BACKGROUND: Spinal cord injury (SCI) persons with chronic neuropathic pain (NP) demonstrate maladaptive autonomic profiles compared to SCI counterparts without NP (SCI - NP) or able-bodied (AB) controls. These aberrations may be secondary to maladaptive neuroplasticity in the shared circuitry of the pain neuromatrix-central autonomic network interface (PNM-CAN). In this study, we explored the proposed PNM-CAN mechanism in SCI + NP and AB cohorts following centrally-directed neuromodulation to assess if the PNM and CAN are capable of being differentially modulated. MATERIALS AND METHODS: Central neuromodulation was administered via breathing-controlled electrical stimulation (BreEStim), previously evidenced to operate at the PNM. To quantify CAN activity, conventional heart rate variability (HRV) recordings were used to gather time and frequency domain parameters of autonomic modulation. SCI + NP (n = 10) and AB (n = 13) cohorts received null and active BreEStim randomly in crossover fashion. HRV data were gathered pretest and 30 minutes posttest. Pain modulation was quantified at both time-points by visual analog scale (VAS) for SCI + NP persons and electrical detection and pain threshold levels (EDT, EPT) for AB persons. RESULTS: Following active BreEStim only, SCI + NP persons demonstrated increased parasympathetic tone (increased NN50, p = 0.03, and pNN50, p = 0.02, HRV parameters). This parasympathetic restoration was associated with analgesia (VAS reduction, p < 0.01). Similarly, AB persons demonstrated increased noxious tolerance (increased EPT, p = 0.03, with preserved EDL, p = 0.78) only following active BreEStim. However, this increased pain threshold was not associated with autonomic changes. CONCLUSIONS: Central modulation targeting the PNM produced autonomic changes in SCI + NP persons but not AB persons. These findings suggest that AB persons exhibit intact CAN mechanisms capable of compensating for PNM aberrations or simply that SCI + NP persons exhibit altered PNM-CAN machinery altogether. Our collective findings confirm the interconnectedness and maladaptive plasticity of PNM-CAN machinery in SCI + NP persons and suggest that the PNM and CAN circuitry can be differentially modulated.