BACKGROUND: Recent findings have implicated supraspinal origins from the pain neuromatrix- central autonomic network (PNM-CAN) in the generation of neuropathic pain (NP) after spinal cord injury (SCI). The aim of this study was to further investigate the theorized PNM-CAN mechanisms in persons with SCI by using a centrally directed pain intervention, provided by breathing-controlled electrical stimulation (BreEStim), to measure resultant autonomic changes measured by time and frequency domain heart rate variability (HRV) analysis. METHODS: Null and active BreEStim interventions were administered to SCI+NP subjects (n=10) in a random order. HRV data and VAS pain scores were collected at resting pre-test and 30 minutes post-test time points. Resting HRV data were also collected from SCI-NP subjects (n=11). RESULTS: SCI+NP subjects demonstrated a lower baseline HRV and parasympathetic tone, via SD of the normal-to-normal intervals (SDNN) and low frequency (LF) parameters, compared with SCI-NP subjects. However, following active BreEStim, SCI+NP subjects exhibited an increase in HRV and parasympathetic tone, most notably via pairs of successive R-R beat lengths varying by greater than 50 ms (NN50) and proportion of NN50 for total number of beats (pNN50) parameters along with lower VAS scores. Additionally, the post-test SCI+NP group was found to have a statistically comparable autonomic profile to the SCI-NP group across all HRV variables, including SDNN and LF parameters. CONCLUSION: The analgesic effects of active BreEStim in SCI+NP subjects were associated with restoration of autonomic dysfunction in this population.