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bioRxiv2023

A glutamatergic DRN-VTA pathway for neuropathic pain and comorbid depression-like behavior modulation

Chronic pain causes both physical suffering and comorbid mental disorders such as depression. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here, we report a pathway from vesicular glutamate transporter3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN[->]DAVTA), of which population activity in response to innocuous mechanical stimuli and sucrose consumption, is respectively inhibited and attenuated by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN[->]DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN[->]DAVTA activation alleviates neuropathic pain and comorbid depression-like behavior (CDB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesia and antidepressant effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN[->]DAVTA inhibition produces pain-like hypersensitivity and depression-like behavior in healthy mice. These findings reveal a novel VGluT3DRN[->]DAVTA[->]D2/D1NAcMed pathway in establishing and modulating chronic pain and comorbid depressive-like behavior.

neuroscience↗

bioRxiv2020

Fructose fuels tumor growth through the polyol pathway and GLUT 8 transporter

Fructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, it remains unclear why cancer cells favor fructose metabolism and how they acquire a sufficient amount of fructose. Here we report that cancer cells convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respirations self-control to supply excessive metabolites to glycolysis and promotes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancer. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study suggests that the Warburg effect is achieved by means of fructose metabolism, instead of glucose metabolism alone.

cancer biology↗