Tonic excitation by astrocytic GABA causes neuropathic pain by augmenting neuronal activity and glucose metabolism

Abstract

Neuropathic pain is a debilitating condition caused by the hyperexcitability of spinal dorsal horn neurons and is often characterized by allodynia. Although neuron-independent mechanisms of hyperexcitability have been investigated, the contribution of astrocyte-neuron interactions remains unclear. Here, we show evidence of reactive astrocytes and their excessive GABA release in the spinal dorsal horn, which paradoxically leads to the tonic excitation of neighboring neurons in a neuropathic pain model. Using multiple electrophysiological methods, we demonstrated that neuronal hyperexcitability is attributed to both increased astrocytic GABA synthesis via monoamine oxidase B (MAOB) and the depolarized reversal potential of GABA-mediated currents (EGABA) via the downregulation of the neuronal K+/Cl- cotransporter KCC2. Furthermore, longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET imaging demonstrated increased regional glucose metabolism in the ipsilateral dorsal horn, reflecting neuronal hyperexcitability. Importantly, inhibiting MAOB restored the entire astrocytic GABA-mediated cascade and abrogated the increased glucose metabolism and mechanical allodynia. Overall, astrocytic GABA-mediated tonic excitation is critical for neuronal hyperexcitability, leading to mechanical allodynia and neuropathic pain. Neuropathic pain can greatly affect a person's life by causing disability and financial strain. The cause of this pain is complex and many factors have been studied to understand it. In this research, it was found that neuropathic pain comes from overactive and overly sensitive neurons in the spinal cord after a nerve injury. This overactivity can be caused by a paradoxical tonic excitation by astrocytic GABA, which is mediated by an impaired homeostasis of chloride ion at the spinal dorsal horn. The research was done on rats and involved surgery, drug use, and various tests. The results showed that blocking the production of astrocytic GABA can decrease the abnormally high neuronal activity and metabolism, ultimately reducing mechanical allodynia. The researchers concluded that adjusting the astrocytic GABA production could be a potential treatment for neuropathic pain.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.