Chronic widespread pain (CWP) as occurs in fibromyalgia is common and debilitating. Fibromyalgia is also associated with orthostatic intolerance, sleep disruption and fatigue. Autonomic nervous system dysfunction has been implicated in the etiology of this disease. Parasympathetic-mediated heart rate variability (HRV) is decreased in people with fibromyalgia with reports of increased sympathetic activity that could contribute to pain by sensitizing nociceptors. Exercise training has been shown to reduce pain in fibromyalgia. The aims of this study were to characterize autonomic dysregulation in an established mouse model of CWP [1], and determine if short duration (5-day) voluntary wheel-running influences neuro-cardiovascular regulation in either healthy or CWP mice. Blood pressure (BP) and heart rate (HR) were measured by telemetry in conscious, young (10-12 wks) C57BL6 mice. CWP was induced by two intramuscular injections of acidic saline into the left gastrocnemius muscle (100 μl of sterile saline at pH 5, 5 days apart) under 2-5% isoflurane, combined with 2 hours of fatiguing exercise. CWP mice eat, drink, and groom normally, have normal gait patterns, and continue to gain weight similar to mice injected with pH 7.2 as a control (no hyperalgesia), or naïve animals [2]. CWP (hyperalgesia) was assessed by measuring the threshold for hindlimb withdrawal during application of a series of von Frey filaments to the paw. Data (mean±SEM) were analyzed using t-tests and repeated measures ANOVA as applicable, with significance taken at P<0.05 (see Table). Mice were killed with an overdose of pentobarbital at the end of the experiment. Induction of CWP decreased parasympathetic-mediated HRV (RMSSD) without affecting mean BP or sympathetic vasomotor tone measured by the depressor response to the ganglionic blocker chlorisondamine (Table, *P<0.05, CWP vs. Control, n=4-6). Five days of voluntary wheel-running decreased HR, BP and sympathetic tone measured at rest in healthy mice (*P<0.05, Exerc vs. Control) and mice subjected to induction of CWP (†P<0.05), and prevented both the decrease in HRV and secondary mechanical hyperalgesia in the ipsilateral paw (n=8) in CWP mice (†P<0.05, Exerc+CWP vs. CWP, n=4-8). We conclude: 1) This mouse model of CWP exhibits selective impairment of parasympathetic modulation of HR with preserved sympathetic vasomotor tone; and 2) Voluntary wheel-running decreases sympathetic tone, HR and BP in both healthy and CWP mice; and prevents hyperalgesia and decreased HRV in CWP mice. Future studies will explore the mechanisms underlying the beneficial effects of short-duration voluntary exercise.