It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain.

Moderate‐intensity exercise performed during wound healing has been reported to decrease inflammatory cytokines and chemokines and accelerate wound healing. However, its effect on macrophage phenotype and the mechanism by which exercise accelerates wound healing remain unclear. The purpose of this study was to investigate the effect of exercise on macrophage phenotype during wound healing and to clarify the relationship between angiogenesis and wound healing. 12‐week‐old male C57BL/6J mice were divided into sedentary (n = 6) and exercise groups (n = 6). The exercise group performed moderate‐intensity treadmill running exercise (9.0 m/min, 60 min) for 10 days. Double immunofluorescence analysis was performed using F4/80⁺ inducible nitric oxide synthase (iNOS)⁺ for M1 macrophages, F4/80⁺ transforming growth factor‐beta (TGF‐β)1⁺ for M2 macrophages, and CD31⁺ alpha smooth muscle actin (α‐SMA)⁺ for angiogenesis. The exercise group showed significantly accelerated wound healing compared with the sedentary group. From early wound healing onward, exercise significantly inhibited M1 macrophage infiltration and increased M2 macrophage count. Exercise also significantly increased angiogenesis. Furthermore, the M2 macrophage phenotype was significantly correlated with angiogenesis in the exercise group, indicating that M2 macrophages and angiogenesis are related to accelerated wound healing. These findings suggest that moderate‐intensity exercise increases TGF‐β1 derived from M2 macrophages, which may be associated with enhanced angiogenesis and wound healing in young mice.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.

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 FosB⁺cells and GABAergic interneurons (parvalbumin-positive [PV⁺] and somatostatin-positive [SOM⁺]) in the vHPC-CA1 in neuropathic pain (NPP) model mice. VR significantly improved thermal hyperalgesia in the NPP model. The number of the FosB⁺cells was significantly higher in partial sciatic nerve ligation-sedentary mice than in Sham and Naive mice, whereas VR significantly suppressed the FosB⁺cells in the vHPC-CA1. Furthermore, VR significantly increased the proportion of activated PV⁺and SOM⁺interneurons in the vHPC-CA1, and tracer experiments indicated that approximately 24% of neurons projecting from the vHPC-CA1 to the basolateral nucleus of amygdala were activated in NPP mice. These results indicate that feedforward suppression of the activated neurons via VR-induced activation of GABAergic interneurons in the vHPC-CA1 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.

Physical activity and exercise not only improve physical fitness, mental health, and quality of life but also play an important role in preventing and improving several chronic diseases, including chronic pain. Exercise–induced hypoalgesia (EIH) is a notable phenomenon underlying pain relief, which has been demonstrated in healthy adults, chronic pain patients, and animals. In this mini–review, we describe the possible roles of anti–inflammatory cytokines, serotonin, endogenous opioids, and myokines in developing the EIH effect. We consider three brain systems involved in producing EIH: the reward, the medial part of the basal amygdala–nucleus accumbens, and the ventral hippocampus–basolateral amygdala systems constituting the mesocorticolimbic system. Furthermore, we discuss how orexin neurons located in the lateral hypothalamus may assist in triggering this system. Notably, the EIH effect was not observed in mice that were subjected to ultrahigh–intensity treadmill running and exhibited anxiety, fear, and aversion behaviors, suggesting that negative emotions hinder EIH development. Thus, the effects of exercise are not only dependent on the intensity, duration, and frequency of exercise but also strongly influenced by emotions, which may be produced by or during the exercise. In conclusion, the present review supports the development of more effective pain relief strategies for both chronic pain patients and healthy people.

Effects of inhibited interleukin‐6 (IL‐6) signal using the rat anti‐mouse IL6 receptor (MR16‐1) with or without heat treatment on the regeneration of injured skeletal muscle was studied in mice. 10‐week‐old C57BL/6JJc1 mice were divided into 5 groups: (1) normal controls, (2) cardiotoxin injection (CTX), (3) administration of MR16‐1 after CTX injection (CTX‐MR), (4) heat treatment after CTX injection (CTX‐H), and (5) administration of MR16‐1 plus heat treatment after CTX injection (CTX‐MR‐H). The CTX (10 μl) was injected into the right tibialis anterior (TA) muscle. MR16‐1 (2 mg) was injected i.p immediately after CTX injection. For heat treatment, the conscious mice were placed in a heat chamber (42 °C) for 60 min 1, 3, and 5 days after CTX injection. Muscles were sampled 7 days after these treatments and cross‐sectional analyses were performed. Regenerating myofibers with centrally located nuclei were noted 7 days after CTX injection. Immunohistochemical analyses revealed that desmin‐ and dystrophin‐positive (+) cells were increased in CTX‐MR and CTX‐MR‐H groups. Further, a number of myogenin + cells were seen in the damaged myofibers of CTX‐H group. These results suggest that blockage of IL‐6 signal and heat treatment facilitate the regeneration of skeletal muscle. This study was supported by Grant‐in‐Aid for Scientific Research S (19100009) from the Japan Society for the Promotion of Science.