Edited by: James J. Galligan, Michigan State University, USA
Reviewed by: Christopher J. Madden, Oregon Health and Science University, USA; Florian Beissner, Hannover Medical School, Germany
*Correspondence: Vaughan G. Macefield
This article was submitted to Autonomic Neuroscience, a section of the journal Frontiers in Neuroscience
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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.
Pain is important for survival by helping to avoid tissue damage, mobilizing all relevant homeostatic systems for a fight-and-flight response or, alternatively, promoting conservation of energy, and thus promoting healing (Craig,
We have been using subcutaneous or intramuscular injection of hypertonic saline—a specific stimulus for nociceptors (Graven-Nielsen and Mense,
These data call into question the idea that noxious stimuli produce invariant responses and raise the prospect that these differential responses may be related to an individual's particular traits, which may be reproducible over time. That is, in some individuals muscle pain
Experiments were performed on 25 female and 25 male healthy subjects, aged 18–39 years. Data from 35 new participants were pooled with those from 15 participants reported previously (Fazalbhoy et al.,
The subjects were seated in a comfortable reclined position with the legs supported in an extended position. The room was kept quiet and at a constant temperature of 22°C. The course of the common peroneal nerve was identified via external stimulation (2–10 mA) using a 1 mm surface probe which delivered 0.2 ms pulses at 1 Hz from an isolated stimulator (Stimulus Isolator; ADInstruments, Sydney, Australia). Spontaneous bursts of muscle sympathetic nerve activity (MSNA) were recorded from muscle fascicles of the common peroneal nerve supplying the ankle or toe extensor or foot everter muscles via tungsten microelectrodes (FHC, Bowdoin, ME, USA) inserted percutaneously at the level of the fibular head. Multi-unit neural activity was amplified (gain 20 000, bandpass 0.3–5.0 kHz) using an isolated amplifier (NeuroAmp EX, ADInstruments, Sydney, Australia) and stored on computer (10-kHz sampling) using a computer-based data acquisition and analysis system (PowerLab 16SP hardware and LabChart 7 software; ADInstruments, Sydney, Australia). ECG (0.3–1.0 kHz) was recorded with Ag–AgCl surface electrodes on the chest and sampled at 2 kHz. Blood pressure was recorded continuously using finger pulse plethysmography (Finometer Pro, Finapres Medical Systems, The Netherlands) and sampled at 400 Hz. Respiration (DC-100 Hz) was recorded using a strain-gauge transducer (Pneumotrace, UFI, Morro Bay CA, USA) wrapped around the chest.
A 7% hypertonic saline solution was prepared by diluting sterile, 20% hypertonic saline with sterile water. Two syringes of 10 ml each were filled with the 7% hypertonic saline, placed in an infusion pump (Harvard Instruments, USA), and connected to a three-way tap via a 75 cm extension tubing primed with hypertonic saline. A 23 gauge butterfly needle was then attached to the three-way tap via a cannula, primed, and inserted 1.5 cm deep into the belly of the ipsilateral tibialis anterior muscle, about 5 cm lateral and 10 cm inferior to the tibial tuberosity. The cannula was inserted as soon as a stable recording of spontaneous MSNA was achieved. Prior to infusion of the saline solution, a 5 min baseline recording of MSNA, blood pressure, respiration, and heart rate was obtained. Infusion of the 7% hypertonic saline solution was started at a time unknown to the subject, and was maintained for 45 min; as described previously (Fazalbhoy et al.,
LabChart 7 Pro software (ADInstruments, Sydney, Australia) was used to record the following parameters: muscle sympathetic nerve activity (burst amplitude and frequency), heart rate, blood pressure, respiration, pulse pressure, heart rate variability (HRV), and pain ratings. Individual bursts of MSNA were displayed as a mean-voltage neurogram, computed as the root-mean-square (RMS) processed signal with a moving time average window of 200 ms. This signal was then analyzed using the “Peak Analysis” module of the LabChart 7 Pro software to calculate the amplitude of each burst. The absolute values were averaged into 5-min blocks and reported as percentages from the “baseline” values. An average of all blocks was taken to determine the direction of the response. Subjects with overall average MSNA amplitude 10% lower than baseline were arbitrarily assigned to the decreasing group; averages 10% higher than baseline were considered as increasing. Baseline MSNA amplitude was compared to the 5-min block with the mean value calculated over the entire infusion period, and to the highest average for the increasing group and to the lowest average value for the decreasing group. Changes in mean heart rate and mean blood pressure were also measured in 5 min epochs, normalized to the baseline value prior to the infusion of hypertonic saline. HRV was assessed over a 5-min steady state period before the infusion, and then again over 5 min when the subject experienced a steady-state level of pain during the infusion. The parameters of HRV that were analyzed included the low frequency (LF) and high frequency (HF) power, as well as the Root Mean Square Successive Difference of cardiac intervals (RMSSD). Statistical analysis—non-paired two-tailed
In all subjects intramuscular infusion of hypertonic saline induced a steady state level of muscle pain in the tibialis anterior muscle. The level of pain was kept constant, typically around 5 out of 10—throughout the period of infusion by adjusting the rate of infusion according to the subject's tracking of the pain level. The mean pain rating was 4.9 ± 0.1. Using the McGill Pain Questionnaire, 36 of the 50 subjects (72%) described the pain as “aching,” 48% described it as “heavy” and 48% as “dull.” After these, “throbbing,” “cramping,” “hurting,” “discomforting,” and “continuous” were the most frequent descriptions used.
Experimental records from two subjects are shown in Figures
As expected, when all subjects were analyzed according to their pattern of MSNA response to muscle pain two distinct groups of responses emerged: 24 subjects (48%) showed a significant increase in burst amplitude over the entire infusion period (132.6 ± 6.1%
Interestingly, those subjects who showed an increase in MSNA showed a significantly larger increase in blood pressure than those in whom MSNA decreased. Systolic pressure increased from 132.0 ± 5.5 (baseline) to 159.9 ± 5.8 mmHg (steady level of pain) in the increasing group but from only 133.0 ± 4.7 to 142.7 ± 5.3 in the decreasing group. Diastolic pressure increased from 70.2 ± 5.2 (baseline) to 86.6 ± 4.5 mmHg (steady level of pain) and from 75.1 ± 4.2 to 76.7 ± 4.3 in the increasing and decreasing groups, respectively. Relative changes in blood pressure, heart rate and MSNA in the two groups are presented in Figure
When comparing the increasing and decreasing groups, there were no differences in baseline MSNA (19.0 ± 1.5 vs. 18.9 ± 1.2 bursts/min;
Number of subjects | 11female±13male | 14female±12male | 0.78 |
Age (years) | 22.1±1.3 | 22.4±0.9 | 0.34 |
Height (cm) | 168.7±1.6 | 170.1±2.1 | 0.60 |
Weight (kg) | 65.7±2.6 | 68.0±2.9 | 0.56 |
BMI (kg/m2) | 23.1±1.0 | 23.4±0.8 | 0.65 |
Muscle mass (kg) | 49.5±2.2 | 48.7±2.3 | 0.80 |
Pain rating (/10) | 4.7±0.2 | 5.1±0.2 | 0.18 |
MSNA (bursts/min) | 19.0±1.5 | 18.9±1.2 | 0.99 |
SAP (mmHg) | 132.0±5.5 | 133.0±4.7 | 0.52 |
DAP (mmHg) | 70.2±5.2 | 75.1±4.2 | 0.32 |
MAP (mmHg) | 88.1±5.2 | 88.0±3.8 | 0.78 |
HR (beats/min) | 74.7±2.0 | 72.8±1.8 | 0.44 |
LF HRV (nu) | 56.9±3.8 | 59.4±4.0 | 0.80 |
HF HRV (nu) | 38.4±3.4 | 35.6±3.7 | 0.58 |
LF/HF HRV | 1.8±0.2 | 2.2±0.3 | 0.38 |
RMSSD HRV (ms) | 40.5±4.1 | 40.8±4.0 | 0.99 |
Of the 24 subjects in whom MSNA increased, 11 were female and 13 were male, while there were 14 females and 12 males in whom MSNA decreased. These data indicate that there was no difference in the
There were no statistically significant differences in resting MSNA between the female and male subjects (18.8 ± 1.5 vs. 20.2 ± 1.5 bursts/min;
Number of subjects | 25 | 25 | |
Age (years) | 22.8±0.8 | 21.8±1.5 | <0.01 |
Height (cm) | 164.0±1.1 | 175.9±1.7 | <0.0001 |
Weight (kg) | 61.5±2.7 | 72.6±2.2 | <0.02 |
BMI (kg/m2) | 22.9±1.0 | 23.4±0.5 | 0.05 |
Muscle mass (kg) | 43.3±0.8 | 57.8±2.1 | <0.0001 |
Pain rating (/10) | 4.9±0.2 | 4.9±0.2 | 0.87 |
MSNA (bursts/min) | 18.8±1.5 | 20.2±1.5 | 0.19 |
SAP (mmHg) | 131.7±6.3 | 133.3±3.3 | 0.96 |
DAP (mmHg) | 72.7±5.4 | 72.7±3.9 | 0.69 |
MAP (mmHg) | 89.5±5.5 | 86.6±3.3 | 0.96 |
HR (beats/min) | 75.0±1.9 | 72.3±1.9 | 0.32 |
LF HRV (nu) | 61.7±3.5 | 57.4±3.2 | 0.21 |
HF HRV (nu) | 33.8±3.2 | 37.2±3.0 | 0.16 |
LF/HF HRV | 2.2±0.3 | 1.8±0.3 | 0.15 |
RMSSD HRV (ms) | 39.0±3.9 | 41.9±4.5 | 0.64 |
This study extends the recent work conducted in our laboratory on the effects of experimental muscle pain on the sympathetic nervous system (Burton et al.,
The findings of the current study suggest that the cardiovascular responses to long-lasting muscle pain are not determined by our measured baseline physiological levels; both the direction of the response and the magnitude of change were independent of baseline MSNA, heart rate, blood pressure, heart rate variability, as well as age, sex, and BMI. This is consistent with studies showing comparable control and sensitivity of the sympathetic baroreflex in young men and young women (Tank et al.,
In this larger sample of subjects we found no correlation between MSNA and heart rate, unlike the parallel changes observed in the smaller data sets reported previously (Fazalbhoy et al.,
Although, there was no difference in the changes in heart rate and the change in MSNA between the two groups, in the group of subjects in whom MSNA increased during tonic muscle pain blood pressure was significantly higher than in the group in whom MSNA decreased. This suggests that the increase in MSNA was driving the increase in blood pressure, as an increase in blood pressure should, via the baroreflex, lead to a fall in MSNA. Indeed, the latter mechanism may explain why in some subjects MSNA fell despite an increase in blood pressure: in these cases, it would appear that the increase in blood pressure was causing a baroreflex-mediated reduction in MSNA, while in other instances a reduction in both blood pressure and MSNA could be the result of a nociceptor-driven withdrawal of MSNA. However, for those subjects in whom both MSNA and blood pressure increased during tonic muscle pain, we would like to suggest that nociceptor-driven increases in blood pressure could potentially be a risk factor for the development of clinically significant high blood pressure in the future, given that some individuals with chronic pain go on to develop hypertension. Indeed, patients with post-surgical chronic pain have nearly twice the prevalence of clinical hypertension than medical patients without pain (Bruehl et al.,
Heart rate variability is widely reported to reflect the degree of sympathetic and parasympathetic control over the heart. The LF band is proposed to represent (primarily) sympathetic cardiac activation (Malliani et al.,
The intramuscular infusion of hypertonic saline occurred at a time unknown to the subject, who was asked to continuously report the development of pain, as a rating out of 10, via the linear potentiometer provided. Infusion rates were titrated—by increasing or decreasing the rate of infusion in increments of 0.02 ml/min—to maintain a constant level of pain. Although we did not routinely record either the rate of infusion, or the total volume infused, in each subject, we never exceeded 20 ml (as noted in Methods we used two syringes of 10 ml each). Nevertheless, there were no differences in total muscle mass in the group in whom MSNA increased and the group in whom MSNA decreased and, given that the infusion caused a notable distension of the muscle belly in both groups, it is reasonable to assume that there any changes in plasma osmolality were limited to the muscle compartment and that comparable depolarization of small-diameter axons by the hypertonic saline occurred in the two groups. In other words, the noxious sensory input was the same in the two groups, as reflected in the fact that there were no significant differences in mean pain ratings between the two groups. The same was true when we separated the cohort into males and females: the only significant differences here being the higher BMI and lower total muscle mass in the females, both of which are expected. Of course, one could argue that the intramuscular infusion of hypertonic saline would have a greater effect in a smaller muscle (in the females), but in our experience we see no differences in mean pain ratings in small muscles (e.g., intrinsic muscles of the hand) and large muscles (e.g., flexor carpi radialis, deltoid, tibialis anterior), and pain ratings were the same in males and females.
We have shown, in a large sample of subjects (
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the National Health and Medical Research Council of Australia (GNT1029782).