Hyperalgesia in an immobilized rat hindlimb: Effect of treadmill exercise using non-immobilized limbs

Abstract

Cast immobilization of limbs causes hyperalgesia, which is a decline of the threshold of mechanical and thermal mechanical stimuli. The immobilization-induced hyperalgesia (IIH) can disturb rehabilitation and activities of daily living in patients with orthopedic disorders. However, it is unclear what therapeutic and preventive approaches can be used to alleviate IIH. Exercise that activates the descending pain modulatory system may be effective for IIH. The purpose of this study was to investigate the effects of treadmill exercise during the immobilization period, using the non-immobilized limbs, on IIH. Thirty-six 8-week-old Wistar rats were randomly divided into 1) control, 2) immobilization (Im), and 3) immobilization and treadmill exercise (Im+Ex) groups. In the Im and Im+Ex groups, the right ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for an 8-week period. In the Im+Ex group, treadmill exercise (15 m/min, 30 min/day, 5 days/week) was administered during the immobilization period while the right hindlimb was kept immobilized. Mechanical hyperalgesia was measured using von Frey filaments every week. To investigate possible activation of the descending pain modulatory system, beta-endorphin expression levels in hypothalamus and midbrain periaqueductal gray were analyzed. Although IIH clearly occurred in the Im group, the hyperalgesia was partially but significantly reduced in the Im+Ex group. Beta-endorphin, which is one of the endogenous opioids, was selectively increased in the hypothalamus and midbrain periaqueductal gray of the Im+Ex group. Our data suggest that treadmill running using the non-immobilized limbs reduces the amount of hyperalgesia induced in the immobilized limb even if it is not freed. This ameliorating effect might be due to the descending pain modulatory system being activated by upregulation of beta-endorphin in the brain.

Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model

“…Rodent exercise studies almost uniformly show analgesic effects in a variety of pain models using various types and intensities of exercise. 22–27 Some studies have reported reoccurrence and others observed no reoccurrence of neuropathic pain after stopping exercise. 25,26 No prior exercise studies have utilized the TFM or examined exercise effects on skin, nerve, and spinal cord neuropeptide or cytokine expression.…”

The Impact of Exercise in Rodent Models of Chronic Pain

“…Exercise improves measures of neurological function in the periphery and spinal cord [ 90 , 94 , 97 , 111 , 115 , 119 , 121 , 123 ] as well as improved musculoskeletal outcomes [ 99 ••, 114 ••, 120 , 126 ]. In addition, exercise improved neurotrophic receptor signaling in the spinal cord and periphery [ 87 , 97 , 108 •, 109 , 111 , 115 , 122 – 124 ]; restoration to pre-injury levels of cytokines and other neuroimmune products in the brainstem, spinal cord, and periphery [ 87 , 88 , 90 , 93 , 96 , 112 , 113 , 116 , 117 , 119 , 121 , 123 , 124 , 127 , 128 ]; and increased endogenous opioid activity in the rostroventral medulla (RVM), spinal cord, and dorsal root ganglia (DRG) [ 91 •, 106 , 110 , 114 ••, 121 , 129 , 130 ]. Importantly, while endogenous opioid-mediated mechanisms can produce analgesia at acute post-exercise time points, some studies suggest that longer-term endogenous opioid-mediated effects also occur.…”

“…However, the apparent intensity-dependence of acute exercise for activation of the endogenous opioid system [ 75 – 78 ] , reviewed in [ 79 , 80 ] seems to argue against its involvement in low-intensity exercises such as walking. In the rodent exercise literature, activity of the endogenous opioid system is also widely reported [ 91 •, 106 , 110 , 114 ••, 121 , 129 , 130 ]. However, these studies employed forced treadmill running, which can be highly stressful [ 102 •, 147 – 154 ].…”

Sole vibration improves locomotion through the recovery of joint movements in a mouse cast model

“…Previous studies have showed that immobilization in rodents causes hypersensitivity [ 17 – 20 ] and that continuous vibration or treadmill training partially recovers the hypersensitivity [ 21 – 23 ]. Further, Hamaue et al claimed that only a 4-week immobilization resulted in hypersensitivity [ 18 ].…”