Sex differences in the relationships between parasympathetic activity and pain modulation

Higher parasympathetic activity is related to lower pain perception in healthy subjects and pain patients. We aimed to examine whether this relationship depends on sex, in healthy subjects. Parasympathetic activity was assessed using time- and frequency-domain heart rate variability indices and deep breathing ratio. Pain perception parameters, consisting of heat pain thresholds and pain ratings of supra-thresholds stimuli, as well as pain modulation parameters of mechanical temporal summation, pain adaptation, offset analgesia and conditioned pain modulation (CPM) response were examined. Forty healthy subjects were examined (20 men). Women demonstrated higher parasympathetic activity compared to men (high frequency power of 0.55 ± 0.2 and 0.40 ± 0.2, respectively, p=0.02) and less pain reduction in the offset analgesia paradigm (-35.4 ±29.1 and -55.0 ±31.2, respectively, p=0.046). Separate slopes models analyses revealed sex differences such that a significant negative correlation was observed between higher rMSSD (the root mean square of successive differences) and higher pain adaptation in men (r=-0.649, p=0.003) but not in women (r=0.382, p=0.106). Similarly, a significant negative correlation was found between higher rMSSD and higher efficiency of the CPM response in men (r=-0.510, p=0.026) but not in women (r=0.406, p = 0.085). Sex hormones levels, psychological factors or baseline autonomic activity can be possible explanations for these sex differences. Future autonomic interventions destined to change pain modulation should consider sex as an important intervening factor.