EXERCISE IS AN IMPORTANT component in managing. Low-Intensity Exercise Reverses Chronic Muscle Pain in the Rat in a Naloxone-Dependent Manner

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1 1736 ORIGINAL ARTICLE Low-Intensity Exercise Reverses Chronic Muscle Pain in the Rat in a Naloxone-Dependent Manner Marie K. Hoeger Bement, PT, PhD, Kathleen A. Sluka, PT, PhD ABSTRACT. Hoeger Bement MK, Sluka KA. Low-intensity exercise reverses chronic muscle pain in the rat in a naloxonedependent manner. Arch Phys Med Rehabil 2005;86: Objective: To determine the effects of low-intensity exercise on chronic muscle pain and potential activation of the endogenous opioid system. Design: Randomized placebo-controlled trial. Setting: Animal laboratory. Animals: Sixty-three male Sprague-Dawley rats. Interventions: Rats performed a low-intensity exercise protocol for 5 consecutive days after the induction of chronic muscle pain. In a separate experiment, naloxone or saline was administered systemically before 5 low-intensity exercise sessions. Main Outcome Measure: Mechanical hyperalgesia was measured using von Frey filaments to determine the mechanical withdrawal threshold. Results: Low-intensity exercise increased mechanical withdrawal threshold in the chronic muscle pain model. Naloxone attenuated the antihyperalgesic effects of low-intensity exercise. Conclusions: Low-intensity exercise reversed mechanical hyperalgesia in the chronic muscle pain model through activation of the endogenous opioid system. Key Words: Analgesia; Exercise; Opioids; Pain; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation From the Physical Therapy Department, Integrative Neuroscience Research Center, College of Health Sciences, Marquette University, Milwaukee, WI (Hoeger Bement); and the Physical Therapy and Rehabilitation Science Graduate Program, Neuroscience Graduate Program, Pain Research Program, College of Medicine, University of Iowa, Iowa City, IA (Sluka). Supported by the American Physical Therapy Association (Mary McMillan Doctoral Scholarship) and the National Institutes of Health (grant nos. F31 NS43962, K02 AR02201, R01 NS 39734). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Marie K. Hoeger Bement, PT, PhD, Physical Therapy Dept, Integrative Neuroscience Research Ctr, College of Health Sciences, Marquette University, Milwaukee, WI 53201, mariehoeger.bement@marquette.edu /05/ $30.00/0 doi: /j.apmr EXERCISE IS AN IMPORTANT component in managing pain conditions. Low-intensity exercise protocols are used in rehabilitation to treat patients with chronic musculoskeletal conditions such as fibromyalgia, chronic low back pain, and myofascial pain. 1-6 The American College of Rheumatology recommends that people with fibromyalgia participate in a daily gentle aerobic exercise program. Exercise benefits, including a decrease in pain, are evident for patients who participate in a low-intensity walking program. 4 Despite the use of low-intensity exercise in treating pain conditions, there appears to be an exercise threshold for both intensity and duration to produce analgesia. 7,8 In healthy subjects, analgesia occurred after 30 minutes of exercise at 75% maximum oxygen uptake (V O2 max). 7 No changes in pain ratings were evident after 10 minutes of exercise or exercise at 50% V O2 max. 7 In animal studies, the increase in pain threshold was related to the amount of exercise activity. 9 The intensity and duration needed to produce exercise-induced analgesia in pain conditions continue to be explored (for a review on exercise and pain, see O Connor and Cook 10 ). One mechanism of action in exercise-induced analgesia in healthy people and animals is the activation of endogenous opioids. 11 Release of -endorphin into the bloodstream occurs with exercise of a sufficient intensity and duration. 12 Thus, the release of endorphins may not occur with low-intensity exercise. Many patients with painful conditions may not be able to exercise at the high intensity that is required in healthy persons to elicit an increase in -endorphin levels. The exercise parameters to achieve analgesia and produce -endorphin release are likely different in people with pain than in those without pain. The effects of exercise in people with pain are complex and poorly understood. Research performed on healthy subjects is difficult to extrapolate to patients experiencing pain. In support of this, an exercise-induced increase in pain threshold occurred in fighter pilots with a history of acute neck pain that was not evident in pilots without neck pain. 13 Further, the exerciseinduced decreases in pain intensity and unpleasantness were greater for the pilots with a history of neck pain. 13 Thus, patients with a history of pain had a greater analgesic response to exercise than subjects without a pain condition. In contrast, people with chronic fatigue syndrome showed a decrease in pain thresholds after graded exercise on a treadmill. 14 Patients with fibromyalgia reported an increase in generalized pain after strenuous exercise. 15 Limited data are available to determine the role of exercise in relieving pain, especially for those who cannot tolerate the typical high-intensity exercise associated with analgesia. The mechanisms of action for low-intensity exercise in chronic pain conditions are not known. Animal models allow the investigation of potential mechanisms that contribute to the development and maintenance of chronic muscle pain. Furthermore, investigators can examine both pharmaceutical and nonpharmaceutical treatments, as well as the mechanisms of these treatments. The purpose of this study was to determine the effects of low-intensity exercise on chronic muscle pain and the potential activation of the endogenous opioid system. It is hypothesized that low-intensity exercise reverses chronic muscle pain in a naloxone-dependent manner. METHODS The following experiments were performed according to the guidelines issued by the National Institutes of Health and the International Association for the Study of Pain on the use of laboratory animals. Male Sprague-Dawley rats were used for this study (n 63; weight range, g). Chronic Muscle Pain Model Two injections of acidic saline solution (ph 4.0; 100 L for each injection) were administered 5 days apart into the left

2 EXERCISE REVERSES CHRONIC MUSCLE PAIN, Hoeger Bement 1737 gastrocnemius of a rat while the animal was anesthetized with vaporized halothane (2% 4%). This model is a noninflammatory muscle pain model that produces long-lasting mechanical hyperalgesia without significant muscle tissue damage. 16 Gross motor deficits, which would negatively influence behavior testing, are absent. 16 Similar results are produced when the intramuscular acid injections are administered 2, but not 10, days apart. 16 Mechanical hyperalgesia does not occur after the first intramuscular acid injection; thus 2 injections are required. 16 All animals that had a decrease in mechanical hyperalgesia after the second intramuscular acid injection were included in the study. Ten animals were excluded from the study because they did not develop mechanical hyperalgesia after the 2 intramuscular acid injections. Behavior Testing The animals were placed in clear plastic cubicles on an elevated screen platform and allowed to acclimate to their new environment for 20 to 30 minutes. After the exercise stimulus, the animals acclimated for approximately 1 minute before behavior testing. Ten von Frey filaments of varying bending forces (1 350mN) were applied to the hindlimb paws to test for a mechanical withdrawal response. The filaments were applied in ascending order, starting with the lowest bending force. The paw must lift for 2 sequential filaments for the force to be recorded. A decrease in mechanical hyperalgesia is demonstrated by an increase in the mechanical withdrawal threshold (ie, the rat lifts its paw at a higher bending force). This type of behavior testing shows good test-retest reliability (r 2.73, P.001). 17 Drugs Naloxone dissolved in 0.9% saline solution was administered (10mg/kg intraperitoneal) to test if opioid receptors mediate exercise-induced analgesia. 18,19 In a separate group of animals, saline solution (ph 7.2 intraperitoneal) was administered as a control. The effects of naloxone, without exercise, were tested in the chronic muscle pain model to verify that naloxone by itself does not affect mechanical hyperalgesia. Naloxone had no significant effect on mechanical hyperalgesia (n 4). Exercise All rats were trained for 4 days on a treadmill. On the first day, the rats were placed on the treadmill and allowed to acclimate to the new environment for 40 minutes. During the remaining 3 days, the rats were placed for 5 minutes on a slow-moving treadmill (3.05m/min [10ft/min]) to initiate walking. During the training and exercise protocol, a cloth was placed over one end of the treadmill to prompt the rats to walk. Preliminary data showed that the rats performed better with a cloth covering the end of the treadmill, possibly because of their preference for a dark environment. Six rats were eliminated from this study because they were unable to walk on the treadmill. Previous research studies report that 10% to 20% of rats have difficulty with exercise training on a treadmill. Research Design To show the effects of low-intensity exercise on chronic muscle-induced hyperalgesia, the exercise protocol was initiated 4 hours after the second intramuscular acid injection (fig 1). The exercise protocol consisted of the animals (n 8) walking (6.10 m/min [20ft/min]) on the treadmill for 5 consecutive days to duplicate a daily exercise program. The animals walked Fig 1. Timeline of the first exercise experiment. In the second experiment, all the rats exercised, and naloxone or saline was administered systemically 20 minutes prior to exercise. Before both experiments, the rats trained on the treadmill for 4 days. for 15 minutes on days 1 and 2, and 30 minutes on days 3 through 5. Control animals (n 6) were placed on a nonmoving treadmill for the same time period as the exercise session. The mechanical withdrawal threshold, used to assess mechanical hyperalgesia, was measured before each intramuscular acid injection, before and after each exercise session, and the day after the final exercise session (day 6). To study whether the low-intensity exercise protocol activated the endogenous opioid system, naloxone (10mg/kg intraperitoneal, n 15) or saline solution (intraperitoneal, n 14) was administered 20 minutes before each exercise session. The exercise sessions were the same as previously described except that all the rats exercised. Mechanical withdrawal threshold was measured before each intramuscular acid injection, before and after each exercise session, and the day after the final exercise session (day 6). Statistical Analysis A Kruskal-Wallis 1-way analysis of variance (ANOVA) by ranks compared mechanical withdrawal thresholds between exercising rats and nonexercising rats. Data were converted to the area under the curve (AUC) for the exercise and nonexercising group, and the naloxone- and saline-treated exercising rats. The AUC was computed by the sum of the differences between the withdrawal threshold 24 hours after each exercise session and the withdrawal threshold 4 hours after the second intramuscular acid injection. The AUC was compared between groups, exercising versus nonexercising and saline versus naloxone, using a 1-way ANOVA. Significance was determined using an level of.05. RESULTS Chronic Muscle Pain Model The behavioral effects of repeated intramuscular acid injections were the same as previously reported. 14 Specifically, there

3 1738 EXERCISE REVERSES CHRONIC MUSCLE PAIN, Hoeger Bement Fig 2. Low-intensity exercise reverses mechanical hyperalgesia in a chronic muscle pain model. Mechanical withdrawal threshold decreased bilaterally 4 hours after the second intramuscular acid injection. Fifteen to 30 minutes of exercise reversed this decrease in mechanical threshold compared with nonexercising controls. Data are median with the 25th and 75th percentiles. Abbreviations: INJ1, before intramuscular injection 1 of ph 4.0 saline; INJ2, before intramuscular injection 2 of ph 4.0 saline. *Significantly increased from nonexercising control (P<.05). was a bilateral decrease in mechanical withdrawal threshold, indicating mechanical hyperalgesia, 4 hours after the second intramuscular acid injection. This decrease in mechanical withdrawal threshold is interpreted as mechanical hyperalgesia. Low-Intensity Exercise Low-intensity exercise decreased mechanical hyperalgesia bilaterally in the chronic muscle pain model (figs 2, 3). The mechanical hyperalgesia decreased immediately after exercise on day 1 (see fig 2). The decrease in mechanical hyperalgesia transitioned from decreasing immediately after exercise to decreasing 24 hours after each exercise interval, which may be associated with the increase in the exercise session to 30 minutes starting on day 3 (see fig 2). Analysis of the AUC showed a significant reversal in mechanical hyperalgesia bilaterally in the rats that exercised compared with those that did not (see fig 3). Naloxone Effects on Low-Intensity Exercise Daily treatment with naloxone prevented the antihyperalgesic effects produced by exercise in the chronic muscle pain model. Specifically, systemic naloxone administration significantly prevented the antihyperalgesic bilateral effects of exercise when compared with systemic saline administration (fig 4). It appears that naloxone did not completely prevent the antihyperalgesic effects of exercise. DISCUSSION This study shows that low-intensity exercise reversed mechanical hyperalgesia in a chronic muscle pain model in rats. Naloxone attenuated the antihyperalgesia produced by exercise, indicating that low-intensity exercise in this pain model involves activation of opioid receptors. Little research has been conducted on exercise-induced analgesia in animal models of hyperalgesia. Most exercise-induced analgesia research has been conducted on animals without hyperalgesia (for a review, see Koltyn 11 ). Use of animal models allows one to control the extent and type of injury, to minimize the placebo effect, and importantly, to test mechanisms of action. One animal study 23 tested the effects of a forced swimming exercise protocol on mice using an acute tissue injury model, formalin. Forced swimming, which may have a stress-induced analgesic component, decreased hyperalgesia through an opiate-mediated mechanism; naloxone (1mg/kg intraperitoneal) prevented the antihyperalgesic effects of the 3-minute swim. 19 The current study is the first to examine the mechanisms of action of a lowintensity exercise protocol in a chronic muscle pain model. Interestingly, this chronic muscle pain model presents with bilateral mechanical hyperalgesia despite a unilateral noxious stimulus (ie, intramuscular acid injection). Contralateral hyperalgesia after a unilateral insult also occurs in other models. Fig 3. Analysis of the AUC shows a reversal in mechanical withdrawal threshold in the rats that exercised versus those that did not. The difference between the mechanical withdrawal threshold 24 hours after each exercise session and the withdrawal threshold 4 hours after the second intramuscular acid injection (ie, hyperalgesia) was analyzed for the AUC. We used the same procedure for the nonexercising controls. Exercise significantly decreased mechanical hyperalgesia compared with the nonexercising controls. Data are mean standard error of the mean (SEM). *Significantly increased from nonexercising control (P<.05).

4 EXERCISE REVERSES CHRONIC MUSCLE PAIN, Hoeger Bement 1739 Fig 4. Analysis of the AUC shows that daily naloxone administration (10mg/kg intraperitoneal) before exercise significantly attenuated the antihyperalgesic effects of exercise when compared with animals that received daily saline before exercise. Data are mean SEM. *Significantly decreased from control (P<.05). Specifically, intra-articular application of mustard oil, noxious heat, carrageenan injection into muscle or knee, and injection of capsaicin into muscle or joint result in both ipsilateral and contralateral changes Similarly, contralateral effects are apparent following inflammatory conditions such as rheumatoid arthritis and inflammatory joint disease, which are dependent on the amount of inflammation present Koltzenburg et al 32 reported that a unilateral peripheral nerve lesion causes contralateral changes that are most likely attributable to central mechanisms, such as the activation of commissural spinal interneurons. Supraspinal sites are likely involved with contralateral hyperalgesia. 33 Specifically, bilateral lesions of the rostral medial medulla decrease bee venom induced contralateral heat hyperalgesia but not primary heat and mechanical hyperalgesia. 33 Thus, contralateral changes are evident after a unilateral insult, which is mediated by the central nervous system (CNS). Exercise decreased both the ipsilateral and contralateral hyperalgesia, indicating that exercise likely has CNS effects (see figs 2, 3). Furthermore, the reduction in hyperalgesia was reversed by naloxone (see fig 4). Because naloxone was administered systemically, the effects of exercise may involve peripheral and/or central mechanisms. Opioids, specifically -endorphins, are released during exercise 12 ; -endorphins may influence supraspinal sites via the hypothalamus, resulting in CNS changes. In contrast, -endorphins may be released into the bloodstream via the anterior pituitary and result in changes in the peripheral nervous system. Future studies are warranted to localize the mechanism of action. Naloxone does not always alter, or only partially alters, pain perception after exercise, which supports the concept of both opioid and nonopioid mechanisms in exercise-induced analgesia. 11,34-36 Other theories include activation of large afferent fibers incorporating the gate-control theory of pain; return of function and removal of mechanical and shearing forces, thus eliminating nociceptor irritation; enhanced psychologic wellbeing; distraction; and activation of endogenous cannabinoids Thus, low-intensity exercise may have both opioid and nonopioid mechanisms in producing analgesia in chronic muscle pain. Six rats were not able to learn the walking exercise protocol and were excluded from the study. These rats may have responded differently to the exercise protocol than the rats that were included in the study. In patients with myofascial pain, exercise may increase or decrease pain, which may be explained in part by the differential effects of exercise in subgroups of the same pain condition. 41 Perhaps low-intensity exercise decreased mechanical hyperalgesia only in the subgroup of rats that learned to walk on the treadmill. A few rats had minor vocalizations while they were walking on the treadmill. Stress may be a contributing factor in the decrease in mechanical hyperalgesia following the low-intensity exercise protocol. However, this may not be a limiting factor because, clinically, there is an element of stress for patients who are being introduced to exercise pain management. Patients who are being taught to walk on a treadmill may experience slight stress as a result of the introduction of new equipment, initiation of exercise therapy, or fear of exacerbation of their symptoms. In addition to the potential for exercise to induce stress, the animals may have experienced stress-induced analgesia after the saline and naloxone injections. Unfortunately, the 2 experiments could not be directly compared because they were 2 separate independent experiments and the animals were not tested simultaneously. Alternatively, the differences in the AUCs between the 2 experiments showed normal variability within experimental groups. CONCLUSIONS Low-intensity exercise reversed mechanical hyperalgesia in this chronic muscle pain model through the activation of opioid receptors. These experiments are the first to show that lowintensity exercise activates opioid receptors to reduce hyperalgesia associated with chronic musculoskeletal pain. References 1. Gowans SE, dehueck A. 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