Central modulation of exercise-induced muscle pain in humans

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1 J Physiol (27) pp Central modulation of exercise-induced muscle pain in humans Chester A. Ray 1 and Jason R. Carter 2 1 Heart and Vascular Institute, Pennsylvania State University College of Medicine, Hershey, PA 1733, USA 2 Department of Exercise Science, Health and Physical Education, Michigan Technological University, Houghton, MI 49931, USA The purpose of the current study was to determine if exercise-induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 3% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n = 9) and codeine (6 mg oral; n = 7). All measured variables increased with exercise duration. During the control trial in all subjects (n = 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 ±.8 to 9.5 ± 1.; P <.1). However, MSNA did not significantly change compared with IHG (7 ± 1to7± 1 bursts (15 s) 1 ), whereas mean arterial blood pressure was slightly reduced (4 ± 4 to ± 3 mmhg; P <.5) and heart rate returned to baseline values during PEMI (83 ± 3to67± 2 beats min 1 ; P <.1). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study (n = 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise-induced muscle pain. (Received 11 July 27; accepted after revision 24 September 27; first published online 11 October 27) Corresponding author C. A. Ray: Penn State College of Medicine, The Milton S. Hershey Medical Center, Heart & Vascular Institute H47, 5 University Drive, Hershey, PA , USA. caray@psu.edu Pain is an emotional and subjective experience that involves both peripheral and central mechanisms. Modulation of pain is a complex system in which processing can occur in both ascending and descending pathways. Nociceptors of the periphery sense pain and relay this perception of pain to the central nervous system via group III and IV afferent fibres (Besson, 1999; Millan, 22). Nociceptive afferents synapse primarily in the dorsal horn of the spinal cord where the nociceptive signals are processed and transmitted to supraspinal brain areas (Millan, 22). Several supraspinal sites have been implicated in nociceptive processing, but the most recognized are the hypothalamus, periaqueductal grey (PAG), rostral ventrolateral medulla (RVM) and dorsolateral pontomesencephalic tegmentum (DLPT). Although central processing of pain has been extensively studied, one area that has received little attention is central modulation of exercise-induced pain in humans. Several studies indicate an analgesic effect during exercise, but the mechanisms underlying this phenomenon are poorly understood (Cook et al. 1997). In a previous study, Cook et al. (2) examined the role of the endogenous opioid system on forearm muscle pain by recording muscle pain perception during dynamic handgrip after administration of either codeine (an opioid agonist), naltrexone (an opioid antagonist) or placebo. Ratings of muscle pain perception were not different among trials, indicating the endogenous opioid system does not alter muscle pain perception during exercise (Cook et al. 2). However, the experimental design of this study by Cook et al. (2) could not definitively assess if pain perception during exercise was centrally modulated by higher brain systems (i.e. central command) because endogenous opioid receptors are found on peripheral (group III and IV afferents) and central (PAG, RVM and DLPT) sites involved in pain processing (Millan, 22). Furthermore, it has been demonstrated that central motor command can inhibit group III muscle afferent input to DOI:.1113/jphysiol

2 288 C. A. Ray and J. R. Carter J Physiol the dorsal horn (Degtyarenko & Kaufman, 23). Thus, it is possible that central command may have interacted with afferent feedback from the muscle and the opioid system to modulate pain perception. Therefore, the primary purpose of this study was to examine the effect of central command on muscle pain perception during exercise. Muscle pain perception was compared during isometric handgrip (IHG) and postexercise muscle ischaemia (PEMI) because IHG engages central command whereas PEMI does not. Central command affects both cardiovascular and ventilatory control during exercise (Williamson et al. 26); thus we hypothesized that central command may also influence the perception of exercise-induced muscle pain. Specifically, it was hypothesized that perception of exercise-induced muscle pain would be augmented during PEMI when central command is minimal. A secondary purpose was to test the hypothesis that endogenous opioids alter central modulation of muscle pain. Our results suggest that central command attenuates muscle pain perception during exercise and that endogenous opioids, arterial blood pressure and MSNA do not appear to influence this central modulation of pain. Methods Subjects Twenty-four healthy men and women (18 men and 6 women; age 25 ± 1 years, height 176 ± 2 cm, weight 77 ± 4 kg) volunteered to participate in the study. Subjects abstained from nicotine, alcohol and caffeine for a minimum of 8 h prior to the experiment. The Institutional Review Board at The Pennsylvania State University College of Medicine approved the study and the written informed consent form. All participants signed the informed consent form after verbal explanation of the testing procedures. Experimental design Study 1. Subjects performed two bouts of exercise. The first exercise bout was designated as the control trial because no drug intervention was performed. The second exercise bout was performed after administration of either naloxone (n = 9) or codeine (n = 7). Naloxone was infused intravenously (16 mg) over 2 min into the non-exercising arm 2 min after the control exercise bout. Another 2 min elapsed between final infusion and the start of the second exercise bout to allow systemic distribution of the drug. During the codeine trial, subjects received a 6 mg capsule of codeine immediately following the control exercise bout. After 1 h, the exercise protocol was repeated. The timing of codeine administration was based on previous reports that peak plasma concentrations occur 1 h after a single oral does of 6 mg (Quiding et al. 1986). Subjects were randomly assigned to naloxone and codeine groups, and both the investigator and the subjects were blinded with regard to the drug intervention until analysis of data was completed. During each exercise bout, subjects performed IHG (3% maximum voluntary contraction) to fatigue, followed by 2 min of PEMI before (control) and after administration of either naloxone or codeine. Maximal voluntary contraction was established using the peak force generated from three maximal handgrip efforts. PEMI was induced 5 s prior to the cessation of exercise by inflating a blood pressure cuff on the arm to suprasystolic levels (24 mmhg). Each exercise trial began and ended with a 3 min baseline and recovery period. Forearm muscle pain and exertion ratings were obtained every 15 s of IHG and PEMI. Study 2. To determine if cuff inflation during PEMI influenced pain perception, a second study (n = 8) was performed in which subjects performed IHG during muscle ischaemia induced by the same cuff compression used during PEMI. This ischaemic IHG was followed by 2 min of PEMI. IHG was performed until subjects reached fatigue or until a pain perception score of seven or greater was reported. This number was selected to match the level of pain reached by subjects in the first study. Forearm muscle pain and exertion ratings were obtained every 15 s of ischaemic IHG and PEMI. Pain and exertion assessment Forearm muscle pain perception was assessed using a category scale with ratio properties. The pain intensity scale ranged from (no pain at all) to (extremely intense pain, almost unbearable). If the subjective intensity increased above, the subject chose any number larger in proportion to that described the proportional growth of the sensation. Prior work has provided evidence for the validity and reliability of this scale for quantifying naturally occurring muscle pain during exercise (Cook et al. 1997). Ratings of perceived exertion were assessed during and after exercise by using Borg s 6 2 category scale (Borg, 1978). Measurements Multifibre recordings of MSNA were made by inserting a tungsten microelectrode into the peroneal nerve at the head of the fibula of a resting leg. A reference electrode was inserted subcutaneously 2 3 cm from the recording electrode. Both electrodes were connected to a differential preamplifier, and then to an amplifier (total gain between 4 and 8 ) where the nerve signal was band-pass filtered (7 2 Hz), and integrated (time constant,.1s) to obtain a mean voltage display of the nerve

3 J Physiol Central modulation of pain during exercise 289 Table 1. Preexercise baseline values during the control, naloxone, and codeine trials Variable Control (n = 16) Naloxone (n = 9) Codeine (n = 7) MSNA (bursts (15 s) 1 ) 4 ± 1 3 ± 1 4 ± 1 MSNA, total 191 ± ± ± 52 HR (beats min 1 ) 65 ± 2 65± 3 61 ± 3 SAP (mmhg) 12 ± ± 4 12 ± 2 DAP (mmhg) 63 ± 2 63 ± 3 65 ± 2 MAP (mmhg) 79 ± 2 8 ± 3 8 ± 2 MPP (a.u.) ± ± ± RPE (a.u.) 6 ± 6 ± 6 ± Values are mean ± S.E.M.; MSNA, muscle sympathetic nerve activity; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, mean arterial pressure; MPP, muscle pain perception; RPE, rating of perceived exertion; a.u., arbitrary units. Baseline values for all three trials were not different from each other; P >.5. Subjects were randomly assigned to the naloxone and codeine groups. activity. Satisfactory recordings of MSNA were defined by spontaneous, pulse synchronous bursts that increased during end-expiratory apnoea, and did not change during stroking of the skin or auditory stimulation (yell). Arterial blood pressure and heart rate (HR) were recorded using a Finapres (Ohmeda, Louisville, CO, USA) positioned on the middle digit of the subject s non-exercising hand. A pneumograph bellows was wrapped around the subject s chest to monitor respiratory rate and to ensure subjects avoided a Valsalva manoeuver during IHG. Force output from handgrip and all other recorded variables were routed and recorded to an on-line computer (MacLab 8E, ADInstruments, Milford, MA, USA). Data analysis As control trials were not different in the naloxone and codeine groups, these results were combined for data presentation. The naloxone and codeine trials were analysed using a two-within-factor (intervention (placebo versus drug) exercise bout) repeated analysis of variance. Pearson correlations were used to examine the relations between systolic arterial pressure, MSNA and muscle pain perception. Muscle pain perception was reported every 15 s, and the highest values reported during IHG and PEMI were used for data analysis. Significance was accepted at the P <.5 level. All data are presented as mean ± s.e.m. Results Study 1: Isometric handgrip Preexercise baseline values before (control) and after administration of either naloxone or codeine are presented in Table 1. Naloxone and codeine did not change baseline values of MSNA, heart rate and arterial blood pressure. Subjects reported no muscle pain or perceived exertion during baseline. Heart rate and mean arterial blood pressure (MAP) significantly increased during IHG for all trials (Fig. 1). During PEMI, MAP remained elevated from baseline, but MAP decreased slightly compared with IHG. Heart rate returned to baseline levels during PEMI. MSNA increased during IHG and PEMI for all trials, but increases in MSNA during IHG and PEMI were not different (Fig. 1). Muscle pain perception significantly increased during IHG and PEMI with and without any drug intervention (Fig. 2). During PEMI, muscle pain perception was significantly greater than IHG values during the control and codeine trials (P <.1) and tended to increase in the naloxone trial (P <.9). Increases in muscle pain perception were not correlated to changes in arterial blood pressure during IHG and PEMI for any of the trials (Fig. 3). Similarly, muscle pain perception was not correlated to changes in MSNA during IHG (total activity, R 2 =.1; burst frequency, R 2 =.16) or PEMI (total activity, R 2 =.5; burst frequency, R 2 =.6). Ratings of perceived exertion increased as a function of exercise duration and were not different between trials (peak value 19 ± units). Study 2: Ischaemic isometric handgrip Heart rate (6 ± 2 to 78± 6 beats min 1 ) and MAP (93 ± 2 to 113± 4 mmhg) increased during ischaemic IHG. During PEMI, MAP (111 ± 9 mmhg) remained elevated from baseline, but heart rate (64 ± 3 beats min 1 ) returned to baseline levels. Muscle pain perception significantly increased during ischaemic IHG (5.9 ±.9 units), but increased even further during PEMI (8.4 ± 1.1 units, P <.5; Fig. 4). Discussion This study identifies three novel findings: (1) muscle pain perception increases during PEMI compared with IHG; (2) endogenous opioids do not modulate muscle

4 29 C. A. Ray and J. R. Carter J Physiol pain perception during either forearm exercise or muscle ischaemia; and (3) muscle pain perception during forearm exercise or PEMI is not correlated to changes in arterial blood pressure or MSNA. Since PEMI reduces central command but not muscle afferent feedback, our results suggest that central command attenuates muscle pain perception during exercise and thus serves as a modulator of acute exercise-induced muscle pain. During exercise, several reflexes are simultaneously engaged, including the muscle metaboreflex, muscle mechanoreflex, arterial baroreflex and central command (Rowell & O Leary, 199). A method commonly used to specifically examine the effect of muscle metaboreflex during exercise is PEMI. During PEMI, the exercising forearm is occluded to prevent removal of the metabolic by-products of exercise. In addition, PEMI eliminates the muscle mechanoreflex and greatly reduces the input from central command. Therefore, any responses suppressed by central command during exercise should be observed during PEMI. To test if central command influences the perception of muscle pain, we induced PEMI after fatiguing IHG. Our subjects reported an increase in muscle pain perception during IHG and a further increase during PEMI. This greater increase in pain perception during 3 Codeine 3 Naloxone IHG PEMI Δ HR (beats/min) 2 2 Δ MAP (mmhg) Δ Total MSNA (%) Pre Post Pre Post Figure 1. Change in heart rate (HR), mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA; total activity) during isometric handgrip (IHG) and postexercise muscle ischaemia (PEMI) before (Pre) and after (Post) codeine and naloxone MSNA and MAP significantly increased during all trials, while HR only increased during IHG trials. Administration of codeine (n = 7) and naloxone (n = 9) did not alter HR, MAP or MSNA responses to IHG or PEMI. P <.5 versus IHG.

5 J Physiol Central modulation of pain during exercise 291 MPP (units) 15 5 Codeine IHG PEMI 15 5 Naloxone Pre Post Pre Post Figure 2. Muscle pain perception during isometric handgrip (IHG) and postexercise muscle ischaemia (PEMI) before (Pre) and after (Post) codeine and naloxone Muscle pain perception increased during IHG for all trials but was greater during PEMI. P <.1 versus baseline; P <.5 versus IHG; P <.9 versus IHG. PEMI strongly suggests that the pain was masked centrally during the IHG trial. These results indicate that central command attenuates the perception of muscle pain. In Study 1, PEMI reduced one stimulus (central command), but added a new stimulus (cuff compression). Thus, the increase in pain rating could have been mediated by (1) the reduction of central influences or (2) the Figure 3. Correlations of muscle pain perception and systolic arterial pressure (SAP) during isometric handgrip and postexercise muscle ischaemia (PEMI) in the control trial for Study 1 There is no correlation between muscle pain perception and SAP during either isometric handgrip or PEMI (n = 16).

6 292 C. A. Ray and J. R. Carter J Physiol addition of cuff compression. Therefore, we designed a second control study that permitted us to determine if the elevation in muscle pain perception during PEMI was due to the added cuff compression. In Study 2, fatiguing IHG was performed during muscle ischaemia and then followed by PEMI. Using this design, the cuff compression was present throughout the experiment and any change in pain perception during PEMI would be due to withdrawal of central command. The data from Study 2 also demonstrate an increase in muscle pain perception during PEMI, thus supporting the results from Study 1. Collectively, both studies indicate that muscle pain perception is modulated by central command during exercise. What central mechanisms could mediate the attenuation of pain perception during muscle contraction? Pain can be modulated at peripheral and central sites. A number of possible areas of the brain modulate pain perception, including the thalamus, hypothalamus, nucleus tractus solitarius, RVM, dorsal reticular nucleus, parabrachial nucleus, periaqueductal grey and amygdala (Millan, 22). It is also possible that GABA and glycine release in the spinal cord may play an important role in the suppression of muscle afferent activity by central command (Degtyarenko & Kaufman, 23). The current study does not permit us to determine which of these areas is most prominent in attenuating the pain perception during exercise, but our results clearly demonstrate that central modulation is occurring during IHG. This modulation could help explain the analgesic effects observed during exercise. Although pain processing by the central nervous system is a complex process, the endogenous opioid system has been recognized as a powerful modulator of pain perception (Kanjhan, 1995; Stein, 1995; Urban & Gebhart, 1999). Endogenous opioid receptors are located on nociceptive afferent fibres and several centres of the MPP (units) 5 IHG + Ischemia PEMI Figure 4. Muscle pain perception during ischaemic isometric handgrip (IHG) and postexercise muscle ischaemia (PEMI) Muscle pain perception increased during ischaemic IHG and increased further during PEMI (n = 8). P <.1 versus baseline; P <.5 versus IHG. brain stem that are involved with pain processing (Millan, 22). Activation of opioid receptors have well-established analgesic actions, including decreasing the sensitivity of pain perception in humans. Cook et al. (2) previously reported that the opioid agonist codeine and the opioid antagonist naltrexone do not alter the perception of muscle pain during exercise. However, this study could not definitively assess whether muscle pain perception during exercise was altered by central mechanisms (i.e. higher brain systems). It is possible that central command may have interacted with afferent feedback from the exercising muscle to modulate pain perception. In the current study, muscle pain perception during PEMI was significantly increased from the corresponding IHG value during the control and codeine trials (P <.1) and tended to increase in the naloxone trial (P <.9). These results suggest that administration of codeine and naloxone had little influence on perception of muscle pain. The current study answers an important question that could not be answered in our first study; opioids do not appear to centrally modulate muscle pain perception. Collectively, these findings indicate that the endogenous opioid system does not alter the perception of acute exercise-induced muscle pain. Previous studies suggest a relation between pain perception and arterial blood pressure (Randich & Maixner, 1984; Ghione et al. 1988; Lovick, 1993; Schobel et al. 1998). Specifically, several studies report that hypertensive subjects have a higher pain threshold compared with nomotensive subjects, suggesting that increased levels of arterial blood pressure are associated with diminished perception of pain (Ghione et al. 1988; Schobel et al. 1998). It has been suggested that the decreased pain perception reported in hypertensive subjects may be modulated by the arterial baroreflexes and the release of endogenous opioids (Randich & Maixner, 1984). Thus, it is reasonable to speculate that the increased arterial blood pressure during exercise may decrease the perception of pain to exercise. Our results reveal that muscle pain perception during exercise is not correlated with changes in arterial blood pressure. This finding suggests that increased arterial blood pressure during exercise is not modulating the perception of pain. In Study 1, PEMI increased muscle pain perception and slightly decreased arterial blood pressure when compared with IHG, but muscle pain perception was not correlated to changes in arterial blood pressure. Study 2 demonstrated that PEMI increased muscle pain perception but did not change arterial pressure when compared with ischaemic IHG. Collectively, these results indicate that increases in arterial blood pressure during exercise are not associated with alterations in muscle pain perception. This also indicates that muscle pain perception during exercise is not modulated by arterial baroreflexes.

7 J Physiol Central modulation of pain during exercise 293 These findings support the concept that the suppression of muscle pain perception during exercise is modulated by central command. It has also been suggested that there may be a potential relation between MSNA and pain perception. Specifically, Knardahl et al. (1998) demonstrated an increased pain threshold that paralleled increases in MSNA after acupuncture, suggesting that pain may be attenuated by increased MSNA. However, Cook et al. (2) reported no correlation between muscle pain perception and MSNA during IHG. Our results support the findings of Cook et al. (2) and extend them by demonstrating no correlation between muscle pain perception and MSNA during PEMI. Furthermore, the naloxone and codeine trials also revealed no correlation between muscle pain perception and MSNA during IHG or PEMI. Ray & Pawelczyk (1994) had previously demonstrated that naloxone did not modulate MSNA during IHG or PEMI, but muscle pain perception was not recorded. To our knowledge, this is the first study that has examined the relation between muscle pain perception and MSNA during both IHG and PEMI. The results of the current study, coupled with prior work (Victor et al. 1987; Ray & Pawelczyk, 1994; Cook et al. 2), support the concept that pain is not correlated to MSNA during exercise. The current study has three potential limitations. First, we cannot guarantee that the ischaemic contractions of Study 2 did not alter group III and IV muscle afferents. Kaufman et al. (1984) demonstrated that some group III and IV muscle afferents are stimulated more during ischaemic static contraction than during non-ischaemic contraction in cats. However, our data from Study 2 (ischaemic IHG) parallel the data from Study 1 (non-ischaemic IHG); thus we do not believe this limitation affects our conclusions. Second, our results indicate that central command modulates exercise-induced muscle pain, but we do not offer a mechanism of action. However, we suggest the dismissal of arterial blood pressure and MSNA as potential mechanisms because muscle pain perception during IHG and PEMI was not correlated to changes in arterial blood pressure or MSNA. Third, our results suggest that the central modulation is not influenced by endogenous opioids, but do not exclude other potential modulators of pain at the spinal level (Jordan et al. 1978, 1979). Furthermore, it must be noted that there are several factors that can interfere with afferent traffic, including presynaptic inhibition or primary afferent depolarization induced by higher brain centres (Lundberg et al. 1962; Lundberg & Voorhoeve, 1962). In summary, this study demonstrates that muscle pain perception increases during exercise and further increases with PEMI. The augmentation of muscle pain perception during PEMI was not related to changes in arterial blood pressure or MSNA. Furthermore, endogenous opioids do not appear to modulate muscle pain perception during isometric forearm exercise. These findings suggest that central command, not an increase in arterial blood pressure or MSNA, modulates the perception of muscle pain during exercise, and reinforces the concept that endogenous opioids do not modulate acute exercise-induced muscle pain. References Besson JM (1999). The neurobiology of pain. Lancet 353, Borg G (1978). Subjective aspects of physical and mental load. Ergonomics 21, Cook DB, O Connor PJ, Eubanks SA, Smith JC & Lee M (1997). Naturally occurring muscle pain during exercise: assessment and experimental evidence. Med Sci Sports Exerc 29, Cook DB, O Connor PJ & Ray CA (2). Muscle pain perception and sympathetic nerve activity to exercise during opioid modulation. Am J Physiol Regul Integr Comp Physiol 279, R1565 R1573. 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8 294 C. A. Ray and J. R. Carter J Physiol Randich A & Maixner W (1984). Interactions between cardiovascular and pain regulatory systems. Neurosci Biobehav Rev 8, Ray CA & Pawelczyk JA (1994). Naloxone does not affect the cardiovascular and sympathetic adjustments to static exercise in humans. J Appl Physiol 77, Rowell LB & O Leary DS (199). Reflex control of the circulation during exercise: chemoreflexes and mechanoreflexes. J Appl Physiol 69, Schobel HP, Handwerker HO, Schmieder RE, Heusser K, Dominiak P & Luft FC (1998). Effects of naloxone on hemodynamic and sympathetic nerve responses to pain in normotensive vs. borderline hypertensive men. J Auton Nerv Syst 69, Stein C (1995). The control of pain in peripheral tissue by opioids. N Engl J Med 332, Urban MO & Gebhart GF (1999). Central mechanisms in pain. Med Clin North Am 83, Victor RG, Seals DR & Mark AL (1987). Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans. J Clin Invest 79, Williamson JW, Fadel PJ & Mitchell JH (26). New insights into central cardiovascular control during exercise in humans: a central command update. Exp Physiol 91, Acknowledgements We thank Noelle P. Dahl and Charity L. Sauder for their technical assistance with this project. This study was supported by the National Institutes of Health (DC-6459, HL-5853 and P1HL7767), NASA (NAG 9-34), National Space Biomedical Research Institute (CA27), and a National Institutes of Health sponsored General Clinical Research Center (M1-RR-732 and C6-RR-16499).