Autonomic regulation of pain inhibition mechanisms: the relationship between baroreflex sensitivity and conditioned pain modulation

Chronic pain is the leading source of morbidity worldwide and a global clinical and societal challenge. As one prevailing theory for the persistence of chronic pain is failure or dysfunction of the body’s pain inhibition mechanisms, a comprehensive understanding of pain inhibition is essential in pain treatment. The body’s capacity to inhibit pain can be measured via a conditioned pain modulation (CPM) paradigm, in which pain from a primary stimulus should be suppressed by pain from a secondary stimulus. Additionally, acute stress is capable of suppressing pain. Evidence suggests that stress-related pain inhibition is influenced by blood pressure (BP)-regulating baroreceptors: natural or experimental increases in BP stimulate baroreceptors elicit subsequent changes in autonomic outflow and produce descending pain inhibition. Despite baroreflex mechanisms being involved in general pain modulation, it is not yet known if the baroreflex is involved in CPM specifically, despite clinical evidence showing that many difficult-to-treat pain conditions are also associated with autonomic dysfunction. Therefore, the purpose of this study was to determine the relationship—which we hypothesized to be positive— between the baroreflex and CPM and explore potential underlying autonomic mechanisms. After being instrumented for the measurement of heart rate (HR), BP, and muscle sympathetic nerve activity (MSNA), healthy participants (n=8: 4 males, 4 females) underwent 10 min of baseline quiet rest. Lastly, a CPM protocol was conducted, consisting of two suprathreshold heat stimulations, a subsequent 30-s cold pressor test, then a final heat stimulation. Baseline systolic BP (SBP) and HR values were continuously measured to calculate cardiovagal baroreflex sensitivity (BRS) via the sequence method. Up-sequences, a marker for parasympathetic activation, and down-sequences, a marker for parasympathetic withdrawal, were quantified, stratified, and then regressed against values of CPM. In a subset of participants (n=5), MSNA was stratified by time and regressed against CPM values. Greater CPM was significantly related to less sensitive parasympathetic withdrawal (r=0.66, p=0.01), whereas MSNA was not significantly related to CPM. In summary, in healthy participants without chronic pain, suppression of parasympathetic withdrawal mechanisms may bolster CPM. Therefore, further research is needed to determine if these mechanisms are inverted or dysfunctional in chronic pain conditions, and if they provide a valuable autonomic target in the treatment of chronic pain, particularly for pain conditions with comorbid autonomic dysfunction. This research was funded by the Canadian Institutes of Health Research and National Science and Engineering Research Council of Canada. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.