rest improved LRHF-induced declines in grip strength, although rest plus NK1RA treatment (Rest/NK1RA) rescued it. Both treatments improved LRHF-induced increases in muscle TGFß1 and collagen type 1 levels, forepaw mechanical hypersensitivity (Rest/NK1RA more effectively), macrophage influx into median nerves, and enhanced collagen deposition in forepaw dermis. Only Rest/NK1RA reduced muscle hypercellularity. However, LRHF+4wk Rest /NK1RA rats showed hyposensitivity to noxious hot temperatures. CONCLUSIONS: While the NK1RA induced hot temperature hyposensitivity should be taken into consideration if this or related drug were used long-term, the NK1RA more effectively reduced muscle hypercellularity and improved grip strength and forepaw mechanical hypersensitivity.

Nerve transfer for restoration of lower motor neuron-lesioned bladder and urethra function: establishment of a canine model and interim pilot study results.

OBJECTIVE: Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. METHODS: Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. RESULTS: Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. CONCLUSIONS: New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.

Investigating neurogenic bowel in experimental spinal cord injury: where to begin?

The devastating losses following traumatic spinal cord injury (SCI) encompass the motor, sensory and autonomic nervous systems. Neurogenic bowel is a slow transit colonic dysfunction marked by constipation, rectal evacuation difficulties, decreased anorectal sensation, fecal incontinence or some combination thereof. Furthermore, neurogenic bowel is one of the most prevalent comorbidities of SCI and is recognized by afflicted individuals and caregivers as a lifelong physical and psychological challenge that profoundly affects quality of life. The restoration of post-injury control of movement has received considerable scientific scrutiny yet the daily necessity of voiding the bowel and bladder remains critically under-investigated. Subsequently, physicians and caregivers are rarely presented with consistent, evidence-based strategies to successfully address the consequences of dysregulated voiding reflexes. Neurogenic bowel is commonly believed to result from the interruption of the supraspinal control of the spinal autonomic circuits regulating the colon. In this mini-review, we discuss the clinical challenges presented by neurogenic bowel and emerging pre-clinical evidence that is revealing that SCI also initiates functional remodeling of the colonic wall concurrent with a decrease in local enteric neurons. Since the enteric input to the colonic smooth muscle is the final common pathway for functional contractions of the colon, changes to the neuromuscular interface must first be understood in order to maximize the efficacy of therapeutic interventions targeting colonic dysfunction following SCI.

Anatomical and Functional Changes to the Colonic Neuromuscular Compartment after Experimental Spinal Cord Injury.

A profound reduction in colorectal transit time accompanies spinal cord injury (SCI), yet the colonic alterations after SCI have yet to be understood fully. The loss of descending supraspinal input to lumbosacral neural circuits innervating the colon is recognized as one causal mechanism. Remodeling of the colonic enteric nervous system/smooth muscle junction in response to inflammation, however, is recognized as one factor leading to colonic dysmotility in other pathophysiological models. We investigated the alterations to the neuromuscular junction in rats with experimental high-thoracic (T3) SCI. One day to three weeks post-injury, both injured and age-matched controls underwent in vivo experimentation followed by tissue harvest for histological evaluation. Spontaneous colonic contractions were reduced significantly in the proximal and distal colon of T3-SCI rats. Histological evaluation of proximal and distal colon demonstrated significant reductions of colonic mucosal crypt depth and width. Markers of intestinal inflammation were assayed by qRT-PCR. Specifically, Icam1, Ccl2 (MCP-1), and Ccl3 (MIP-1α) mRNA was acutely elevated after T3-SCI. Smooth muscle thickness and collagen content of the colon were increased significantly in T3-SCI rats. Colonic cross sections immunohistochemically processed for the pan-neuronal marker HuC/D displayed a significant decrease in colonic enteric neuron density that became more pronounced at three weeks after injury. Our data suggest that post-SCI inflammation and remodeling of the enteric neuromuscular compartment accompanies SCI. These morphological changes may provoke the diminished colonic motility that occurs during this same period, possibly through the disruption of intrinsic neuromuscular control of the colon.