2016 年 31 巻 4 号 p. 238-251
Voluntary wheel running (VWR) is a strong natural reward for the rodents, and also can attenuate pain behaviors in model animals of neuropathic pain (NPP) (exercise–induced hypoalgesia: EIH). On the other hand, it has been known that activation of the mesolimbic reward pathway contributes to suppression of tonic pain. Therefore we hypothesized that activation of the mesolimbic reward pathway by VWR may play a role in producing EIH. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of VWR on dopaminergic neurons in the lateral region of anterior ventral tegmental area (lVTA) that is one of the key reward regions in the brain. PSL–Runner mice freely traveled on the running wheel during 15 days after PSL surgeries, while PSL–Sedentary mice were kept in the cage with the locked running wheel. Although in PSL–Runner mice, PSL surgery dramatically reduced the running distance at 1 day post–surgery, these levels returned to nearly pre–surgical level at 15 days post–surgery. Withdrawal thresholds of von Frey test and latencies of plantar test in PSL–Runner mice were significantly higher than those in PSL–Sedentary mice from 5 days to 15 days after the surgery. In addition, a significant positive–correlation was observed between the assessment of pain behavioral tests and total running distances in PSL–Runner mice. In immunohistochemical analysis, PSL–Sedentary mice showed a marked decrease of tyrosine hydroxylase (TH) immuno reactivities in the lVTA of the contralateral side compared with the ipsilateral side of the surgery, but VWR prevented such a decrease. In addition, the reduced number of phosphorylated cyclic AMP response element–binding protein (pCREB)+ ⁄ TH+ (dopaminergic) neurons in the lVTA of PSL–Sedentary mice was significantly restored by VWR in PSL– Runner mice. Furthermore, we found a significant positive–correlation between the assessment of pain behavioral tests and the number of pCREB+ ⁄ TH+ neurons in the lVTA in PSL–Runner mice. The present study showed that VWR increases the expression of pCREB in the dopaminergic neurons in the lVTA of PSL mice, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. Therefore, we conclude that EIH may be achieved, at least in part, by activation of the mesolimbic reward pathway via VWR.
