Exercise-Induced Pain Requires NMDA Receptor Activation in the Medullary Raphe Nuclei

Abstract

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.

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

“…All sections were immunohistochemically stained simultaneously using an antibody to the protein kinase A (PKA) phosphorylation site of the NR1 subunit of the NMDA receptor (pNR1) (1:1,000, Ser897, catalog no. ABN99; Millipore, Billerica, MA, http://www.millipore.com/) using standard immunofluorescent techniques as previously described (53). On day 1, sections were blocked in 3% normal goat serum (NGS), avidin, and biotin and then incubated in the primary antibody overnight at room temperature.…”

“…Rather, only 8 wk of regular physical activity was able to delay the onset of the hyperalgesia in the chronic muscle pain model. Once the hyperalgesia develops in the chronic muscle pain model, it is independent of primary afferent input, but rather it is maintained by activation of neurons in the central nervous system-the RVM and spinal cord (15,52,53). Further, the second injection of acidic saline requires activation of RVM facilitation neurons (60).…”

“…Indeed there are increases in release of endogenous opioids (met-enkephalin) in brainstem nuclei, including the RVM, during exercise, and blockade of central, but not peripheral, opioid receptors prevents the analgesia produced by exercise (58). In addition to mediating analgesia, the RVM also facilitates pain behaviors after tissue insult, including chronic muscle pain (44,53,55). The N-methyl-D-aspartate (NMDA) glutamate receptor in the RVM is critical for the development of hypersensitivity after muscle insult: increasing the NR1 subunit of the NMDA receptor enhances nociception, decreasing NR1 prevents chronic muscle pain (13), and blocking the NMDA receptor reverses pain sensitivity (13,53).…”

“…In addition to mediating analgesia, the RVM also facilitates pain behaviors after tissue insult, including chronic muscle pain (44,53,55). The N-methyl-D-aspartate (NMDA) glutamate receptor in the RVM is critical for the development of hypersensitivity after muscle insult: increasing the NR1 subunit of the NMDA receptor enhances nociception, decreasing NR1 prevents chronic muscle pain (13), and blocking the NMDA receptor reverses pain sensitivity (13,53). Further, there is increased phosphorylation of NR1 (p-NR1) in animal models of chronic muscle pain (13); these experiments were done in sedentary animals.…”

“…The chronic noninflammatory pain model is associated with secondary hyperalgesia and is maintained by central nervous system sensitization (54,60). The exercise-enhanced pain model is associated with primary hyperalgesia that results from the acute inflammation and secondary hyperalgesia that results from changes in the central nervous system (53,55). Thus the different animal models mimic different disease conditions and utilize different pain processing mechanisms.…”