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  3. Astrocytic pyruvate dehydrogenase kinase-lactic acid axis involvement in glia-neuron crosstalk contributes to morphine-induced hyperalgesia in mice

Astrocytic pyruvate dehydrogenase kinase-lactic acid axis involvement in glia-neuron crosstalk contributes to morphine-induced hyperalgesia in mice

  • Fundam Res. 2023 Mar 6;4(4):820-828. doi: 10.1016/j.fmre.2023.02.013.
Xiaqing Ma 1 2,  Qi Qi 1,  Wenying Wang 1,  Min Huang 1,  Haiyan Wang 1,  Limin Luo 1,  Xiaotao Xu 1,  Tifei Yuan 3,  Haibo Shi 4,  Wei Jiang 1,  Tao Xu 1 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 2 Department of Anesthesiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
  • 3 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 4 Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China.
  • 5 Department of Anesthesiology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China.
PMID: 39161415 DOI: 10.1016/j.fmre.2023.02.013
Abstract

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.

Keywords

Astrocyte-neuron lactate shuttle; Lactate; Opioid-induced hyperalgesia; Phosphorylated pyruvate dehydrogenase; Pyruvate dehydrogenase kinase 4.

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