The activation of spinal astrocytes accounts for opioid-induced hyperalgesia(OIH),but the underlying mechanisms remain elusive.The presence of astrocyte-neuron lactate shuttle(ANLS)makes astrocytes necessary for some ...The activation of spinal astrocytes accounts for opioid-induced hyperalgesia(OIH),but the underlying mechanisms remain elusive.The presence of astrocyte-neuron lactate shuttle(ANLS)makes astrocytes necessary for some neural function and communication.The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH.After 7 days consecutive morphine injection,a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4(PDK4),phosphorylated pyruvate dehydrogenase(p-PDH)and accumulation of L-lactate was elevated in the spinal dorsal horn.Intrathecally administration of inhibitors of PDK,lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns.The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro.In this study,we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS.In this process,PDK-p-PDH-lactate axis serves a pivotal role,which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice.展开更多
基金the National Natural Science Foundation of China(82171486)Natural Science Foundation of Shanghai to T.X.(21ZR1448400)+2 种基金the Interdisciplinary Program of Shanghai Jiao Tong University to T.X.(YG2021ZD23)General Science Foundation of Shanghai Sixth People's Hospital to T.X.(YNMS202114)the Young Scholarship Program of the National Natural Science Foundation of China to Xiaqing Ma(82201366)and by Shanghai Sailing Program(21YF1434200).
文摘The activation of spinal astrocytes accounts for opioid-induced hyperalgesia(OIH),but the underlying mechanisms remain elusive.The presence of astrocyte-neuron lactate shuttle(ANLS)makes astrocytes necessary for some neural function and communication.The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH.After 7 days consecutive morphine injection,a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4(PDK4),phosphorylated pyruvate dehydrogenase(p-PDH)and accumulation of L-lactate was elevated in the spinal dorsal horn.Intrathecally administration of inhibitors of PDK,lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns.The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro.In this study,we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS.In this process,PDK-p-PDH-lactate axis serves a pivotal role,which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice.
