OBJECTIVE Accumulating evidence reveals that spinal glias, inchding astrocytes and micrnglias, play an impor tant role in the processing of chronic pain, especially neuropathic pain.Aquaporin 4 (AQP4), the predominant water channel ex isting in astrocytes, has been proved to modulate astrocytic func tions, as well as neuronal functions via the interaction between as trocytes and neurons.In the present study, we investigated the role of AQP4 in acute and chronic pain and the possible mecha nism.METHODS We first studied the effect of acetazolamide,a non-selective AQP4 inhibitor, on pain.Then we investigated the role of AQP4 deficiency in acute pain and chronic pain including neuropathic pain and inflammatory pain.In the SNI model, the AQP4 expression, the GFAP and CR3 expressions, markers of as trocytes activation and microglia activation, were analyzed by Western blot and the proinflammatory cytokines (IL-13, IL-6 and TNF-αt) contents in spinal cord were detected by ELISA.RE SULTS Acetazolamide, non-selective AQP4 inhibitor, produced dose-dependent analgesia in the rat sciatic nerve chronic constric tion injury (CCI) model (P <0.01), a model of neuropathic pain, but not in the mouse tail-flick and hot-plate tests, two mod els of thermal-stimulated acute pain, suggesting AQP4 might par ticipate in chronic pain, rather than acute pain.Then we used wild-type (WT) and AQP4 knockout (KO) mice to study the role of AQP4 in acute pain and chronic pain.We found that AQP4 de ficiency failed to affect the responses of mice to the acute pain in duced by thernal (tail-flick and hot-plate tests), chemical (for malin and capsaicin tests) and mechanical (yon Frey hair test)stimuli.However, AQP4 deficiency attenuated the mechanical all odynia in the models of spared nerve injury (SNI)-induced neuro pathic pain and complete Freunds adjuvant (CFA)-induced in flammatory pain.Furthermore, the possible mechanism was inves tigated.In the SNI medel, A * QP4 expression was significantly increased in WT-SNI group (P <0.001) compared with WT-sham group, 14 d after injury.Meanwhile, GFAP expression in the spi nal cord was also significantly increased in WT-SNI group (P < 0.001) compared with WT-shum group, whereas no changes of the GFAP expression were detected in KO-Sham group and KO-SNI group.However, no changes of the CR3 expression were detected in all the groups.In addition, the IL-1β, IL-6 and TNF-α con tents were elevated in the spinal cord of WT-SNI group compared with WT-sham group (P < 0.05), whereas no changes of the proinflammatory cytokines contents were detected in KO-sham group and KO-SNI group.CONCLUSION Taken together, our findings demonstrated that AQP4 appears to contribute to chronic pain, especially neuropathic pain, but not acute pain.The sup pression of astrocytes activation and proinflammatory cytokines re lease might mediate the attenuation of AQP4 deficiency to the neu ropathic pain.