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

Katsuya Kami, Fumihiro Tajima, Emiko Senba
2018 Scientific Reports  
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
more » ... 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/noncholinergic 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. 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 . Many studies have demonstrated using neuropathic pain (NPP) and inflammatory pain (IFP) model animals that physical exercise significantly improves pain-related behaviors such as mechanical allodynia and heat hyperalgesia (exercise-induced hypoalgesia: EIH) 3 . Furthermore, multiple events, including marked alterations in cytokines, neurotrophins, neurotransmitters, and endogenous opioids in injured peripheral nerves, dorsal root ganglia, spinal dorsal horns and the brainstem following physical exercise have been proposed as potential mechanisms of EIH effects 3 . However, few studies have focused on the central nervous system to elucidate the mechanisms underlying EIH effects even though chronic pain patients exhibit severe dysfunction in multiple brain regions related to perception, emotion, cognition and behavior 4 . Ventral tegmental area (VTA) dopamine (DA) neurons are the primary source of dopamine in target structures, such as the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), which constitute the mesolimbic reward system. The 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 . A recent study found that the excitability of VTA-DA neurons projecting to the NAc markedly decreases in NPP model mice, whereas optogenetic stimulation of VTA-DA neurons produces analgesic effects 6 . The levels of DA, kappa-opioid receptor, dopamine receptor-D1A and -D2 in the NAc were reduced in inflammatory and NPP model animals 7,8 . Furthermore, human imaging studies indicate that chronic pain leads to a significant impairment of mesolimbic dopamine activity, which may underlie a key system mediating depression with chronic pain 9-13 . Thus, the mesolimbic reward system is a neuronal pathway that can control chronic pain, and activation of the VTA-DA neurons in particular may be effective in improving and preventing chronic pain. Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific REPORTS | (2018) 8:11540 | Herrera et al. 14 demonstrated that voluntary wheel running (VWR) and forced treadmill running enhanced activation of both DA neurons in the VTA and FosB expression in the NAc. Specific activation of the VTA-DA neurons and neural pathway from the VTA to NAc markedly increased the amount of VWR 15 . Greenwoods et al. 16 reported that VWR in rats enhances the mRNA level of tyrosine hydroxylase (TH), a rate-limiting enzyme for DA, and increases expression of FosB in the NAc. In addition, it is well-known that rats and mice preferentially select wheel running 14,17 . These findings suggest that similar with feeding and drug abuse, physical exercise is a rewarding behavior for rodents. 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 . In addition, 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. However, neuronal mechanisms by which physical exercise activates VTA-DA neurons are unknown. VTA-DA neurons were reported to receive excitatory inputs from cholinergic and glutamatergic neurons in the LDT and from orexin neurons in the lateral hypothalamic area (LHA) 5,20 . Therefore, we hypothesized that the LDT and/or LHA neurons activated by physical exercise may play a role in activating VTA-DA neurons, which may consequently produce EIH effects. Here, we investigated whether LDT and LHA neurons projecting to the VTA are activated by physical exercise in NPP model mice. Results As shown in Fig. 1A , Naive-, Sham-, and partial sciatic nerve ligation (PSL)-Runner mice were allowed to run freely on the running wheel, while Sedentary mice were reared in cages with a locked running wheel. Mice were divided into six groups: (1)
doi:10.1038/s41598-018-29915-4 pmid:30069057 pmcid:PMC6070570 fatcat:jkre6dawczehldvxfgbwudnwxe