Tactile allodynia refers to a painful sensation induced by a simple touch. It is a serious and often debilitating medical problem associated with nerve injury and inflammation. In experiments supported by this grant over the last funding period, we have demonstrated the presence of a polysynaptic excitatory pathway, normally under powerful inhibitory control mediated by GABAA and glycine receptor activation that connects low threshold afferent input ?:touch?;to nociceptive output neurons ?:pain?;within the spinal cord dorsal horn. This means that there is built in circuitry within the spinal cord dorsal horn that permits the mixing of sensory modalities, allowing input generated by light touch to drive the pain projection neurons sending axons to higher brain centers. That is, there is an existing circuitry that is likely to contribute to allodynia. This pathway becomes revealed with pharmacological disinhibition ?:Torsney and MacDermott, 2006?;or by disinhibition associated with peripheral nerve injury and tactile allodynia?:Keller et al., 2007?;. Over the next two years, we propose to investigate the inhibitory control mechanisms that may keep the polysynaptic excitatory pathway suppressed under normal conditions.
In Specific Aim one, we will test whether inhibitory neurons in lamina I through III receive low threshold mono or polysynaptic afferent drive and how the strength of that afferent drive varies with stimulation frequency.
In Specific Aim two, we will investigate tonic inhibition of excitatory and inhibitory neurons in lamina I-III to provide insight into how the inhibitory GABA and glycine receptors contribute to suppression of the polysynaptic low threshold pathway in the spinal cord slice preparation.
In Specific Aim 3, we will investigate is presynaptic inhibition of low threshold afferents. The model we will test is whether the disinhibition allowing low threshold drive of lamina I pain neurons, which can be mimicked with GABAA and glycine receptor antagonists, works, at least in part by relief of endogenous presynaptic inhibition of low threshold afferents.
Chronic pain is an important and debilitating medical problem for many people within the United States and worldwide. Our proposal is directly focused on identifying the neuronal circuitry and molecules within the spinal cord that allow some forms of chronic pain to develop. Improved understanding of this circuitry and associated receptors and molecules will greatly improve the rate of drug discovery to help control chronic pain.
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