Voluntary running-induced activation of ventral hippocampal GABAergic interneurons contributes to exercise-induced hypoalgesia in neuropathic pain model mice

The exact mechanism of exercise-induced hypoalgesia (EIH) in exercise therapy to improve chronic pain has not been fully clarified. Recent studies have suggested the importance of the ventral hippocampus (vHPC) in inducing chronic pain. We investigated the effects of voluntary running (VR) on glutamate (Glu) neurons and GABAergic interneurons (parvalbumin-positive [PV + ] and somatostatin-positive [SOM + ]) in the vHPC-CA1 region in neuropathic pain (NPP) model mice. VR significantly improved thermal hyperalgesia in the NPP model. The number of activated (FosB + ) glutamate (Glu) neurons was significantly higher in partial sciatic nerve ligation-sedentary mice than in Sham and Naive mice, whereas VR significantly suppressed the activation of Glu neurons in the vHPC-CA1 region. Furthermore, VR significantly increased the proportion of activated PV + and SOM + interneurons in the vHPC-CA1 region, and tracer experiments indicated that approximately 24% of neurons projecting from the vHPC-CA1 region to the basolateral nucleus of amygdala were activated in NPP mice. These results indicate that feedforward suppression of Glu neurons via VR-induced activation of GABAergic interneurons in the vHPC-CA1 region may be a mechanism to produce EIH effects, and suggested that disappearance of negative emotions such as fear and anxiety by VR may play a critical role in improving chronic pain.