Sluka KA, O'Donnell JM, Danielson J, Rasmussen LA. Regular physical activity prevents development of chronic pain and activation of central neurons.

Purpose Pain in response to physical activity is common in people with chronic musculoskeletal pain and is likely a barrier to regular exercise, which would lead to a sedentary lifestyle. We recently developed a model of exercise-induced pain that is associated with increased activation of neurons in the medullary raphe nuclei, i.e., the nucleus raphe obscurus (NRO) and nucleus raphe pallidus (NRP). Because the NRO and NRP not only modulate motor output but also respond to noxious stimuli, we hypothesized that the NRO and NRP were key nuclei in the interaction between pain and exercise. We tested whether exercise enhances hyperalgesia through activation of N-methyl D-aspartate (NMDA) receptors in the NRO/NRP. Methods Muscle insult was induced by two injections of pH 5.0 saline 5 d apart into one gastrocnemius muscle. We initially tested whether hyperalgesia developed in mice injected with acidic saline (pH 5.0) into the gastrocnemius muscle immediately after a 30-min or 2-h exercise task or 2 h after a 2-h exercise task. Next, we tested whether blockade of NMDA receptors in the NRO/NRP during the exercise task prevented the development of exercise-induced hyperalgesia. Finally, we evaluated changes in phosphorylation of the NR1 subunit of the NMDA receptor (pNR1) after the exercise task at times in which muscle insult was given in behavioral experiments, i.e., immediately after a 30-min or 2-h exercise task or 2 h after the 2-h exercise task. Results All exercise conditions enhanced nociception (hyperalgesia) after combining with two injections of pH 5.0 saline. Microinjection of AP5 (1.0–0.1 nmol; 2-amino-5-phophonopenanoate) dose-dependently prevented the development of exercise-induced hyperalgesia. All exercise conditions increased pNR1 in the NRO and NRP. Conclusions Thus, exercise-induced pain in sedentary mice is associated with increased phosphorylation and activation of NMDA receptors in the NRO/NRP, suggesting that changes in central excitability mediate an interaction between unaccustomed exercise and pain.

Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA. Enhanced muscle fatigue occurs in male but not female ASIC3Ϫ/Ϫ mice. Am J Physiol Regul Integr Comp Physiol 294: R1347-R1355, 2008. First published February 27, 2008 doi:10.1152/ajpregu.00687.2007.-Muscle fatigue is associated with a number of clinical diseases, including chronic pain conditions. Decreases in extracellular pH activates acid-sensing ion channel 3 (ASIC3), depolarizes muscle, protects against fatigue, and produces pain. We examined whether ASIC3Ϫ/Ϫ mice were more fatigable than ASIC3ϩ/ϩ mice in a task-dependent manner. We developed two exercise protocols to measure exercise-induced muscle fatigue: ( fatigue task 1, three 1-h runs; fatigue task 2, three 30-min runs). In fatigue task 1, male ASIC3ϩ/ϩ mice muscle showed less fatigue than male ASIC3Ϫ/Ϫ mice and female ASIC3ϩ/ϩ mice. No differences in fatigue were observed in fatigue task 2. We then tested whether the development of muscle fatigue was dependent on sex and modulated by testosterone. Female ASIC3ϩ/ϩ mice that were ovariectomized and administered testosterone developed less muscle fatigue than female ASIC3ϩ/ϩ mice and behaved similarly to male ASIC3ϩ/ϩ mice. However, testosterone was unable to rescue the muscle fatigue responses in ovariectomized ASIC3Ϫ/Ϫ mice. Plasma levels of testosterone from male ASIC3Ϫ/Ϫ mice were significantly lower than in male ASIC3ϩ/ϩ mice and were similar to female ASIC3ϩ/ϩ mice. Muscle fiber types, measured by counting ATPase-stained whole muscle sections, were similar in calf muscles from male and female ASIC3ϩ/ϩ mice. These data suggest that both ASIC3 and testosterone are necessary to protect against muscle fatigue in a task-dependent manner. Also, differences in expression of ASIC3 and the development of exercise-induced fatigue could explain the female predominance in clinical syndromes of pain that include muscle fatigue.

This placebo-controlled, explanatory, randomized, controlled trial demonstrated that adding pain science education to exercise for Achilles tendinopathy did not enhance improvements in pain and function.

Background Achilles tendinopathy (AT) rehabilitation traditionally includes progressive tendon loading exercises. Recent evidence suggests a biopsychosocial approach that incorporates patient education on psychosocial factors and mechanisms of pain can reduce pain and disability in individuals with chronic pain. This is yet to be examined in individuals with AT. Objective This study aims to compare the effects on movement-evoked pain and self-reported function of pain education as part of a biopsychosocial approach with pathoanatomical education for people with AT when combined with a progressive tendon loading exercise program. Methods A single-site, randomized, double-blind, placebo-controlled clinical trial will be conducted in a university-based hospital in a laboratory setting and/or by telehealth. A total of 66 participants with chronic (>3 months) midportion or insertional AT will be randomized for the Tendinopathy Education of the Achilles (TEAch) study. All participants will complete progressive Achilles tendon loading exercises over 12 weeks and will be encouraged to continue with self-selected exercises as tolerated. All participants will complete 6-7 one-to-one sessions with a physical therapist to progress exercises in a standardized manner over 8 weeks. During the last 4 weeks of the intervention, participants will be encouraged to maintain their home exercise program. Participants will be randomized to 1 of 2 types of education (pain education or pathoanatomic), in addition to exercise. Pain education will focus on the biological and psychological mechanisms of pain within a biopsychosocial framing of AT. Pathoanatomic education will focus on biological processes within a more traditional biomedical framework of AT. Evaluation sessions will be completed at baseline and 8-week follow-up, and self-reported outcome measures will be completed at the 12-week follow-up. Both groups will complete progressive Achilles loading exercises in 4 phases throughout the 12 weeks and will be encouraged to continue with self-selected exercises as tolerated. Primary outcomes are movement-evoked pain during heel raises and self-reported function (patient-reported outcome measure information system—Physical Function). Secondary outcomes assess central nervous system nociceptive processing, psychological factors, motor function, and feasibility. Results Institutional review board approval was obtained on April 15, 2019, and study funding began in July 2019. As of March 2020, we randomized 23 out of 66 participants. In September 2020, we screened 267 individuals, consented 68 participants, and randomized 51 participants. We anticipate completing the primary data analysis by March 2022. Conclusions The TEAch study will evaluate the utility of pain education for those with AT and the effects of improved patient knowledge on pain, physical function, and clinical outcomes. International Registered Report Identifier (IRRID) DERR1-10.2196/19111