Elucidating mechanism in pathological pain condition
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Pathological pain is a debilitating condition affecting millions of people worldwide and is poorly treated by conventional therapeutics. In this dissertation, a series of mechanistic studies are presented to identify novel therapeutic strategies to develop analgesic for the treatment of pain. This dissertation comprises four chapters. Chapter one a literature review of the role of neuronal dysfunction in chronic pain conditions. In the chronic pain condition, hyperexcitation of neuronal cells and neuroinflammation are hallmark events in the nociceptive pathway. Homeostasis between excitatory and inhibitory receptor activities is crucial to maintain normal neuronal activities in the central nervous system (CNS). In chapter two we have successfully shown in the paclitaxel-induced neuropathic pain model that local application of GAT-1 transporter activity inhibitors at the spinal enlargement reverses the attenuated GABAergic disinhibition and ameliorates neuropathic pain. Thus, targeting GAT-1 transporters for reversing GABAergic disinhibition in the spinal dorsal horn could be a useful approach for treating paclitaxel-induced neuropathic pain. Tissue and nerve injury produce neuroinflammation which is a critical component, contributing to the genesis of pathological pain. Activation of glial cells, accumulation of proinflammatory cytokines and release of various algesic mediators in the spinal cord produces long-lasting cellular and behavior changes as a consequence of widespread alterations in gene expression profile. Epigenetics mechanism such as post-translation modification of histone tails residues plays important role in various gene activation and suppression. In chapter three we have presented compelling evidence demonstrating global change of enhancer zeste homolog-2 (EZH2) activities and methylation levels of H3K27 in the spinal dorsal horn is associated with glia cells activation and neuroinflammation following nerve injury. Inhibition of EZH2 prevented and attenuated the neuropathic pain condition thus provide compelling evidence that targeting signaling pathways regulating gene expression could prove to be an effective approach for the development of new analgesics for the treatment of neuropathic pain. Lastly, chapter four provides a discussion of pharmacological management of pain with a focus on the remaining challenges in the translation of pain therapeutics.