The subjective experience of pain varies drastically between people, but subjective measures of pain correlation provide an important understanding of its underlying mechanisms. Emerging literature on pain points to a relationship between muscle sympathetic nerve activity (MSNA)—a measure of how active the sympathetic nervous system is while signalling blood vessels to constrict—and acute pain. MSNA is closely tied to the cardiovascular system and typically rises with painful stimulation, linking autonomic arousal to the perception of pain.
The autonomic nervous system has two branches: The sympathetic nervous system, which controls the ‘fight or flight’ response, and the parasympathetic nervous system, which is associated with promoting states of calm. Previous research has shown that brief painful stimuli and standard cold-pressor paradigms—where participants submerge their hand in a bowl of ice-water—elevate MSNA, blood pressure, and pain ratings in both sexes. However, little is understood about MSNA’s relationship to chronic pain, defined as pain persisting over three months, or whether sex contributes to variability in MSNA responses to pain.
In her PhD Sex Differences in the Relationship between Pain and Autonomic Outflow during a Cold Pressor Test, published in Biology of Sex Differences, Laila A. Chaudhry seeks to address the research gap on the relationship between MSNA and chronic pain. In an interview with The Tribune, Chaudhry spoke about conducting the first such study, segregating pain measures by sex to distinguish whether there was a significant difference in its interaction with autonomic arousal.
“It encourages a shift from viewing sex differences in pain from purely a psycho-social [phenomenon] to something grounded in physiological differences,” Chaudhry said. “This [research] is very indicative that it is actually at the biological level as well, including something as simple as nerve conductance is different between the sexes.”
To test her hypothesis, the intervention protocol included a six-minute tonic cold pressor test (CPT) to simulate chronic pain—a longer protocol than previously tested. While participants submerged their hands in ice-water, they reported a tingling, throbbing, and persistent pain resembling chronic pain symptoms. The team collected subjective pain ratings and objective autonomic measures—heart rate (HR), mean arterial blood pressure (MAP), and MSNA—at various time points throughout the test. The team reported sex-aggregated interactions between time, pain, and the various autonomic markers during the intervention.
Although HR, MAP, and MSNA all increased in the initial submersion for both cohorts, a positive relationship between pain and HR emerged only in males for durations over 30 seconds. This association is an index of parasympathetic activity, meaning it points to predominant vagal withdrawal—as opposed to large vasoconstrictor surges, which indicate sympathetic activity—as the pathway linking sustained pain to cardiovascular arousal in men once the initial shock phase passes.
In contrast, females showed greater pain-related sympathetic responses, with 2.2 times higher MSNA burst frequency than males. Mechanistically, this suggests that sympathetic drive in response to sustained pain may be implicated in amplifying and maintaining pain more strongly in females.
“[A] prevailing theory is that larger axons are less likely to produce chronic pain because, essentially, they don’t get over-fired [….] They have greater neurotransmitter release just because they have larger burst amplitudes, and men, just because of their physical size, are more likely to have larger axons and larger nerves,” Chaudhry said.
In other words, chronic pain in men is characterized by a reduction in the pain-inhibiting activity of the parasympathetic branch, whereas in females, it involves higher activity of the ‘fight-or-flight’ system of the sympathetic branch. The discovery of different relationships between pain ratings and autonomic indices by sex—pain versus HR in men and pain versus MSNA variables in women—suggests sex-specific autonomic signatures of tonic pain. Chaudhry explained where this study falls within existing pain literature.
“This was part of a larger set of studies looking at sympathetic factors in pain [….] Pain treatment is interdisciplinary, and other techniques that work to target the sympathetic or parasympathetic systems could be informed by this knowledge of sex differences in chronic pain patients,” Chaudhry said.
Continuing to study the interaction between sex and pain is crucial for developing treatment protocols that adequately address differing physiological profiles and guiding targeted prevention and treatment.
