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

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.