Plasticity in the injured spinal cord: can we use it to advantage to reestablish effective bladder voiding and continence?

Abstract

Micturition is coordinated at the level of the spinal cord and the brainstem. Spinal cord injury therefore directly interrupts spinal neuronal pathways to the brainstem and results in bladder areflexia. Some time after injury, however, dyssynergic bladder and sphincter function emerges. The changes mediating the appearance of bladder function after spinal cord injury are currently unknown. Primary afferent neurons have been shown to sprout in response to spinal cord injury. Sprouting primary afferents have been linked to the pathophysiology of centrally manifested disorders, such as autonomic dysreflexia and neuropathic pain. It is proposed that sprouting of bladder primary afferents contributes to disordered bladder functioning after spinal cord injury. During development of the central nervous system, the levels of specific neuronal growth-promoting and guidance molecules are high. After spinal cord injury, some of these molecules are upregulated in the bladder and spinal cord, suggesting that axonal outgrowth is occurring. Sprouting in lumbosacral spinal cord is likely not restricted to neurons involved in the micturition reflex. Furthermore, sprouting of some afferents may be contributing to bladder function after injury, whereas sprouting of others might be hindering emergence of function. Thus selective manipulation of sprouting targeting afferents that are contributing to emergence of bladder function after injury is critical. Further research regarding the role that neuronal sprouting plays in the emergence of bladder function may contribute to improved treatment of bladder dyssynergia after spinal cord injury.

Introduction

Axonal outgrowth and pathfinding are limited within the adult central nervous system (CNS). During development, however, axonal outgrowth and pathfinding are critical for a properly wired, and thus, functioning nervous system (Crowley et al., 1994; Maier et al., 1999). Developing neurons exist within an environment rich in molecules that are important for axonal guidance, outgrowth and targeting (Drescher et al., 1997; Dickson and Senti, 2002). These molecules act by either attracting or repelling the leading edge of growing axons (the growth cone), thus directing developing axons to their appropriate targets (Gallo and Letourneau, 2004; Gordon-Weeks, 2004). It has been proposed that there is a decrease or absence in growth-promoting molecules once adulthood is reached, and that this is why the adult CNS is unable to promote neuronal plasticity. For this reason, much research has focused on reproducing the molecular environment that is present during development with the hopes of aiding neuronal repair and regrowth after CNS injury.

On the other hand, CNS plasticity may also have negative consequences. There is increasing evidence that upregulation of key elements involved in aiding axonal outgrowth contributes to the pathogenesis of centrally manifested disorders. These include neuropathic pain (Theodosiou et al., 1999) as well as autonomic dysreflexia (Krenz et al., 1999). Spinal cord injury, depending on its severity, affects many centrally mediated visceral functions, including bladder function. Normal micturition requires supraspinal integration at the level of the pontine micturition center (Barrington, 1915). Suprasacral spinal cord injury disconnects the parasympathetic spinal outflow from the pons rendering the bladder areflexic. Bladder function is novel in that micturition emerges some time after spinal cord injury without neuronal integration at the level of the brainstem (Yoshiyama et al., 1999). However, post spinal cord injury, voiding is dysfunctional due to lack of coordination between the detrusor muscle and the external urethral sphincter, clinically termed detrusor–sphincter dyssynergia (Kruse et al., 1993). For spinal cord-injured patients, this results in hyperactive inefficient bladder function. Treatments for these patients focus on alleviating hyperactive bladder dysfunction pharmacologically via non-selective anti-muscarinic agents (Pannek et al., 2000), reducing dyssynergy surgically through external sphincterotomy (Reynard et al., 2003) and generating voiding on demand by sacral anterior root stimulation (Schumacher et al., 1999).

Spinal cord injury has been shown to induce neuronal sprouting within the spinal cord. Plasticity of neurons within the micturition reflex circuit is a possible mechanism by which bladder function emerges after spinal cord injury. Continued research regarding the role that neuronal sprouting plays in bladder function after spinal cord injury will aid in the development of treatment methods which target the cause of bladder dysfunction after injury rather than its symptoms. In this chapter, we will discuss the evidence for neuronal plasticity occurring in the micturition reflex path and how this may mediate the emergence of bladder dysfunction after spinal cord injury.

The micturition reflex is subject to extensive remodeling during development. For approximately the first 3 weeks of life, micturition in rats and cats is evoked by stimulation of somatic perineal afferents, via licking of the perineum by the mother (Maggi et al., 1986; Thor et al., 1989). The efferent limb, through the pelvic nerve, stimulates detrusor contraction, thereby facilitating bladder emptying. This somatic-bladder reflex is a spinal reflex that becomes progressively weaker throughout postnatal life to a point where there appears to be a switch from spinally mediated to supraspinally mediated micturition (de Groat et al., 1998). Micturition in these animals, as in adults, is in response to bladder stretch, having both afferent and efferent limbs in the pelvic nerve. This switch is thought to be accompanied by major changes in neuronal circuits used to elicit micturition.

Developing nervous systems undergo a great deal of synaptic strengthening and neuronal refinement. One process thought to play a major role during development of the micturition reflex is synaptic competition. The numbers of synapses on spinal neurons derived from spinal and supraspinal sources change throughout development (Fig. 1). It is thought that synaptic input to the parasympathetic preganglionic nucleus from supraspinal centers increases during postnatal development and out competes sacral interneurons for the same target (de Groat, 2002). This may explain the loss of spinally mediated micturition and the emergence of supraspinally mediated micturition during development.

Coincidently, spinal cord injury in adult animals triggers a switch back to micturition mediated via a spinal reflex (Kakizaki and de Groat, 1997; Shefchyk & Buss (1998), Shefchyk & Buss (1998)) thereby making synaptic competition an hypothesis not only for the emergence of brain stem-mediated micturition during development, but also for the emergence of spinal reflex micturition after spinal cord injury.

If the alternative neuronal pathways for eliciting bladder contraction already exist in the spinal cord, why does it take so long for a spinal reflex to emerge after spinal cord injury? Assuming that spinal shock accounts for bladder areflexia during the first few days after injury, reflex mediated micturition should occur soon after resolution of areflexia. However, micturition does not emerge in rats until around 2 weeks after spinal cord transection (Yoshiyama et al., 1999) and in humans, depending on the severity of the injury, it may not emerge for months (Weld and Dmochowski, 2000). This delay in emergence of the bladder function implies that other changes associated with neurons in the micturition reflex, both phenotypic and anatomical, may be involved in emergence of bladder function after spinal cord injury.