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Remodeling of the nervous system serves as a protective mechanism during abrupt disturbance of neuronal homeostasis. This offers adequate maintenance of overall network activity that includes both synaptic scaling and regulation of intrinsic neuronal excitability in an adaptive process known as homeostatic plasticity. Although alterations in neuronal excitability of nociceptors have been associated with the development of different forms of chronic pain, the involvement of homeostatic plasticity in the excitability of nociceptors, in the context of prolonged excitation, and in the pathophysiology of chronic pain is poorly understood. Using a combination of pharmacological, optogenetic and electrophysiological approaches, we show that sustained depolarization of cultured dorsal root ganglia (DRG) neurons, especially nociceptors, strongly reduces intrinsic excitability of mouse and human DRG neurons. These changes include decreases in input resistance, action potential (AP) fall time and AP half width, and an increase in rheobase associated with an overall decrease in AP firing, thus suggesting that mechanisms of homeostatic plasticity are engaged in mouse and human nociceptors. Unexpectedly, RNA sequencing studies show that there are not significant changes in the global mouse and human DRG neuronal gene expression after sustained depolarization, suggesting that transcriptional changes are not the underlying cause of homeostatic plasticity in nociceptors. Our data reveal the presence of intrinsic homeostatic mechanisms that regulate neuronal excitability in response to sustained depolarization of mouse and human nociceptors. Therefore, dysregulation of these homeostatic mechanisms could contribute to the understanding of the pathophysiology of chronic pain syndromes. Grant support from NS042595; The Dr. Seymour and Rose T. Brown Professorship in Anesthesiology K00NS113422 American Neuromuscular Foundation Career Development Award F32DA051160-01.
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