Regular physical activity prevents development of chronic pain and activation of central neurons

Abstract

Chronic musculoskeletal pain is a significant health problem and is associated with increases in pain during acute physical activity. Regular physical activity is protective against many chronic diseases; however, it is unknown if it plays a role in development of chronic pain. The current study induced physical activity by placing running wheels in home cages of mice for 5 days or 8 wk and compared these to sedentary mice without running wheels in their home cages. Chronic muscle pain was induced by repeated intramuscular injection of pH 4.0 saline, exercise-enhanced pain was induced by combining a 2-h fatiguing exercise task with a low-dose muscle inflammation (0.03% carrageenan), and acute muscle inflammation was induced by 3% carrageenan. We tested the responses of the paw (response frequency) and muscle (withdrawal threshold) to nociceptive stimuli. Because the rostral ventromedial medulla (RVM) is involved in exercise-induced analgesia and chronic muscle pain, we tested for changes in phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the RVM. We demonstrate that regular physical activity prevents the development of chronic muscle pain and exercise-induced muscle pain by reducing phosphorylation of the NR1 subunit of the NMDA receptor in the central nervous system. However, regular physical activity has no effect on development of acute pain. Thus physical inactivity is a risk factor for development of chronic pain and may set the nervous system to respond in an exaggerated way to low-intensity muscle insults.

Fig. 1.

Experiment 1. Top: in the chronic muscle pain model, 8 wk of physical activity, but not 5 days, significantly prevents the decrease in withdrawal threshold of the muscle and the increase in paw responses that normally occurs in this model compared with sedentary mice (*P < 0.05). Middle: in the exercise-enhanced pain model, 5 days or 8 wk of running wheel activity significantly prevents the increase in paw responses compared with sedentary mice (*P < 0.05). The muscle withdrawal thresholds decrease significantly in all three groups after induction of the exercise-enhanced pain model. Bottom: in the acute inflammation model, 8 wk of regular physical activity had no effect on the development of hyperalgesia of the paw or muscle. Base, after running wheel activity but before induction of model; 24 h, after induction of the model. Data are means ± SE.

Fig. 2.

Experiment 2. Time course of effects of regular physical activity on the chronic muscle pain model (A) and the exercise-enhanced pain model (B). Access to running wheels was stopped at the time of induction of the model. A: in the chronic muscle pain model, 8 wk of running wheel activity prevents the decreases in muscle withdrawal threshold and increased responses of the paw for up to 72 h after induction of the model (*P < 0.05). By 1 wk these responses are significantly increased (P < 0.05) and similar to sedentary mice. B: in the exercise-enhanced pain model, both 5 days and 8 wk of running wheel activity prevented the increases in paw responses to noxious stimuli for 72 h after induction of the model (*P < 0.05). By 1 wk these responses were significantly increased (P < 0.05). The muscle withdrawal threshold decreased in the sedentary and physically active animals to a similar extent (P < 0.05). B, before running wheel activity; E, after running wheel activity; D5, 5 days after the first acid injection and before the second acid injection; 24 h, 72 h, and 1wk refer to time after induction of the model. Data are means ± SE.

Fig. 3.

Experiment 3. Effects of regular physical activity on motor function in uninjured animals. A: grip force strength test shows a significant increase in strength for both the hindpaw and the forepaw after 8 wk of running wheel activity compared with sedentary animals; 5 days of running wheel activity had no effect on strength (*P < 0.05). B: Rota-rod coordination test reveals no difference in coordination in animals after 5 days or 8 wk of running wheel activity compared with sedentary mice. Data are means ± SE.

Fig. 4.

Experiment 4. Immunohistochemical staining for p-NR1 in the rostral ventromedial medulla. A: 24 h after induction of the exercise-enhanced pain model in sedentary mice (Ex+Cg) compared with controls. B: 24 h after induction of the chronic muscle pain model (pH 4.0) in sedentary mice compared with controls (pH 7.2). C: 24 h after induction of exercise-enhanced pain (Ex+Cg) in mice with 5 days of running wheel activity compared with sedentary mice with exercise-enhanced pain. D: 24 h after induction of chronic muscle pain in mice with 8 wk of running wheel activity compared with sedentary mice with chronic muscle pain. *P < 0.05, significantly different between comparison group. Data are means ± SE.

Fig. 5.

Schematic diagram representing a proposed pathway for the control of excitability within the rostral ventromedial medulla (RVM). A: under sedentary conditions, unaccustomed exercise and muscle insult increase the phosphorylation of the NR1 subunit (p-NR1) of the N-methyl-d-aspartate (NMDA) receptor at the protein kinase A (PKA) site as shown in the current study. Increases in p-NR1 are expected to increase excitability and produce hyperalgesia and pain. B: regular exercise and physical activity increase release of met-enkephalin in the RVM and use opioid receptors centrally to mediate analgesia (58). This would activate mu-opioid receptors on the pain facilitation neurons to inhibit activation of the cAMP-PKA pathway reducing p-NR1. Thus, in the physically active condition, there is increased activity within the opioid system that reduces cell excitability by reducing phosphorylation of the NR1 subunit to result in prevention of pain to unaccustomed exercise and chronic muscle pain. We propose that the normal state of the nervous system is under conditions of regular physical activity and that the “abnormal state” occurs under sedentary conditions. We further suggest that a sedentary lifestyle or physical inactivity is a risk factor for the development of chronic pain. NR2, NMDA receptor subunit 2.