Spasticity, which is defined as an increased resistance of a limb to externally imposed joint extension, is caused by increased stretch reflex excitability. In spinal cord injury, the distribution of these augmented stretch reflex responses strongly favors flexor muscles. In some patients, especially those with incomplete spinal cord injury, flexor spasticity may be quite severe, promoting fixed postural deformity of the limbs and, sometimes, painful and disabling flexor muscle spasms. For all these reasons, the cellular mechanisms of flexor spasticity are important to understand, as a basis for rational therapeutic intervention. The central thesis of this proposal is that the predominant hyperexcitability of flexor musculature is driven by altered interneuronal processing in key segmental reflex pathways. The most potent effects come from alterations in the responsiveness of the interneuronal population excited by free nerve ending afferent within muscles. We also believe that descending monoaminergic systems, traversing dorsolateral white matter of the spinal cord, are instrumental in modifying the relative excitability of specific excitatory and inhibitory interneuronal populations. Accordingly, we plan to study the discharge patterns of interneuronal populations in the unanesthetized spinal cord of the decerebrate cat, using controlled cooling of the dorsal cord as a substitute for surgical or traumatic interruption of the dorsolateral white matter. We plan to asses the following hypothesis regarding the effects of cooling of the dorsolateral white matter: 1) Hyperexcitability in the interneurons receiving input form free nerve ending mechanoreceptor originating in the hindlimb muscles cause severe flexor spasticity coupled with widespread extensor inhibition (i.e. clasp knife inhibition). The result is a severe disruption in the normal reciprocal control of flexors and extensors around a single joint. 2) Key cutaneous interneurons that normally induce focused excitation of hindlimb muscles become much more diffuse in their actions, producing generalized flexor excitation and extensor inhibition. 3) Altered interneuronal processing modifies interlimb coupling of the hindlimbs by inverting the normal organization of crossed extension reflex responses. 4) Certain monoaminergic subtype agonists will provide effective restoration of normal patterns of interneuronal excitability for free nerve ending, cutaneous and crossed inputs. These studies should provide a quantitative understanding of the disruptions in spinal cord circuitry that augment reflex responsiveness in flexor muscles in acute spinal cord injured preparations and assess the potential of monoaminergic subtype specific agents for development of effective therapeutic strategies.
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