Sympathetic responses to noxious stimulation of muscle and skin

© 2016 Burton, Fazalbhoy and Macefield. 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

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

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

© 2016 Wiley Periodicals, Inc. 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 individual's baseline physiological or psychological measures. The aim of this study was to inve stigate 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. © 2016 Wiley Periodicals, Inc

Consistent interindividual increases or decreases in muscle sympathetic nerve activity during tonic muscle pain: implications for chronic pain

We recently showed that long-lasting muscle pain, induced by intramuscular infusion of hypertonic saline, evoked two patterns of cardiovascular responses across subjects: one group showed parallel increases in muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate, while the other group showed parallel decreases. Given that MSNA is consistent day to day, we tested the hypothesis that individuals who show increases in MSNA during experimental muscle pain will show consistent responses over time. MSNA was recorded from the peroneal nerve, together with blood pressure and heart rate, during an intramuscular infusion of hypertonic saline causing pain for an hour in 15 subjects on two occasions, 2-27 weeks apart. Pain intensity ratings were not significantly different between the first (5.8 ± 0.4/10) and second (6.1 ± 0.2) recording sessions. While four subjects showed significant decreases in the first session (46.6 ± 9.2 % of baseline) and significant increases in the second (159.6 ± 8.9 %), in 11 subjects, there was consistency in the changes in MSNA over time: either a sustained decrease (55.6 ± 6.8 %, n = 6) or a sustained increase (143.5 ± 6.1 %, n = 5) occurred in both recording sessions. There were no differences in pain ratings between sessions for any subjects. We conclude that the changes in MSNA during long-lasting muscle pain are consistent over time in the majority of individuals, reflecting the importance of studying interindividual differences in physiology

Muscle energy technique for chronic obstructive pulmonary disease: a systematic review

Background: Chronic Obstructive Pulmonary Disease (COPD) is an increasingly prevalent respiratory disease that impacts on daily living. In addition to difficulty breathing, many people experience extrapulmonary comorbidities such as musculoskeletal disorders. Pulmonary rehabilitation can improve fitness and strength but may be difficult for patients with musculoskeletal disorders. Recent research indicates promising benefits of adding manual therapy to standard care to improve clinical outcomes. Objectives: To evaluate the efficacy and safety of Muscle Energy Technique (MET) for people with COPD. Methods: Ten databases were searched from inceptions to May 2018. Eligible studies were randomised controlled trials assessing MET compared to any control for COPD. Outcomes included lung function, exercise capacity, health-related quality of life, and adverse events. Results: Three randomised controlled trials assessing 90 participants were included. The quality of the research was limited by reporting of outcome measures and results, varying treatment protocols, and small sample sizes. Results from one study showed that pulmonary function was not statistically different between groups at end of treatment (FEV1% MD 4.87%; 95% CI − 0.79 to 10.53). Exercise capacity and perceived dyspnoea ratings were improved in single studies. Adverse events were unrelated to the MET intervention. Conclusions: The use of MET for COPD is an emerging field of research, with few studies evaluating its efficacy and safety. Currently, there is insufficient evidence to support the use of MET in the management of COPD. Rigorously designed studies with larger sample sizes are needed to better understand the role of MET for COPD

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

Biphasic effects of tonic muscle pain on skin sympathetic nerve activity in human subjects

Skin sympathetic nerve activity (SSNA) controls skin blood flow and sweat release, and acute noxious stimulation of skin has been shown to cause a decrease in SSNA in the anaesthetised or spinal cat. In awake human subjects, acute muscle pain causes a transient rise in SSNA, but the impact of long-lasting (tonic) stimulation of muscle nociceptors on skin sympathetic outflow, blood flow and sweat release is unknown. We tested the hypothesis that tonic stimulation of muscle nociceptors causes a sustained increase in sympathetic outflow to the skin. SSNA was recorded from the common peroneal nerve of 10 awake human subjects. Tonic muscle pain was induced by infusing hypertonic saline (7 %) into the tibialis anterior muscle over similar to 40 min, titrated to achieve a constant level of muscle pain. SSNA initially increased following the onset of the infusion, reaching a peak of 164 % of baseline within 5 min, but then showed a prolonged and sustained decrease, reaching a nadir of 77 % in 20 min. Conversely, skin blood flow (and vascular conductance) initially decreased, followed by a progressive increase; there were no consistent changes in sweat release. In 9 of 10 subjects, SSNA and skin blood flow were inversely related. We conclude that sympathetic outflow to the skin exhibits a biphasic response to long-lasting stimulation of muscle nociceptors: an initial increase presumably related to the 'arousal' or 'alerting' component of pain, characterised by increased SSNA and decreased skin blood flow, followed by a prolonged decrease in SSNA and increased skin blood flow. The latter may be a purposeful response that contributes to wound healing

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

Introduction: 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. Aim: The aim of this study was to investigate brain regions that are functionally coupled to the generation of an MSNA burst at rest and to determine their behavior during tonic muscle pain. Methods: Functional magnetic resonance imaging of the brain was performed concurrently with microelectrode recording of MSNA from the common peroneal nerve during a 40 min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle of 37 healthy human subjects. Results: At rest, blood oxygen level-dependent signal intensity coupled to bursts of MSNA increased in the rostral ventrolateral medulla, insula, dorsolateral prefrontal cortex, posterior cingulate cortex, and precuneus and decreased in the region of the midbrain periaqueductal gray. During pain, MSNA-coupled signal intensity was greater in the region of the nucleus tractus solitarius, midbrain periaqueductal gray, dorsolateral prefrontal, medial prefrontal, and anterior cingulate cortices, than at rest. Conversely, MSNA-coupled signal intensity decreased during pain in parts of the prefrontal cortex. Conclusions: These results suggest that multiple brain regions are recruited in a burst-to- burst manner, and the magnitude of these signal changes is correlated to the overall change in MSNA amplitude during tonic muscle pain