Exercise reverses pain-related weight asymmetry and differentially modulates trabecular bone microarchitecture in a rat model of osteoarthritis

Abstract

There is great interest in developing and utilizing non-pharmacological/non-invasive forms of therapy for osteoarthritis (OA) pain including exercise and other physical fitness regimens. Aims The present experiments determined the effects of prior wheel running on OA-induced weight asymmetry and trabecular bone microarchitecture. Main methods Wheel running included 7 or 21 days of prior voluntary access to wheels followed by OA induction, followed by 21 days post-OA access to wheels. OA was induced with monosodium iodoacetate (MIA), and weight asymmetry was measured using a hind limb weight bearing apparatus. Bone microarchitecture was characterized using ex vivo μCT. Key findings Relative to saline controls, MIA (3.2 mg/25 μl) produced significant weight asymmetry measured on post-days (PDs) 3, 7, 14, 21 in sedentary rats. Seven days of prior running failed to alter MIA-induced weight asymmetry. In contrast, 21 days of prior running resulted in complete reversal of MIA-induced weight asymmetry on all days tested. As a comparator, the opioid agonist morphine (3.2– 10 mg/kg) dose-dependently reversed weight asymmetry on PDs 3, 7, 14, but was ineffective in later-stage (PD 21) OA. In runners, Cohen’s d (effect sizes) for OA vs. controls indicated large increases in bone volume fraction, trabecular number, trabecular thickness, and connective density in lateral compartment, and large decreases in the same parameters in medial compartment. In contrast, effect sizes were small to moderate for sedentary OA vs. controls. Significance Results indicate that voluntary exercise may protect against OA pain, the effect varies as a function of prior exercise duration, and is associated with distinct trabecular bone modifications.

The Impact of Exercise in Rodent Models of Chronic Pain

“…In these studies, exercise was performed for between 20 and 60 min/day for 4–7 days/week. The six studies (15%) using voluntary wheel running generally allowed longer wheel access (2–24 h/day [ 87 , 97 , 98 , 99 ••, 100 ••] but see [ 101 ]) for 4–7 days per week. However, it should be noted that the actual running time in voluntary exercise paradigms is unknown because rodents do not necessarily engage in constant running during periods of wheel access.…”

“…While three of the four studies showing no beneficial effect of therapeutic exercise on mechanical hypersensitivity initiated exercise 8 or more days after injury [ 92 , 98 , 118 ], other studies using similar delays in initiation of exercise were effective [ 87 , 91 •, 114 ••, 116 , 119 , 120 ]. Similarly, while two of the four studies showing no beneficial effect of therapeutic exercise on mechanical hypersensitivity used voluntary exercise paradigms [ 98 , 101 ], other studies using voluntary exercise were effective [ 87 , 97 , 99 ••, 100 ••]. Of the 36 studies showing that exercise was effective, a few indicate that some approaches were not as effective as others [ 91 •, 95 , 99 ••].…”

“…Similarly, while two of the four studies showing no beneficial effect of therapeutic exercise on mechanical hypersensitivity used voluntary exercise paradigms [ 98 , 101 ], other studies using voluntary exercise were effective [ 87 , 97 , 99 ••, 100 ••]. Of the 36 studies showing that exercise was effective, a few indicate that some approaches were not as effective as others [ 91 •, 95 , 99 ••]. Specifically, Stagg et al reported that 3 weeks at a slower treadmill speed of 10 m/min did not improve mechanical hypersensitivity, whereas the same duration at a higher speed of 16 m/min was effective [ 91 •].…”

“…On the other hand, Wakaizumi et al showed that while 2 weeks of slow running (6 m/min) was effective, 1 week of faster running (12 m/min) was not effective [ 95 ]. Finally, Cormier et al indicated that while 3 weeks of pre-training followed by 3 weeks of therapeutic running resulted in beneficial effects, 1 week of pre-training followed by 3 weeks of therapeutic running was not beneficial [ 99 ••]. Importantly, in all of these cases, other studies using similar exercise parameters show effectiveness.…”

“…As illustrated in Tables 1 and 2 , both voluntary wheel running and forced treadmill running promote favorable outcomes in a number of physiological systems impacted by persistent 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 ].…”