Activation of mesolimbic reward system via laterodorsal tegmental nucleus and hypothalamus in exercise-induced hypoalgesia

Katsuya Kami,Emiko Senba,Fumihiro Tajima

doi:10.1038/s41598-018-29915-4

Katsuya Kami, Emiko Senba + Show 1 more

Open Access

https://doi.org/10.1038/s41598-018-29915-4

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Abstract

Ventral tegmental area (VTA) dopamine (DA) neurons are the primary source of dopamine in target structures that constitute the mesolimbic reward system. Previous studies demonstrated that voluntary wheel running (VWR) by neuropathic pain (NPP) model mice produces exercise-induced hypoalgesia (EIH), and that activation of mesolimbic reward system may lead to EIH. However, the neuronal mechanism by which the mesolimbic reward system is activated by VWR is unknown. Here, we found that VWR produces EIH effects and reverses the marked reduction in activated lateral VTA (lVTA)-DA neurons induced by NPP. The proportions of activated laterodorsal tegmental nucleus (LDT)-cholinergic and lateral hypothalamus-orexin neurons were significantly enhanced by VWR. Retrograde tracing and dual immunostaining revealed that VWR activates lVTA-projecting LDT-cholinergic/non-cholinergic and lateral hypothalamic area (LHA)-orexin/non-orexin neurons. Therefore, EIH effects may be produced, at least in part, by activation of the mesolimbic reward system via activation of LDT and LHA neurons.

Highlights

Physical inactivity or a sedentary lifestyle is known as a risk factor for many diseases, including cardiovascular disease, diabetes, cancer, depression, dementia and chronic pain, whereas physical exercise, such as running, swimming and cycling, is approved as an effective non-pharmacological intervention to improve pain[1,2]
The Ventral tegmental area (VTA)-DA neurons play a central role in motivation and reward processing, which are regulated through inputs from multiple brain regions, including the lateral habenular nucleus (LHb), lateral hypothalamus (LH) and laterodorsal tegmental nucleus (LDT)[5]
We hypothesized that the LDT and/or lateral hypothalamic area (LHA) neurons activated by physical exercise may play a role in activating VTA-DA neurons, which may produce exercise-induced hypoalgesia (EIH) effects

Summary

Introduction

Physical inactivity or a sedentary lifestyle is known as a risk factor for many diseases, including cardiovascular disease, diabetes, cancer, depression, dementia and chronic pain, whereas physical exercise, such as running, swimming and cycling, is approved as an effective non-pharmacological intervention to improve pain[1,2]. A recent study demonstrated that specific inhibition of VTA-DA neurons projecting to the NAc attenuates EIH effects in NPP model mice that ran on a treadmill[18]. Based on our preliminary findings, the VWR improves pain behaviors and increases both TH production and the number of phosphorylated cAMP response element binding protein (pCREB)-expressing VTA-DA neurons in NPP model mice[19]. These results indicate that activation of the mesolimbic reward system following physical exercise may be involved in EIH effects. We investigated whether LDT and LHA neurons projecting to the VTA are activated by physical exercise in NPP model mice

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