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.

Harnessing Theta-Gamma Coupled Brainwave Using Ultrasound for Spinal Astrocyte Revitalization and Sustained Neuropathic Pain Relief

“…This suggests that LI-cTBUS may modulate reactive astrocytes and GABAergic signaling, potentially contributing to its analgesic effects by diminishing excitatory GABA transmission in the dorsal horn of the spinal cord. This is consistent with the idea that elevated levels of spinal BDNF might decrease paw withdrawal threshold and induce a depolarizing shift in Eanion, resulting in a switch of GABA's action from inhibitory to excitatory in the pathophysiology of neuropathic pain 20,32 .…”