Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids

Abstract

Background: Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems.

Methods: After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry.

Results: Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area.

Conclusions: Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.

Figure 1:

Exercise training reverses nerve injury-induced sensory hypersensitivity. A. Tactile paw withdrawal threshold in exercise-trained vs. sedentary SNL animals. Data from sham-operated animals are included for comparison. B. Thermal paw withdrawal latency to radiant heat in exercise-trained vs. sedentary SNL animals. Data from shamoperated animals are included for comparison. Baseline measurements were taken one day before surgery. Further measurements were performed one day before and weekly after initiation of exercise training. Measurements were made 23 hrs after exercise. Data shown as mean with 95% two-tailed confidence intervals. *P < 0.05 compared to exercise-trained, spinal nerve-ligated rats. N = 6 animals per group. BL = pre-surgical baseline; SNL = after spinal nerve ligation surgery; SED = sedentary animals; EXC = exercise-trained animals.

Figure 2:

More intense exercise, but not more frequent exercise training resulted in more complete reversal of sensory hypersensitivity. A. Tactile paw withdrawal threshold after exercise training 3 or 5 days per week. B. Tactile paw withdrawal threshold after exercise training at 10 m/min (lower-intensity) or 16 m/min (higher-intensity) 5 days per week. Data shown as mean with 95% two-tailed confidence intervals. *P < 0.05 compared to lower-intensity exercise. N = 6 animals per group. BL = pre-surgical baseline; SNL = after spinal nerve ligation surgery.

Figure 3:

A. Onset of exercise-induced reversal of sensory hypersensitivity occurred 3 weeks after initiation of exercise training. Tactile sensitivity was measured in sedentary SNL, exercise-trained SNL, and delayed-exercise SNL animals. Data shown as mean # with 95% two-tailed confidence intervals. P < 0.05 compared to pre-exercise, spinal nerve-ligated animals. *P < 0.05 compared to delayed exercise group. N = 6 animals per group. B. Tactile hypersensitivity returned 5 days after cessation of exercise training. Data shown as mean with 95% two-tailed confidence intervals. N = 6 animals per group. BL = pre-surgical baseline; SNL = after spinal nerve ligation surgery.

Figure 4:

Opioid receptor antagonists reverse the effects of exercise on sensory hypersensitivity. A. Naloxone reversibly inhibited exercise effects. Exercise-trained SNL animals were administered naloxone (1 mg/kg) subcutaneously.*P < 0.05 compared to pre-naloxone values. B. Subcutaneous naloxone methiodide (0.1 mg/kg) had no effect on tactile hypersensitivity in spinal nerve-ligated, exercise-trained animals. *P < 0.05 compared to spinal nerve-ligated, exercise-trained animals receiving vehicle. #P < 0.05 compared to spinal nerve-ligated, exercise-trained animals receiving naloxone methiodide. C. Reversal of nerve injury-induced sensory hypersensitivity by exercise is mediated by endogenous opioids in the central nervous system. Intracerebroventricular injection of naloxone methiodide (2 μg) reversed exercise-training mediated reversal of sensory hypersensitivity, while intrathecal injection of naloxone methiodide (10 μg) had no effect. *P < 0.05 compared to vehicle-treated, exercise-trained, spinal nerve-ligated animals. D. Continuous naltrexone infusion (70 μg/hr) prevented exercise-induced reversal of tactile hypersensitivity. *P < 0.05 vs. vehicle-infused animals. Data shown as mean with 95% two-tailed confidence intervals. N = 6 animals per group. N. Methiodide = naloxone methiodide; i.c.v. = intracerebroventricular; i.t. = intrathecal; BL = presurgical baseline; SNL = after spinal nerve ligation surgery; SED = sedentary animals; EXER = exercise-trained animals.

Figure 5:

Exercise training increases endogenous opioid content in the midbrain periaqueductal gray area (PAG). A. After 5 weeks of exercise training or sedentary conditions, PAG sections from nerve-injured animals were labeled with antibodies to β-endorphin (a,b) or met-enkephalin (c,d). Images were magnified 20x. B. Densitometry was performed on 10 images from 5 animals per group. *P < 0.05 compared to spinal nerve-ligated, sedentary animals. Data shown as mean with 95% two-tailed confidence intervals.

Figure 6:

Exercise training increases endogenous opioid content in the rostral ventomedial medulla (RVM). A. After 5 weeks of exercise training or sedentary conditions, RVM sections from nerve-injured animals were labeled with antibodies to β-endorphin (a,b) or met-enkephalin (c,d). Images were magnified 40x. B. Densitometry was performed on 26–32 images from 5 animals per group. *P < 0.05 compared to spinal nerve-ligated, sedentary animals. Data shown as mean with 95% two-tailed confidence intervals.