Azharuddin Fazalbhoy

Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure and heart rate

We recently showed that acute muscle pain, induced by bolus intramuscular injection of hypertonic saline, causes a sustained increase in muscle sympathetic nerve activity (MSNA) and a modest increase in blood pressure and heart rate. However, it is not known whether long‐lasting (tonic) pain, which more closely resembles chronic pain, causes a sustained increase in MSNA and blood pressure. We tested this hypothesis by recording MSNA in 12 healthy subjects. Tonic pain was induced for ∼60 min by slow intramuscular infusion of hypertonic saline (7%) into the ipsilateral tibialis anterior muscle. Pain was sustained at a tolerable level (5/10 to 6/10 on a visual analog scale). Seven subjects showed progressive increases in mean MSNA amplitude during tonic pain, increasing to 154 ± 17% (SEM) at 45 min and remaining essentially constant for the duration of the infusion. In these subjects, blood pressure and heart rate also increased. Conversely, for the other five subjects MSNA showed a progressive decline, with a peak fall of 67 ± 11% at 40 min; blood pressure and heart rate also fell in these subjects. We conclude that tonic muscle pain has long‐lasting effects on the sympathetic control of blood pressure, causing a sustained increase in some subjects yet a sustained decrease in others. This may have implications for individual differences in the cardiovascular consequences of chronic pain.

Spontaneous fluctuations in the peripheral photoplethysmographic waveform: roles of arterial pressure and muscle sympathetic nerve activity.

Assessment of spontaneous slow waves in the peripheral blood volume using the photoplethysmogram (PPG) has shown potential clinical value, but the physiological correlates of these fluctuations have not been fully elucidated. This study addressed the contribution of arterial pressure and muscle sympathetic nerve activity (MSNA) in beat-to-beat PPG variability in resting humans under spontaneous breathing conditions. Peripheral PPG waveforms were measured from the fingertip, earlobe, and toe in young and healthy individuals (n = 13), together with the arterial pressure waveform, electrocardiogram, respiration, and direct measurement of MSNA by microneurography. Cross-spectral coherence analysis revealed that among the PPG waveforms, low-frequency fluctuations (0.04-0.15 Hz) in the ear PPG had the highest coherence with arterial pressure (0.71 ± 0.15) and MSNA (0.44 ± 0.18, with a peak of 0.71 ± 0.16 at 0.10 ± 0.03 Hz). The normalized midfrequency powers (0.08-0.15 Hz), with an emphasis on the 0.1-Hz region, were positively correlated between MSNA and the ear PPG (r = 0.77, P = 0.002). Finger and toe PPGs had lower coherence with arterial pressure (0.35 ± 0.10 and 0.30 ± 0.11, respectively) and MSNA (0.33 ± 0.10 and 0.26 ± 0.10, respectively) in the LF band but displayed higher coherence between themselves (0.54 ± 0.09) compared with the ear (P < 0.001), which may suggest the dominance of regional vasomotor activities and a common sympathetic influence in the glabrous skin. These findings highlight the differential mechanisms governing PPG waveform fluctuations across different body sites. Spontaneous PPG variability in the ear includes a major contribution from arterial pressure and MSNA, which may provide a rationale for its clinical utility.

Sympathetic Responses to Noxious Stimulation of Muscle and Skin

Acute pain triggers adaptive physiological responses that serve as protective mechanisms that prevent continuing damage to tissues and cause the individual to react to remove or escape the painful stimulus. However, an extension of the pain response beyond signaling tissue damage and healing, such as in chronic pain states, serves no particular biological function; it is maladaptive. The increasing number of chronic pain sufferers is concerning, and the associated disease burden is putting healthcare systems around the world under significant pressure. The incapacitating effects of long-lasting pain are not just psychological – reflexes driven by nociceptors during the establishment of chronic pain may cause serious physiological consequences on regulation of other body systems. The sympathetic nervous system is inherently involved in a host of physiological responses evoked by noxious stimulation. Experimental animal and human models demonstrate a diverse array of heterogeneous reactions to nociception. The purpose of this review is to understand how pain affects the sympathetic nervous system by investigating the reflex cardiovascular and neural responses to acute pain and the long-lasting physiological responses to prolonged (tonic) pain. By observing the sympathetic responses to long-lasting pain, we can begin to understand the physiological consequences of long-term pain on cardiovascular regulation.

Inter-Individual Responses to Experimental Muscle Pain: Baseline Physiological Parameters Do Not Determine Whether Muscle Sympathetic Nerve Activity Increases or Decreases During Pain.

We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 min, increases muscle sympathetic nerve activity (MSNA)—as well as blood pressure and heart rate—in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-min intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 ± 7.3%), while 26 showed a sustained decrease (55.1 ± 3.5%). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 ± 1.5 vs. 18.9 ± 1.2 bursts/min), mean BP (88.1 ± 5.2 vs. 88.0 ± 3.8 mmHg), HR (74.7 ± 2.0 vs. 72.8 ± 1.8 beats/min) or heart rate variability (LF/HF 1.8 ± 0.2 vs. 2.2 ± 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pain.

Tonic muscle pain does not increase fusimotor drive to human leg muscles: implications for chronic muscle pain

•  What is the central question of this study? Based on data obtained from experimental animals, muscle pain is believed to cause a reflex activation of fusimotor neurones and thereby increase the sensitivity of muscle spindles to stretch. Using a model of long‐lasting muscle pain, we asked the question: does tonic muscle pain increase the resting discharge of muscle spindles in human subjects? •  What is the main finding and its importance? Microelectrode recordings from single muscle spindle afferents revealed no net change in the discharge of spontaneously active spindle endings during moderate–strong pain lasting ∼1 h. We conclude that, unlike the situation in anaesthetized animals, muscle pain does not cause a reflex increase in fusimotor drive and spindle discharge.

Central circuitry responsible for the divergent sympathetic responses to tonic muscle pain in humans

Experimentally induced tonic muscle pain evokes divergent muscle vasoconstrictor responses, with some individuals exhibiting a sustained increase in muscle sympathetic nerve activity (MSNA), and others a sustained decrease. These patterns cannot be predicted from an individuals baseline physiological or psychological measures. The aim of this study was to investigate whether the different muscle sympathetic responses to tonic muscle pain were associated with differential changes in regional brain activity. Functional magnetic resonance imaging (fMRI) of the brain was performed concurrently with microelectrode recording of MSNA from the peroneal nerve during a 40‐min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle. MSNA increased in 26 and decreased in 11 of 37 subjects during tonic muscle pain. Within the prefrontal and cingulate cortices, precuneus, nucleus accumbens, caudate nucleus, and dorsomedial hypothalamus, blood oxygen level dependent (BOLD) signal intensity increased in the increasing‐MSNA group and remained at baseline or decreased in the decreasing‐MSNA group. Similar responses occurred in the dorsolateral pons and in the region of the rostral ventrolateral medulla. By contrast, within the region of the dorsolateral periaqueductal gray (dlPAG) signal intensity initially increased in both groups but returned to baseline levels only in the increasing‐MSNA group. These results suggest that the divergent sympathetic responses to muscle pain result from activation of a neural pathway that includes the dlPAG, an area thought to be responsible for the behavioral and cardiovascular responses to psychological rather than physical stressors. Hum Brain Mapp 38:869–881, 2017.

Inter-individual responses to experimental muscle pain: Baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans.

We have recently shown that intramuscular infusion of hypertonic saline, causing pain lasting ~60min, increases muscle sympathetic nerve activity (MSNA) in one group of subjects, yet decreases it in another. Across subjects these divergent sympathetic responses to long-lasting muscle pain are consistent over time and cannot be foreseen on the basis of baseline MSNA, blood pressure, heart rate or sex. We predicted that differences in anxiety or attitudes to pain may account for these differences. Psychometric measures were assessed prior to the induction of pain using the State and Trait Anxiety Inventory (STAI), Pain Vigilance and Awareness Questionnaire (PVAQ), Pain Anxiety Symptoms Scale (PASS) and Pain Catastrophising Scale (PCS); PCS was also administered after the experiment. MSNA was recorded from the common peroneal nerve, before and during a 45-minute intramuscular infusion of hypertonic saline solution into the tibialis anterior muscle of 66 awake human subjects. Forty-one subjects showed an increase in mean burst amplitude of MSNA (172.8±10.6%) while 25 showed a decrease (69.9±3.8%). None of the measured psychological parameters showed significant differences between the increasing and the decreasing groups. We conclude that inter-individual anxiety or pain attitudes do not determine whether MSNA increases or decreases during long-lasting experimental muscle pain in healthy human subjects.

Muscle sympathetic nerve activity-coupled changes in brain activity during sustained muscle pain.

Long‐lasting experimental muscle pain elicits divergent muscle sympathetic responses, with some individuals exhibiting a persistent increase in muscle sympathetic nerve activity (MSNA), and others a decrease. These divergent responses are thought to result from sustained functional changes in specific brain regions that modulate the cardiovascular responses to pain.