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<p>Chronic post-surgical pain (CPSP) in rats is characterized by persistent mechanical allodynia and spinal neuronal hypersensitivity. Astrocyte-derived <span>l</span>-lactate, a key modulator of neuronal excitability and synaptic plasticity, was herein investigated for its role in CPSP development following skin/muscle incision and retraction (SMIR). SMIR triggered long-lasting mechanical allodynia, concomitantly with astrocyte activation and elevated <span>l</span>-lactate levels in the spinal dorsal horn. Blockage of glycogenolysis by 4-dideoxy-1,4-imino-D-arabinitol (DAB), inhibition of carbonic anhydrase (CA) by acetazolamide or inhibition of soluble adenylyl cyclase (sAC) by bithionol prevented SMIR-induced mechanical allodynia and reduced spinal dorsal horn <span>l</span>-lactate levels, implicating a critical role of astrocyte-derived lactate in CPSP development and maintenance. Chemogenetic inhibition of spinal astrocyte suppressed mechanical allodynia and decreased <span>l</span>-lactate accumulation in the dorsal horn. Notably, exogenous <span>l</span>-lactate enhanced the firing rate of spinal lamina Ⅰ-II neurons but failed to alter excitatory synaptic transmission, suggesting a selective role for <span>l</span>-lactate in modulating spinal neuronal intrinsic excitability. Mechanistically, SMIR elevated plasma glucocorticoid levels, while adrenalectomy (ADX) abolished both SMIR- induced mechanical allodynia and spinal lactate elevation. Collectively, these findings indicate that glucocorticoid receptor signaling drives astrocytic <span>l</span>-lactate release in spinal dorsal horn following SMIR, which promotes spinal neuronal hyperexcitability and contributes to CPSP pathogenesis.</p>

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Glucocorticoid-Mediated Astrocytic l-Lactate Release Drives Chronic Postsurgical Pain via Spinal Neuronal Sensitization

  • 期刊论文

  • 发表日期：

    2026年2月9日

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  • Yuying Li,
  • Yajie An,
  • Ying Wu,
  • Xuhong Wei

摘要

Chronic post-surgical pain (CPSP) in rats is characterized by persistent mechanical allodynia and spinal neuronal hypersensitivity. Astrocyte-derived l-lactate, a key modulator of neuronal excitability and synaptic plasticity, was herein investigated for its role in CPSP development following skin/muscle incision and retraction (SMIR). SMIR triggered long-lasting mechanical allodynia, concomitantly with astrocyte activation and elevated l-lactate levels in the spinal dorsal horn. Blockage of glycogenolysis by 4-dideoxy-1,4-imino-D-arabinitol (DAB), inhibition of carbonic anhydrase (CA) by acetazolamide or inhibition of soluble adenylyl cyclase (sAC) by bithionol prevented SMIR-induced mechanical allodynia and reduced spinal dorsal horn l-lactate levels, implicating a critical role of astrocyte-derived lactate in CPSP development and maintenance. Chemogenetic inhibition of spinal astrocyte suppressed mechanical allodynia and decreased l-lactate accumulation in the dorsal horn. Notably, exogenous l-lactate enhanced the firing rate of spinal lamina Ⅰ-II neurons but failed to alter excitatory synaptic transmission, suggesting a selective role for l-lactate in modulating spinal neuronal intrinsic excitability. Mechanistically, SMIR elevated plasma glucocorticoid levels, while adrenalectomy (ADX) abolished both SMIR- induced mechanical allodynia and spinal lactate elevation. Collectively, these findings indicate that glucocorticoid receptor signaling drives astrocytic l-lactate release in spinal dorsal horn following SMIR, which promotes spinal neuronal hyperexcitability and contributes to CPSP pathogenesis.