Aerobic Exercise Prevents the Loss of Endogenous Pain Modulation in Male and Female Rats with Traumatic Brain Injury

Traumatic brain injury (TBI) patients may suffer from several long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to the development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here, we investigate the effect of exercise on nociceptive outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with prostaglandin E2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies included administration of noradrenergic (NA) and serotoninergic receptor antagonists. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of hindlimb hyperalgesia from ∼5 weeks to 2-3 weeks in female and male TBI rats, respectively. These gains were reversed by administration of the α₁-adrenoceptor (α₁-AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT₇ receptor antagonist, SB-267790, despite this being the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Assessment of neuropathology, conducted acutely after TBI, revealed that both astrocyte and microglial responses to injury were significantly greater in male TBI compared with female TBI rats, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. Exercise significantly reduced axonal loss in the corpus callosum in both male and female TBI rats compared with sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups, respectively. These results demonstrate that exercise is a promising treatment for chronic nociception after TBI in both male and female rats. It also highlights that dysfunction of endogenous pain modulatory pathways in male TBI rats involving a transition from NA to serotonergic antinociception can be blocked by exercise, possibly by reducing axonal loss.