Baroreceptor Modulation of the Cardiovascular System, Pain, Consciousness, and Cognition

Abstract

Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain cardiovascular homeostasis by coordinating the responses to external and internal environmental stressors. While it is well known that carotid and cardiopulmonary baroreceptors modulate sympathetic vasomotor and parasympathetic cardiac neural autonomic drive, to avoid excessive fluctuations in vascular tone and maintain intravascular volume, there is increasing recognition that baroreceptors also modulate a wide range of non-cardiovascular physiological responses via projections from the nucleus of the solitary tract to regions of the central nervous system, including the spinal cord. These projections regulate pain perception, sleep, consciousness, and cognition. In this article, we summarize the physiology of baroreceptor pathways and responses to baroreceptor activation with an emphasis on the mechanisms influencing cardiovascular function, pain perception, consciousness, and cognition. Understanding baroreceptor-mediated effects on cardiac and extra-cardiac autonomic activities will further our understanding of the pathophysiology of multiple common clinical conditions, such as chronic pain, disorders of consciousness (e.g., abnormalities in sleep-wake), and cognitive impairment, which may result in the identification and implementation of novel treatment modalities. © 2021 American Physiological Society. Compr Physiol 11:1373-1423, 2021.

FIGURE 1:

Schematic representation of key nuclei and pathways involved in the interactions between cardiovascular and pain modulatory systems. Panel A: The nucleus of the solitary tract (NTS), afferent input, and descending projections. NTS in the medulla oblongata received inputs from the glossopharyngeal (IX) nerve originating from carotid high-pressure baroreceptors and the vagus (X) nerve originating from the aortic high-pressure baroreceptors, cardiopulmonary low-pressure baroreceptors, concha, lung’s stretch-mechanoreceptors, lung’s chemoreceptors, and inflamed tissues. Afferents from the NTS excite the caudal ventrolateral medulla (CVLM), which in turn inhibits neurons in the rostral ventrolateral medulla (RVLM). Thus, there is a reduction in the RVLM tonic excitation of spinal intermediolateral neurons and a reduction in the sympathetic output to the heart and blood vessels. Afferents from the NTS also excite neurons in the dorsal vagal motor nucleus (DVN and nucleus ambiguous (NA), which enhances parasympathetic output. The resulting autonomic efferent balance diminishes heart rate and AP by a mechanism commonly referred to as the baroreflex. This change in autonomic balance can modulate inflammation, às a result, inflammatory pain. The baroreflex response is associated with increases in the release of acetylcholine (Ach) from vagal efferents, which reduces inflammation by inhibiting the secretion of pro-inflammatory cytokines from macrophages. Also, there is the sympathetic release of norepinephrine (NE) and adrenal epinephrine, which have both pro-inflammatory and anti-inflammatory effects depending on the stage of the inflammation. Panel B: NTS ascending afferent projections to rostral CNS sites. NTS afferents project directly to the parabrachial nucleus (PB), periaqueductal gray (PAG), amygdala (Amy), hypothalamus (Hyp), and thalamus (Thal), involved in autonomic and emotional responses to pain. PB provides a parallel ascending pathway to NTS afferents (continuous orange line). Also, the NTS indirectly projects to the: (1) insula (Ins), somatosensory cortex (SM), prefrontal cortex (PFC), anterior cingulate cortex (ACC) via the thalamus, (2) CA1 region of the dorsal hippocampus (Hip) and amygdala, through the nucleus paragigantocellularis (NGi) and locus coeruleus (LC) (broken black line). The ascending activation of these higher CNS structures by NTS afferents initiates a pattern of autonomic, sensory, and behavioral responses. Conversely, several CNS areas (e.g., Hyp and PAG) exert a descending modulation on NTS and RVLM mediated autonomic activity (not depicted). Similarly, respiratory centers, as well as from peripheral visceral and somatosensory afferents, exert an overall inhibitory influence on the baroreflex nuclei at the brainstem (not depicted).

FIGURE 2.

The relationship between variations in AP pressure and muscle sympathetic activity from recordings made from the right peroneal nerve. Record showing more bursts occurring during decreasing than during increasing AP. Dotted areas indicate corresponding sequences of bursts and heartbeats. There is compensation made for a reflex delay of 1.3 sec between blood pressure and neural events. Reproduced with permission (519).

FIGURE 3.

Hypothetical model for arterial baroreceptor influence on muscle sympathetic activity at two CNS synapses proposed by Kienbaum et al. Baroreceptors modulate the strength and occurrence of sympathetic outflow at two CNS locations depending on the strength of the respective input. Arterial baroreceptor input and other CNS influences have graded effects on the amplitude of the sympathetic impulses on one site, whereas they exert a gate control on the occurrence of a sympathetic discharge on the other site. Reproduced with permission (264).

FIGURE 4.

Intensity-dependent resetting of the carotid baroreflex that controls heart rate and AP during steady-state dynamic exercise. The operating point (OP) is the ongoing, either resting or exercising, prevailing AP before carotid sinus stimulation. The centering point (CP) is the carotid sinus pressure that, when applied to the baroreceptor, can equally evoke either increases or decreases in heart rate or mean AP, and at which the maximal gain of the baroreflex is estimated. The threshold is the point in the stimulus-response curve, where no further increase in mean AP or heart rate occurs despite reductions in the estimated carotid sinus pressure. The stimulus-response curve for heart rate (panel A) and MAP (panel B) gradually resets upward and rightward with increasing levels of exercise intensity without changes in the slope of the curve, i.e., the gain of the baroreflex (BRS) remains constant during steady-state dynamic exercise. Reproduced with permission (167)

FIGURE 5.

Shifts in the baroreflex curve for renal sympathetic nerve activity (RSNA) obtained during pre-exercise (resting), treadmill exercise, and the post-exercise periods. Curves reflect data averaged from 11 animals, whereas symbols and bars indicate means ± s.e.m., respectively, estimated over each 2.5 mmHg bin of arterial pressure (Pa). Unlike the baroreflex controlling heart rate and mean blood, notice an increase in the slope of the curve during the exercise, which indicates a higher gain of the baroreflex. Reproduced with permission (356).

FIGURE 6:

A. Representative muscle sympathetic nerve activity (MSNA; integrated signals) data during control (top), slow (middle), and very slow (bottom) head-up tilt (HUT) tests in a human subject. I (top), a period of inclination of the tilt bed from 0° supine to 30° HUT posture at an inclining speed of 1°/s. Inclining (middle and bottom), a period of inclination of the tilt bed at speeds of 0.1 and 0.0167°/s, respectively. au, Arbitrary units. B. Heart rate, the amplitude of low frequency (LF) and high frequency (HF) component of R-R interval (RRI) variability, and respiratory rate during control (○), slow (▴), and very slow (•) HUT tests. The x-axis to the left of the vertical dotted line indicates that data are averaged over every 10° tilt angle during inclination from 0° supine to 30° HUT, and the x-axis to the right of the dotted line indicates that data are averaged over every 1 min after reaching 30° HUT. #P < 0.05 vs. control and slow tests; *P < 0.05 vs. 0° supine posture. C. Systolic and diastolic arterial pressure (AP) measured at the height of brachial level and predicted at the height of carotid sinus (CS) level, and thoracic impedance (percentage of baseline value at 0° supine) during control (○), slow (▴), and very slow (•) HUT tests. The x-axis to the left of the vertical dotted line indicates that data are averaged over every 10° tilt angle during inclination from 0° supine to 30° HUT, and the x-axis to the right of the dotted line indicates that data are averaged over every 1 min after reaching 30° HUT. *P < 0.05 vs. 0° supine posture. Error bars denote SE. Modified and reproduced with permission (255).

FIGURE 7:

Simulation of a closed-loop step-change in response to exogenous perturbation with (A) or without (B) neural acceleration while the gain of baroreflex is changed from one to three. The magnitude of exogenous step perturbation is one mmHg. Attenuation of pressure changes in response to exogenous perturbation becomes larger with an increased gain of baroreflex, whereas response becomes increasingly oscillatory at a higher gain, indicating instability of the system. Step response at gain 2.0 with the neural acceleration revealed a quick and stable response (bold line in A). In contrast, step response without acceleration showed a slow and undershooting response in arterial pressure (bold line in B), indicating instability of the system. Reproduced with permission (236).

FIGURE 8.

Interaction between the Bezold-Jarisch reflex (evoked by intracoronary veratrine) and the carotid sinus baroreflex. Mean curves representing the mean arterial blood pressure (MABP) – heart rate relationship (top) and MABP – baroreflex sensitivity relationship (bottom) during control and intracoronary veratrine infusion (Ver.-L.C.) in 10 dogs. Note that the Bezold-Jarisch reflex resets mean AP optimal level for maximal BRS to lower levels and diminishes BRS. Control mean baseline values: MABP = 93 mmHg and heart rate = 91 beat/min. Reproduced with permission (613).

FIGURE 9.

Baroreceptor activation and inhibition by external mechanical manipulations of the neck have an opposite influence on pain-evoked potentials in the three groups of normotensive subjects with relatively low, normal, and high resting AP levels. Compared with the inhibitory condition, baroreceptor activation decreases and increases the amplitude of pain-evoked potentials in normotensive subjects with relatively high and low AP, respectively (59).

FIGURE 10.

Interactions between baroreceptors and pain pathways. Panel A. Rostral ventromedial medulla (RVMM) receives two major modulatory inputs from 1) the periaqueductal grey (PAG) that inhibits ON-cells (pro-nociceptive) and excites OFF-cells (anti-nociceptive), underlying stress- and placebo-induced analgesia, and 2) the lateral parabrachial nucleus (lateral PBN) that excites ON-cells (pronociceptive) and inhibits OFF-cells (anti-nociceptive) in the RVMM, facilitating pain reflexes. 3) The superficial lamina of the spinal cord projects to the lateral PBN, which facilitates pain by acting on the RVMM. 4) The mediocaudal nucleus of the solitary tract (mcNTS) projects to the lateral PBN, which inhibits a subset of neurons in the lateral PBN following inputs from vagal baroreceptor afferents. 5) Inhibition of lateral PBN neurons reduces and increases OFF-cell and ON-cell activities in the RVMM, respectively, facilitating C-fiber-driven second-order spinal neurons. 6) The rostral ventrolateral medulla (RVLM) neurons receive a dual input: inhibitory from the mcNTS via caudal ventrolateral medulla (CVLM) that leads to baroreflex-mediated bradycardia and excitatory input from the Lateral PBN that leads to pain-induced tachycardia. Panel B. Ascending and descending pain pathways in the CNS. Noxious stimuli applied to somatic structures and inflamed viscera activate primary afferents, which stimulate second-order spinal neurons of lamina I and V, which give rise to the ascending spinothalamic (continuous red line) and spinoreticular/spinobrachial (broken red line) pathways that reach PAG, parabrachial nucleus (PB), locus coeruleus (LC), cerebellum, and thalamus in humans. The dorsal horn also sends direct nociceptive information to the NTS. PB and PAG afferents project to the amygdala (Amy) and nucleus accumbens in the basal ganglia (BG), whereas thalamic afferents project to the primary somatosensory (SM) cortex S1, secondary SM cortex S2, anterior cingulate cortex (ACC), prefrontal cortex (PFC), and insula (Ins). Multiple descending pathways from brain structures to PAG and rostroventral medulla (RVM) modulate different components of pain perception, such as the ACC-PFC-PAG circuitry related to placebo analgesia and unpleasantness (broken green line) and the superior parietal cortex (SPC)-insula-amygdala-PAG pathway related to modulation of pain by attention (continuous green line). BG, basal ganglia; Hip, hippocampus; Hyp, hypothalamus; Thal, thalamus; PB, parabrachial nucleus.

FIGURE 11.

The reciprocal influence between cardiovascular function and sleep. Arrows represent excitatory (red) and inhibitory (blue) functional influences that occur through monosynaptic or polysynaptic anatomical connections and relay nuclei (e.g., thalamus). Panel A: Oversimplified view of major neural structures involved in baroreceptor modulation of arousal. NTS projections to the ascending arousal system, posterior hypothalamus, and CVLM/RVLM reduce arousal and prompt sleep, whereas NTS projections to the PBN pathways promote arousal. Panel B: Sleep influences cardiovascular function. Non-REM sleep disinhibits the NTS, and as a result, decreases sympathetic output at the spinal lateral column, which enhances baroreflexes and reduces arterial pressure. In contrast, REM sleep reduces the parasympathetic output by inhibiting the nucleus ambiguus, which dampens baroreflexes and leads to a transient increase in AP and heart rate. ACC, anterior cingulate cortex; LC/subLC, locus coeruleus/locus subcoeruleus; Lateral PBN, lateral parabrachial nucleus; RVLM, rostral ventrolateral medulla; CVLM, caudal ventrolateral medulla; NTS, nucleus tractus solitarious. Lateral PBN and LC are part of the ascending reticular activating system.