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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 30% 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 (60 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 ± 0.8 to 9.5 ± 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 ± 1 to 7 ± 1 bursts (15 s)−1), whereas mean arterial blood pressure was slightly reduced (104 ± 4 to 100 ± 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 ± 3 to 67 ± 2 beats min−1; P < 0.01). 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.
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, 2002). 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, 2002). 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. (2000) 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. 2000). However, the experimental design of this study by Cook et al. (2000) 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, 2002). Furthermore, it has been demonstrated that central motor command can inhibit group III muscle afferent input to the dorsal horn (Degtyarenko & Kaufman, 2003). 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. 2006); 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.
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This study identifies three novel findings: (1) muscle pain perception increases during PEMI compared with IHG; (2) endogenous opioids do not modulate muscle 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, 1990). 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 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 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, 2002). 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, 2003). 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 brain stem that are involved with pain processing (Millan, 2002). Activation of opioid receptors have well-established analgesic actions, including decreasing the sensitivity of pain perception in humans.
Cook et al. (2000) 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 < 0.01) and tended to increase in the naloxone trial (P < 0.09). 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. 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. (2000) reported no correlation between muscle pain perception and MSNA during IHG. Our results support the findings of Cook et al. (2000) 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. 2000), 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.