Astrocyte‐neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord

• Published in: Glia Vol. 67; no. 1; pp. 27 - 36
• Main Authors: Miyamoto, Keisuke, Ishikura, Kei‐ichiro, Kume, Kazuhiko, Ohsawa, Masahiro
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.01.2019; Wiley Subscription Services, Inc
• Subjects: Activation; astrocyte; Astrocytes; Attenuation; Cofilin; Dorsal horn; Gliotoxin; Hyperalgesia; Inhibitors; Krebs cycle; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; L‐lactate; mechanical allodynia; Neuralgia; neuropathic pain; Pain; Pain perception; Phosphorylation; Rodents; Spinal cord; Synaptic transmission; Tricarboxylic acid cycle; neuropathic pain; mechanical allodynia; spinal cord; L-lactate; astrocyte
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23474

Astrocytes play a key role in the maintenance of synaptic transmission by producing L‐lactate via the astrocyte‐neuron lactate shuttle (ANLS). Astrocyte activation in the spinal cord is involved in the expression of neuropathic pain. We investigated the role of the ANLS in the spinal cord on hyperalgesia in neuropathic pain in mice. Specific activation of dorsal horn astrocytes induced mechanical hyperalgesia, which was attenuated by α‐cyano‐4‐hydroxycinnamate (4‐CIN), an inhibitor of monocarboxylate transporters that deliver L‐lactate from astrocytes to neurons. Intrathecal L‐lactate administration lowered the mechanical nociceptive threshold, which was attenuated by pretreatment with 4‐CIN and isosafrole (a lactate dehydrogenase inhibitor), but not gliotoxin. Intrathecal L‐lactate administration significantly upregulated c‐Fos and cofilin phosphorylation, which was reversed by 4‐CIN. The lowered mechanical nociceptive threshold was significantly attenuated by intrathecal fluorocitrate (an astrocyte‐specific Krebs cycle inhibitor), 4‐CIN, and isosafrole treatment. Thus, these results suggested that, in neuropathic pain, mechanical hyperalgesia was maintained by excessive L‐lactate supplied by activated astrocytes via an aberrant ANLS. Main Points Our results indicated that selective astrocyte activation induced mechanical hyperalgesia by enhancing the neuronal supply of L‐lactate. In addition, neuropathic pain was ameliorated by L‐lactate inhibition.