OBJECTIVE Accumulating evidence reveals that spinal glias,including astrocytes and microglias,play an important role in the processing of chronic pain,especially neuropathic pain.Aquaporin 4(AQP4),the predominant water channel existing in astrocytes,has been proved to modulate astrocytic functions,as well as neuronal functions via the interaction between astrocytes and neurons.In the present study,we investigated the role of AQP4 in acute and chronic pain and the possible mechanism.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 astrocytes activation and microglia activation,were analyzed by Western blot and the proinflammatory cytokines(IL-1β,IL-6 and TNF-α) contents in spinal cord were detected by ELISA.RESULTS Acetazolamide,non-selective AQP4 inhibitor,produced dose-dependent analgesia in the rat sciatic nerve chronic constriction injury(CCI) model(P<0.01),a model of neuropathic pain,but not in the mouse tail-flick and hot-plate tests,two models of thermal-stimulated acute pain,suggesting AQP4 might participate 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 deficiency failed to affect the responses of mice to the acute pain induced by thermal(tail-flick and hot-plate tests),chemical(formalin and capsaicin tests) and mechanical(von Frey hair test) stimuli.However,AQP4 deficiency attenuated the mechanical allodynia in the models of spared nerve injury(SNI)-induced neuropathic pain and complete Freund′s adjuvant(CFA)-induced inflammatory pain.Furthermore,the possible mechanism was investigated.In the SNI model,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 spinal cord was also significantly increased in WT-SNI group(P<0.001) compared with WT-sham 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 contents 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 suppression of astrocytes activation and proinflammatory cytokines release might mediate the attenuation of AQP4 deficiency to the neuropathic pain. OBJECTIVE Accumulating evidence reveals that spinal glias, including astrocytes and microglias, play an important role in the processing of chronic pain, especially neuropathic pain. Aquaporin 4 (AQP4), the predominant water channel existing in astrocytes, has been proved to modulate astrocytic functions, as well as neuronal functions via the interaction between astrocytes and neurons. the present study, we investigated the role of AQP4 in acute and chronic pain and the possible mechanism. METHODS We first studied the effect of acetazolamide, a non-selective AQP4 inhibitor, on pain. When we investigated the role of AQP4 deficiency in acute pain and chronic pain including neuropathic pain and inflammatory pain. the SNI model, the AQP4 expression, the GFAP and CR3 expressions, markers of astrocytes activation and microglia activation, were analyzed by Western blot and the proinflammatory cytokines (IL-1β, IL-6 and TNF-α) contents in spinal cord were detected by ELISA. RESULTS Acetazolamide, non-selecti ve AQP4 inhibitor, produced dose-dependent analgesia in the rat sciatic nerve chronic constriction injury (CCI) model (P <0.01), a model of neuropathic pain, but not in the mouse tail-flick and hot-plate tests, two models of inflammatory-stimulated acute pain, suggesting AQP4 might participate in chronic pain, rather than acute pain. Chen we used wild-type (WT) and AQP4 knockout (KO) mice to study the role of AQP4 in acute pain and chronic pain. that AQP4 deficiency failed to affect the responses of mice to the acute pain induced by thermal (tail-flick and hot-plate tests), chemical (formalin and capsaicin tests) and mechanical (von Frey hair test) stimuli. Powered, AQP4 deficiency attenuated the mechanical allodynia in the models of spared nerve injury (SNI) -induced neuropathic pain and complete Freund’s adjuvant (CFA) -induced inflammatory pain. Frthermore, the possible mechanism was investigated. In the SNI model, A * QP4 expression was significantly increased in WT-SNI group (P <0.001) compared with WT-s hamgroup, after 14 d after injury. Meanwhile, GFAP expression in the spinal cord was also significantly increased in WT-SNI group (P <0.001) compared with WT-sham group, no change in 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 contents were elevated in the spinal cord of WT-SNI group compared with WT-sham group (P <0.05), no changes of the proinflammatory cytokines contents were detected in KO-sham group and KO-SNI group. CONCLUSION Taken together, our findings that that AQP4 appears to contribute to chronic pain, especially neuropathic pain , but not acute pain. The suppression of astrocytes activation and proinflammatory cytokines release might mediate the attenuation of AQP4 deficiency to the neuropathic pain.