Andalán : periódico quincenal aragonés: Número 183 - (15/09/78)

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 minutes, 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-minute 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 pai

Consistent interindividual increases or decreases in muscle sympathetic nerve activity during experimental muscle 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

Biphasic effects of tonic stimulation of muscle nociceptors 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 *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

The effects of tonic muscle pain on the sympathetic and somatic motor systems in humans

Mechanisms underlying the development of chronic muscle pain in humans remain unknown. Our current understanding is principally based on experimentation in animals, which has resulted in the formulation of a multitude of theories and physiological models to postulate these mechanisms in humans. The vicious cycle theory – a popularised but unsupported theory in humans – suggests that muscle metabolites produced by static muscle contractions stimulate group III and IV muscle nociceptors leading to an excitation of gamma-motoneurones through a reflex mechanism. Increased gamma-motor drive causes intrafusal fibres to contract increasing muscle spindle afferent firing. This activity in turn will raise the likelihood of activation in the pool of alpha-motorneurones projecting to the primary muscle increasing resting muscle tonus.Muscle spindle afferents and postganglionic sympathetic outflow to skin and muscle were recorded from healthy subjects using the technique of microneurography. Cardiorespiratory function (blood pressure, heart rate, and respiration) was measured non-invasively. Muscle pain was induced using a solution of hypertonic saline tonically infused via indwelling cannulae delivered by an infusion pump. The rate of infusion was controlled to ensure subjects experienced mild to moderate pain.Muscle spindle afferents fail to show any change in spontaneous discharge rate in response to tonic muscle pain contradicting the observations and conclusions from animal studies. Sympathetic outflow to skin demonstrated a transient increase followed by a sustained decrease during infusion of hypertonic saline. Sympathetic outflow to muscle demonstrated a dichotomy of responses during muscle pain: half of the subjects showing increasing sympathetic activity, blood pressure, and heart rate; whilst the others showed decreasing sympathetic activity, blood pressure, and heart rate. Consistent responses were seen in the same individuals when the study was reproduced in a second recording.This investigation advances our understanding of the physiological consequences tonic pain has on sympathetic outflow and muscle spindle afferents in the context of developing chronic muscle pain. After undertaking experimentation in awake human subjects there is no apparent evidence to suggest that tonic pain increases the discharge rate of spontaneously active muscle spindle afferents to result in increased muscle tone as proposed by the “vicious cycle” theory. There is, however, evidence of sustained changes in sympathetic outflow to muscle and skin in response to tonic pain that may contribute to the development of chronic pain

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 ~. 60. min, 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

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

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