by Sophia Stone, TMJA contributing author
To understand this possible connection, you have to consider how blood pressure is normally controlled by the nervous system. Barring the lifelong habits of some Buddhist monks or yogis, people normally have no conscious ability to control their blood pressure. That is the job of the autonomic nervous system (ANS) which encompasses two complementary branches: the sympathetic and parasympathetic nervous systems.
The sympathetic branch is popularly known as the “fight-or-flight” system, which drives up your heart rate and blood pressure in tense or stressful situations. The parasympathetic, in contrast, is the “rest-and-digest” system that helps you relax and enjoy a hearty dinner. Normally the two systems operate as checks on each other so that neither one over-reacts. However, if that happens, or if one or the other system consistently fails to respond to stimuli appropriately, it could mean your ANS is dysfunctional. A common example of this is orthostatic hypotension, the failure of the sympathetic nervous system to ramp up blood pressure in a reflex response to a change in position when you move from lying down or sitting to a standing position. Without the reflex increase in pressure, the low blood pressure you experience when you stand can cause you to feel dizzy or even faint.
Now researchers think there might be a relationship between chronic pain and the sensory nerve cells, called baroreceptors, that trigger that reflex. “Baro” is the same root as in barometer, the device used to measure atmospheric pressure. Baroreceptors in arterial walls and at other circulatory sites react to changes in the mechanical forces exerted by the blood circulating through the vessels. In their review paper Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes, Heberto Suarez-Roca and colleagues examine the evidence for how baroreceptors may contribute to chronic pain.
Hypertension and Hypoalgesia
To begin with, the authors note that there’s a sizeable body of evidence linking high blood pressure (hypertension) to reduced pain sensitivity (hypoalgesia). A number of experiments have also shown that inducing hypertension in animal models (sometimes by providing high salt diets) can lower their perception of pain, and that this is reversed by restoring their blood pressure to normal. Moreover, patients with chronic hypertension have also been shown to have higher pain thresholds. It’s also not uncommon for hypotensive individuals (people with with normally low blood pressure) to experience thermal hyperalgesia—a heightened sensitivity to pain at high temperatures.
That said, there are questions surrounding this relationship that have yet to be answered. For example, it’s been shown that hypoalgesia persists in patients even after hypertension has been corrected with blood pressure medication. A possible explanation could be that the mechanisms that improve pain tolerance are maintained even after blood pressure is reduced in hypertensive patients. Other studies have shown that hypoalgesia may precede hypertension, such as one interesting report that pain sensitivity at age 14 is predictive of blood pressure later in life. One explanation here is that venous pressure, not just arterial pressure measured in blood pressure readings, may be in part responsible.
While the mechanisms are not well understood, the authors make the case that baroreceptors are the mediators of hypertension-induced hypoalgesia. During systole (the upper reading in a blood pressure measurement), blood is expelled from the heart into the arteries, causing blood pressure to rise and the arterial walls to stretch to accommodate the greater volume of blood. The arterial wall stretching stimulates the baroreceptors to act to restore pressure to a resting pressure, essentially to maintain “homeostasis,” a balance in pressure neither too high or to low. Baroreceptors orchestrate these pressure changes by signaling the parasympathetic nervous system to relax the arterial walls to relieve the strain and lower blood pressure or, when blood pressure is too low, signaling arteries to constrict so that the circulating blood will exert mechanical forces on the arterial walls and increase pressure. Normally baroreceptor function involves subtle adjustments in both arms of the ANS.
Interestingly, hypoalgesia associated with hypertension peaks during systole (coinciding with maximum blood pressure) as opposed to diastole (the bottom measurement of blood pressure when the heart relaxes and there is minimum blood pressure). Thus, pain sensitivity is reduced in the systolic phase of the cardiac cycle during maximum baroreceptor load, suggesting that altered pain perception may be a function not only of absolute blood pressure, but also of the sensitivity of baroreceptors that regulate blood pressure. A failure of baroreceptors to respond appropriately to arterial stretch is a form of early autonomic dysfunction, and it has also been linked to greater sensitivity to pain.
It’s complicated. A number of factors affect baroreceptor function. The receptors’ sensitivity varies by age, sex, phase of the menstrual cycle, pregnancy, and circadian rhythms. For example, cardiac baroreceptor sensitivity is 50% lower in women, where it is thought to be due to estrogen’s effects on the central nervous system and peripheral arteries. More relevant to chronic pain, reduced baroreceptor sensitivity has been shown to be associated with greater sensitivity to pain. The finding that baroreceptor activation elicits hypoalgesia further suggests that baroreceptors may explain the causal relationship between hypertension and attenuated pain sensitivity.
Baroreceptors and Chronic Pain: Possible Mechanisms
Three mechanisms have been proposed to explain baroreceptors’ effects on pain perception: endogenous opioids (i.e., the brain’s own pain-relieving molecules), adrenergic receptors in the brain, and the process of inflammation.
Endorphins. In the first camp, it’s thought that baroreceptor stimulation may activate opioid networks in the brain, which is supported by the finding that hypertensive patients have higher circulating levels of endogenous opioids. (called endorphins) in the brain, particularly in response to stresses like pain or exercise. This endorphin rush helps mask physical pain and is also thought to explain the euphoric feeling of a runner’s high. It turns out that baroreceptor stretching may be a less painful means of opening the endorphin floodgates!
Stress hormones. Another possible mechanism is the activation of receptors for epinephrine and norepinephrine (also known as adrenaline and noradrenaline) in the brain. These are stress hormones produced by sympathetic nervous system activation of the adrenal glands in response to short-term stress. Norepinephrine levels have been shown to be elevated, along with pain tolerance, in people with high blood pressure. In other words, high levels of stress hormones in hypertensive individuals may be acting on receptors in the brain to blunt their perceptions of pain.
Inflammation. According to a third mechanism, baroreceptors’ effects on pain perception may be explained by the close relationship between ANS dysfunction and chronic inflammation. Reduced baroreceptor sensitivity, has been shown to correlate with markers of inflammation that are a likely source of pain. While chronic inflammation is normally thought of as a cause of ANS dysfunction, the reverse relationship has also been shown in some autoimmune and inflammatory conditions. For instance, those at risk of rheumatoid arthritis (an autoimmune condition) are more likely to show signs of autonomic dysfunction and over-activation of the sympathetic nervous system before they develop arthritis, and reducing sympathetic over- activity in hypertensive individuals also reduces inflammation. There is also extensive evidence that activating baroreceptor reflexes can attenuate inflammatory pathways, and conversely that baroreceptor and autonomic dysfunction trigger inflammation in part by activating sympathetic nerves that release painful inflammatory chemicals. That it to say that when baroreceptors don’t work properly, our sympathetic nervous system gets fired up and releases inflammatory molecules that cause pain.
Postoperative pain. Baroreceptor and ANS dysfunction are predictive of postoperative pain in surgical patients and have also been associated with a number of chronic conditions, including hypertension, diabetes, atherosclerosis, obesity, obstructive sleep apnea, cardiovascular disease, and chronic kidney disease, many of which are associated with chronic pain. An existing model for these associations is that increased sympathetic nervous system activity promotes a state of chronic inflammation and pain, which is associated with elevated inflammatory mediators and stress hormones. Chronically elevated levels of stress hormones may desensitize baroreceptors, making them less effective and setting the stage for ANS dysfunction.
Baroreceptors and TMD. Heightened pain and baroreceptor dysfunction are also more prevalent in chronic musculoskeletal pain conditions such as temporomandibular disorder (TMD), fibromyalgia, and chronic back pain. These chronic pain states are frequently associated with signs of autonomic dysfunction. For example, orthostatic hypotension is common among fibromyalgia patients, whose reduced baroreceptor sensitivity has been shown to correlate with the severity of their symptoms and to be about 35% lower compared to healthy women. It may not be a coincidence that women have both lower baroreceptor sensitivity and a greater incidence of chronic pain conditions like TMD and fibromyalgia; such disparities in baroreceptor or autonomic function may help explain sex differences in chronic pain incidence and treatment responses.
Given this evidence, the authors pose the important question: can baroreceptor function and blood pressure status be considered risk factors for chronic pain and perioperative outcomes? Currently, there are a few things that can be done to improve baroreceptor function. Vagal nerve stimulation is one option, and other interventions (e.g., fluid management, acupuncture, cardiovascular conditioning, biofeedback, etc.) are also being explored. More research—and less invasive treatment—are crucially needed, as it appears that baroreceptor function may represent a promising link between autonomic dysfunction and chronic pain, and quite possibly could pave the way for new approaches to treating chronic conditions.
Source: Heberto Suarez-Roca, Rebecca Y. Klinger, Mihai V. Podgoreanu, Ru-Rong Ji, Martin I. Sigurdsson, Nathan Waldron, Joseph P. Mathew, William Maixner; Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes. Anesthesiology 2019;130(4):634-650. doi: 10.1097/ALN.0000000000002510.