Pelvic Visceral Interaction Following Spinal Cord Injury

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 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) creates a serious health problem due to interruption of communication between supraspinal levels and the spinal cord circuitry. As such, there is loss of conscious sensation below the level of the lesion and loss of descending control of the spinal cord circuitry Both neurogenic bowels and bladders resulting from lesions above T12 are characterized by visceral hyperreflexia and outlet dyssynergia. For the bladder, this results in frequent high pressure non- voiding contractions, while in the bowel there is an increase in wall muscle tone. This activity is thought to arise from uninhibited C-fiber nociceptive mechanosensitive reflexes due to the loss of descending inhibition. Indeed, SCI has also been shown to result in heightened afferent responses in other organ systems distal to the lesion. Thus we suspect that the release of C-fibers from descending inhibitory control, "C-fiber release", is responsible for the time-dependent development of hyperreflexic neurogenic bladder and bowel in high level SCI and may also result in a chronic state of neurogenic inflammation due to uninhibited dorsal root reflexes in response to neurogenic activity. Moreover, release of inflammatory mediators from C-fibers would further sensitize these same afferents (homosensitization). Thus, within each organ, a positive escalation of peripheral and central sensitization may occur and we propose that the resultant chronic inflammatory state is responsible for much of the end organ tissue damage. Additionally, a significant amount of work from our laboratory and others supports the notion of pelvic visceral cross-sensitization (heterosensitization) in spinally intact animals, such that irritation insult of one pelvic organ results in neurogenic reflex irritation in neighboring organs innervated by the same spinal levels, and that this is also mediated by C-fibers. We envision that this process is facilitated by C-fiber release. Thus, we predict that unde conditions of SCI and C-fiber release, pelvic organ insults (e.g. infection) may more readily result in neurogenic inflammation of neighboring organs. For example, the repeated urinary tract infections common in SCI patients are predicted to easily result in a reflex neurogenic inflammation of the distal colon. Such effects may be occult in nature due to lack of pathogen in the cross-sensitized organ and lack of conscious sensation of discomfort or pain. As most of the nociceptive C-fibers of hollow viscera reside in the mucosa and submucosa, it is a common outcome of neurogenic inflammation to result in epithelial barrier dysfunction, which may have serious health consequences. Our overarching hypothesis is that interruption of descending control results in C-fiber release which in turn results in a sensitization of C-fiber nociceptors n each organ and amplification of responses to irritative stimuli in both the insulted and uninsulted organ. We will study homo- and heterosensitization of pelvic organ C-fiber afferents before and after acute spinal anesthesia (to eliminate descending control) in the same animals, and between chronic SCI animals and controls. We predict that threshold for noxious distension will be lowered following C-fiber release and that pelvic organ homo- and heterosensitization due to chemical peripheral irritation of one organ will likewise be enhanced. We therefore further expect that C-fiber sensitization and the degree of heterosensitization responsiveness increases progressively in parallel to the progressive development of C-fiber control of the sacral parasympathetic nucleus in chronic SCI.