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ORIGINAL ARTICLES |
From the Department of Psychology (S.L., N.R., S.S), Department of Preventative and Community Dentistry (H.L., K.I), Dow’s institute for Dental Research (H.L.K.), and Departments of Urology and Microbiology (D.L.), University of Iowa, Iowa City, IA.
Address reprint requests to: Susan Lutgendorf, PhD, Department of Psychology, E11 Seashore Hall, University of Iowa, Iowa City, IA 52242. Email: susan-lutgendorf{at}uiowa.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHODS: Fifty subjects (28 men and 22 women) were pretrained in relaxation using an imagery-based relaxation tape and then randomized to experimental condition. Subjects participated in an evening reactivity session including 20 minutes of a stress (Stroop test), relaxation (tape), or control (video) manipulation, followed by a capsaicin injection in the forearm. Digitized flare measurements were taken for 1 hour postcapsaicin, and measurements of cardiovascular variables, cortisol, adrenocorticotrophic hormone, and norepinephrine were taken at regular intervals.
RESULTS: The size of the maximum capsaicin-induced flare was significantly smaller in the relaxation condition than in the stress or control conditions, which did not differ from each other. Increases in norepinephrine, heart rate, and systolic blood pressure during the experimental task, but not after capsaicin, significantly predicted size of maximum flare and total area under the curve of flare measurements.
CONCLUSIONS: These findings suggest that stress reduction may affect local inflammatory processes. Results are consistent with sympathetic modulation of the effects of relaxation on the flare response.
Key Words: neurogenic inflammation • capsaicin • stress • relaxation • sympatheticnervous system
Abbreviations: ACTH = adrenocorticotrophic hormone; SBP = systolic bloodpressure; DBP = diastolic blood pressure; HR = heart rate; SP = substance P; CGRP = calcitonin gene related peptide; HPA = hypothalamic pituitary adrenocortical; NE =norepinephrine; AUC = area under the curve.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Neurogenic inflammation refers to an inflammatory tissue reaction induced by the activation of nerve fibers (14). Although sensory afferent neurons have been most studied in this regard (14), the sympathetic nervous system, particularly via postganglionic sympathetic neurons, also plays an important part in neurogenic inflammation (15–17). Activated sensory afferent neurons release neuropeptides such as SP, CGRP, and bradykinin, which can directly or indirectly induce increases in microvascular permeability, vasodilation, and plasma extravasation (14–15, 18). Mediators such as SP also induce degranulation of mast cells, releasing histamine and proinflammatory cytokines, and thus activating an antigenic inflammatory process that can amplify the inflammatory process initiated by the nervous system (15).
Whereas the putative role of stress in the exacerbation of antigenic inflammation has been examined, little is known about the effects of stress or relaxation on neurogenic inflammation. The acute stress response activates both the sympatho-adreno-medullary and hypothalamic pituitary adrenal axes, with an immediate release of catecholamines and other peptides via the sympathetic nervous system and a slower release of cortisol from the adrenals, within approximately 20 to 30 minutes (1, 19, 20). Whereas cortisol generally has antiinflammatory properties, sympathetic activation has both pro- and antiinflammatory consequences that are direct and indirect (1). Among the proinflammatory effects of enhanced sympathetic outflow are increased vasodilation, plasma extravasation, cellular permeability (15), and recruitment of immune cells (21). Interactions between sympathetic efferents and primary afferent fibers can also contribute to inflammation (22, 23). Because both stress and neurogenic inflammation are implicated in several chronic inflammatory conditions, understanding their interaction and the effect of reducing stress could have profound implications. This study used the model of the local capsaicin-induced flare to examine the effects of stress and relaxation on acute neurogenic inflammation.
Neurogenic inflammation has been successfully modeled using capsaicin, the active ingredient in red chili peppers (Capsicum) (24). When injected intradermally, capsaicin evokes a temporary burning sensation lasting 3 to 5 minutes and a characteristic localized flare consisting of a red flush with slight edema (14). The capsaicin flare is thought to be induced by a local axon reflex involving release of neuropeptides such as SP and CGRP from sensory neurons (14). Additional mediators of the capsaicin flare are thought to include cytokines, prostaglandins, and other neuropeptides (24, 25). Within normal individuals, the size of the capsaicin flare over time is quite consistent (10).
The effect of glucocorticoids and catecholamines on the capsaicin-induced flare have been minimally examined. Application of topical glucocorticoids inhibited several types of neurogenic inflammation (26); however, glucocorticoids have not been shown to block the capsaicin-induced flare (27). Alpha adrenoreceptors are known to be involved in the pain response to capsaicin (28, 29), and local application of norepinephrine enhances the hyperalgesic effects of capsaicin, but effects on the flare have not been examined (30).
The effects of stress and relaxation on the capsaicin-induced flare have received limited attention. In a pilot study utilizing a crossover design in which 10 male subjects received 20 minutes of either stress or relaxation before a capsaicin injection, we found smaller mean capsaicin-induced flares after stress than after relaxation (H. Logan, unpublished observations). Although highly suggestive, these findings were equivocal because for two of the subjects, the flare was consistently larger in the stress condition and there was also no control condition. Furthermore, because the previous study only tested men, and because women more frequently suffer from chronic inflammatory conditions, the generalizability of previous findings to women was not known.
The purpose of the present study was to examine how a randomized behavioral manipulation of stress would affect the flare response to a capsaicin challenge. We examined effects of stress, relaxation, and control conditions on the size of the flare. We also examined neuroendocrine and cardiovascular responses to the experimental manipulation and to capsaicin to better understand potential mechanisms involved in stress-related influences on the flare.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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All potential subjects were trained in relaxation for the purposes of ensuring homogeneous preexperimental conditions. Sixty-six subjects met initial screening criteria for inclusion in the relaxation training part of the study. One subject dropped out before the start of the study and five subjects dropped out during the relaxation training for reasons of inconvenience or scheduling difficulties. Of those remaining, 50 participants achieved the criterion necessary to be included in the capsaicin reactivity part of the study (discussed below). The final sample included 28 men and 22 women.
Procedure
Potentially eligible subjects completed an informed consent and attended three separate group relaxation training sessions held over a 1-week period in the Clinical Research Center (CRC). At the first session, demographic characteristics were assessed and a finger temperature sensor was attached to the tip of the middle finger of the nondominant hand. Temperature was measured every minute while participants listened to a 20-minute relaxation tape through individual tape recorders with headphones. The tape was an imagery-based passive progressive relaxation tape. This tape had been used in a previous relaxation study and had been shown to reliably elicit a relaxation response (H. Logan, unpublished observations). Participants were accepted into the study if they were able to achieve a 2°F raise in finger temperature during at least two of the three relaxation training sessions (31). The final sample included 50 subjects who were randomized to stress, relaxation, and control conditions in a 2:2:1 ratio. Nineteen subjects were in the stress condition, 20 were in the relaxation condition, and 11 were controls.
Participants were scheduled for a study appointment and asked to refrain from exercise, consumption of alcohol, and ingestion of nonprescription medication (eg, over-the-counter antiinflammatory agents and antihistamines) for 24 hours before the study. They were asked to refrain from drinking coffee, tea, or caffeinated beverages for 15 hours before their appointment and to reschedule their appointment if they became ill or experienced a major stressful life event. To avoid potential confounding effects of variability in estrogen levels, women were scheduled during the follicular phase of their menstrual cycle (days 3–10) (32).
The study appointment was held in the early evening (starting at 5:30 PM) at the CRC, and lasted for approximately 2 hours. Women were given a pregnancy test before the session and were excluded if pregnant. Subjects were seated in a comfortable chair in the CRC, and instructions for the reactivity session were given. A standardized grid with eight spokes emanating from a center point was drawn on the nondominant arm from a template on a piece of transparent acetate. At the center of the grid was the standardized location of the capsaicin injection, drawn at the midpoint between the wrist crease and the center of the elbow crease and centered distally. The grid was used to guide subsequent flare measurements. After the grid was drawn, an IV catheter was inserted into the antecubital vein of the nondominant arm and a blood pressure cuff was placed on the dominant arm. Next, participants had a 30-minute rest period to allow for stabilization of neuroendocrine measures. During this time they completed the Perceived Stress Scale (33) and then read magazines. Cardiovascular measures were sampled every 2 minutes for the last 8 minutes before the experimental task to provide a baseline. At 28 minutes, subjects completed a relaxation inventory (34).
At 30 minutes, blood was sampled from the catheter, and subjects began the experimental manipulation. The stress group was administered a 20-minute computerized version of the Stroop color-word test (35), a task that has been shown to elicit a reliable sympathetic response (36). Participants were urged to improve their performance by the examiner at 5-minute intervals. Those in the relaxation group listened to the same tape used in the relaxation training sessions, using a portable tape recorder and large headphones to minimize distracting noise. The control group watched a 20-minute informational video, "The Bridges and Ferries of Iowa City." During these tasks, cardiovascular measures were sampled every 4 minutes to enable ongoing assessment while providing a minimum of distraction to subjects who were relaxing. After the task, subjects completed a relaxation questionnaire and had a second blood draw.
Next, participants received an intradermal injection of 100 µg of capsaicin in the distal portion of the nondominant forearm, at the center of the previously drawn grid (37). Tracings of the flare were made at 5, 10, 15, 20, 30, 45, and 60 minutes, and blood was sampled at 10, 15, 30, and 60 minutes postcapsaicin. Cardiovascular measures were sampled every 2 minutes postcapsaicin. The capsaicin preparation consisted of 100 µg of capsaicin (8-methyl-N-vanillyl 6-nonenamide) suspended in 10 µl of a polyoxyethylene (20) sorbitan monooleate (Tween 80) saline vehicle. A stock solution of capsaicin was prepared containing 10% capsaicin in ethanol (weight:volume) using previously published methodology (37). Two-milliliter aliquots were withdrawn and diluted to 1% with ethanol, which was then removed by vacuum, and the capsaicin was dissolved in 0.14 ml of 7.5% Tween 80 by weight in saline. This was brought into a colloidal mixture with 1.86 ml of 0.9% saline by sonication and then injected through a Millipore filter (0.2-mm pore size) into a sterile injection vial. The vial was frozen at -20°C until use. Before use, the vial was warmed to room temperature and shaken by hand for 30 seconds.
Physiological Measures
Cardiovascular Measures.
SBP, DBP, and HR were measured during the experimental session using a Critikon Dinamap Plus vital signs monitor applied to the dominant arm. Cardiovascular measures were used as indicators of autonomic response to the experimental manipulation and to the capsaicin injection. Because capsaicin elicits a transitory rise in cardiovascular measures, only the immediate cardiovascular response to capsaicin was examined in relation to the flare.
Neuroendocrine Measures.
NE was examined as an indicator of sympathetic nervous system activity in response to the experimental manipulation and to capsaicin (19). ACTH and cortisol were measured as indicators of the HPA response to the manipulation and to capsaicin (20) and to test the potential antiinflammatory role of cortisol in these conditions (1).
ACTH.
Aliquots of EDTA plasma were separated from blood samples, put on ice, and measured by a chemiluminescence immunoassay (Nichols Institute Diagnostics) in the CRC Endocrinology Lab. The sensitivity of the assay is 0.5 pg/ml. Interassay coefficients of variability range from 4.6% to 7.0%, and intraassay coefficients of variability range from 3.4% to 3.8%.
Cortisol.
Aliquots of serum were separated from blood samples, and assayed by competitive radioimmunoassay (EURO/DPC’s Double Antibody Cortisol RIA; Diagnostic Products Corporation, Los Angeles, CA) in the CRC Endocrinology Lab. Approximate sensitivity of the assay is 0.3 µg/dl. Interassay coefficients of variability range from 5.8% to 7.8%, and intraassay coefficients of variability range from 2.4% to 4.5%. Controls with low, intermediate, and high cortisol concentrations are routinely assayed for quality control.
Norepinephrine.
Plasma NE was measured in the Cardiovascular Center Core Laboratory using HPLC-EC. In brief, catecholamines were adsorbed onto acid-washed alumina and eluted with 0.1 M perchloric acid. After microfiltration, the eluate was buffered and chromatographed on a Biophase ODS (C-18) HPLC column with a mobile phase of 0.1 M KH2PO4, 0.1 mM EDTA, 7.8% methanol, and 4 mM heptane sulfonic acid as the ion pairing agent. NE was detected with a BAS LC-4B electrochemical detector using a glassy carbon working electrode (Bioanalytical Systems, Inc., West Lafayette, IN). Peaks were quantitated on a Shimadzu CR 3-A integrator. Sensitivity of the HPLC-EC system was 50 pg. In addition to pretask and posttask measures, NE was assessed 10 minutes after capsaicin to capture relatively early changes in this measure (19).
Three aliquots of blood drawn for catecholamines (one relaxer and two stress group) were hemolyzed at baseline and were thus not able to be tested. Blood could not be drawn from two subjects in the stress group at 10, 15, and 30 minutes postcapsaicin. At 10 minutes postcapsaicin, blood samples of three controls and one relaxer drawn for catecholamines was hemolyzed and thus could not be tested. Blood samples were only assayed when baseline measures were available. Thus cortisol and ACTH blood measures were available for 48 subjects, and NE measures were available for 41 subjects.
Psychological Measures
Relaxation Inventory.
The Relaxation Inventory (34) is a 45-item self-report measure with three subscales: physiological tension, physical assessment, and cognitive tension. Physical assessment contains items such as "My muscles feel relaxed" and "I feel serene"; the physiological tension scale contains items such as "My heart rate is increasing" and "I am sweating because I am tense"; the cognitive tension scale contains items such as "I am thinking about my problems." Test–retest reliability for this measure is between 0.87 and 0.97. Alpha coefficients range from 0.81 to 0.95 for the three subscales. This inventory was used to assess perceived changes in tension/relaxation from pre- to postmanipulation.
Perceived Stress Scale (33).
The Perceived Stress Scale (PSS) is a 14-item inventory measures the extent to which an individual feels in control vs. overwhelmed by life stressors. It has been used in studies associating levels of life stress with infectious illness (38). The PSS has a high internal reliability and has demonstrated high construct validity with other measures of life stress (33). This scale was used to control for levels of chronic stress in the last week.
Image Analysis
The area of inflammation was mapped using a transparent acetate sheet placed over the area of inflammation and traced according to markings on the grid. Tracings were performed by two trained examiners who had established reliability by comparing tracings for two subjects at a total of nine time points after capsaicin injections. The reliability of the two examiners was tested using interclass correlations. Results indicated a correlation of 0.80 between examiners.
Image analysis was performed in the University of Iowa Image analysis facility. Transparencies were digitized using the Kodak Meggaplus Camera model 1.4 and acquired using an Adobe Photoshop 4.0 plug-in on a Power Mac 7100/80aw. The transparency, the background, and a metric ruler for calibration were captured at the same resolution and under the same lighting conditions. The background was subtracted from the transparency using the standard algorithm of [(transparency pixel value - background pixel value)/2 + 128]. The subtracted tiff image was transferred to a Silicon Graphics O2 workstation for quantitative analysis. Analysis was performed using The University of Iowa Image Analysis Facility software, Volume Trace Motif Version 1.23. Images were calibrated to metric units (cm2). For the area of flare images, the region of interest was defined by setting a threshold and finding the inner border of the enclosed flare outline. A straight line was then used to connect the ends of the region of interest. We were interested in the maximum extent of inflammation in each condition as well as the emergence and resolution of the flare over time. The maximum flare was defined as the largest flare area achieved by an individual at any time point. Total flare size over time was calculated using the AUC of the flare measurements calculated by means of the trapezoidal formula.
Statistical Analysis
Reduction of cardiovascular data were done as follows. The four pretask cardiovascular measures were averaged to form a pretask baseline. Mean levels of cardiovascular measures during the experimental task were calculated from the average of the five cardiovascular measures sampled during the task. Immediate cardiovascular response to capsaicin was calculated using the maximum response during the first 4 minutes postcapsaicin. Data analysis used the Statistical Package for the Social Sciences version 7.5 for PC and SAS version 6.12 for PC.
Model assumptions were tested and appropriate adjustments were made when necessary. Cardiovascular and neuroendocrine data were normalized using logarithmic transformations. Equivalence of groups at baseline on physiological measures was tested using one-way analysis of variance (ANOVA). The first set of analyses tested the efficacy of the experimental manipulation and the degree to which the manipulation was perceived as stressful or relaxing. Pretask neuroendocrine measures were subtracted from posttask values to obtain delta scores on which one-way ANOVAs were applied to compare the experimental conditions. For cardiovascular variables, manipulation checks were done using ANOVAs on the delta scores of the mean task level minus the baseline for each measure, following the recommendations of Llabre et al. (39). The three subscales of the relaxation inventory were analyzed using a multivariate analysis of variance (MANOVA) with univariate follow-up tests on the individual scales. Tukey post hoc tests were performed on significant ANOVAs to determine differences between conditions.
The second set of analyses examined the effects of the experimental manipulation on the capsaicin flare. Group differences in the maximum size of the flare were tested using an ANOVA. To assess whether there were changes over time and differences by condition, a repeated-measures analysis was performed on the area of the outer flare.
The third set of analyses examined postcapsaicin changes in neuroendocrine and cardiovascular measures over time. For the flare, ACTH, and cortisol repeated-measures analyses, a mixed linear model using maximum-likelihood estimation and a first-order autoregressive (flare) or banded (ACTH and cortisol) covariance structure was used (40, 41). This type of analysis is appropriate for longitudinal data in which the measures within an individual are correlated and independent across individuals. The banded covariance structure used is also called a full Toeplitz structure. In the ACTH and cortisol models, we found evidence of unequal covariance matrices across experimental condition. Therefore, we allowed this heterogeneity by estimating a separate (banded) covariance matrix for each condition. In the flare model, we found no evidence of covariance heterogeneity, thus were able to model a single matrix. Finally, because observations were obtained for all subjects at the same measurement times, time was treated as discrete in each model. Because there was only one measure of norepinephrine postcapsaicin, an ANCOVA, covarying for pretask baseline, was performed on NE at 10 minutes postinjection to test for group differences in the NE response to capsaicin. To test for effects of condition on the immediate cardiovascular response to capsaicin, the maximum value of each cardiovascular measure in the first 4 minutes postcapsaicin was determined and ANCOVAs were performed on peak cardiovascular values adjusting for pretask baselines.
The final set of analyses was exploratory and examined relationships between flare size and changes in cardiovascular and neuroendocrine measures during the task and in response to capsaicin. We expected the maximum cardiovascular and neuroendocrine response during the task and postcapsaicin to be related to flare size. Therefore changes in cardiovascular and neuroendocrine measures during the task and after capsaicin were calculated using the peak value achieved either during the task or after capsaicin, minus the pretask baseline level. These delta scores were correlated with maximum flare size and AUC of the total flare. Relationships between self-reported relaxation and flare size were also examined. Partial correlations, adjusting for sex, were used to examine these relationships.
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RESULTS |
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These findings suggest that the experimental manipulation was successful in that the stress condition was experienced as physiologically and psychologically most evocative. For all measures except cortisol, the lowest response evoked by the task was shown consistently in the relaxation group. Significant differences between the relaxation and the control groups were evidenced with respect to DBP and self-reported physical relaxation.
Flare Response to Capsaicin Challenge.
We were interested in the maximum size of the outer flare achieved postcapsaicin, as well as the course of the flare emergence and resolution. There was no interaction between sex and group in the flare response, but there was a trend for a main effect for men to have larger flares (p < .09) than women. Therefore, in all analyses involving flare, as a conservative measure, we adjusted for sex. There was a significant difference between groups in the size of the maximum flare (F(2,45) = 3.28, p < .05). The relaxation group had significantly smaller flares at maximum than either the stress group (F(1,45) = 4.34, p = .04) or the control group (F(1,45) = 4.91, p = .03), which did not differ from each other (Figure 4). The time of maximum flare did not significantly differ between groups (p > .25). The majority of subjects (85.7%) had achieved their maximum flare by 20 minutes, with 19.6% demonstrating the maximum flare at 10 minutes and 35.3% demonstrating the maximum flare at 15 minutes. A mixed linear model indicated a main effect for time in the size of the flare (F(6,25) = 48.81, p < .0001), as seen in Figure 5, and a trend toward a main effect for group (F(2,51.9) = 2.83, p = .068). There were no interactions, indicating that the time course of the flare did not differ according to experimental condition. The AUC of the flare over time was 15.1% less for the relaxation group than for the stress group. In contrast, the AUC of the flares of the stress and control groups differed from each other by approximately 1%.
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Cardiovascular Response to Capsaicin Challenge.
The peak cardiovascular response to capsaicin in all groups was observed at the first reading 2 minutes after the capsaicin injection and then dropped rapidly. Mean HR averaged across groups returned to precapsaicin baselines by 4 minutes postcapsaicin, and both mean SBP and DBP averaged across groups had returned to within 3 mm Hg of precapsaicin baselines within 6 minutes. To determine group differences in the peak response after capsaicin, ANCOVAs were performed on peak levels of each cardiovascular measure, covarying for pretask baselines. These tests indicated that there were significant differences between the three conditions in the maximum SBP level postcapsaicin (F(2,46) = 5.64, p = .006). The peak SBP level of the relaxation group was significantly lower than that of either the stress group (p = .002), or the control group (p = .03), which did not differ from each other (p = .63). There were no significant differences between groups in peak DBP level ( p = .72), and there was a trend toward a group difference in peak postcapsaicin HR (F(2,46) = 3.05, p = .057), with the highest level reached in the stress group (Table 2).
Relationships Between Cardiovascular and Neuroendocrine Response and Flare Size.
To examine potential mechanisms contributing to the flare response, we analyzed relationships between peak task-induced and capsaicin-induced changes in cardiovascular and neuroendocrine measures and the size of the maximum flare and total flare (AUC from 0 to 60 minutes). Partial correlations, controlling for sex, were used to examine these relationships (Table 3). Greater increases in SBP and HR during the experimental task were associated with significantly larger maximum flare areas (pr = 0.31, p = .03 for both measures) and flare AUC (pr = 0.34, p = .02; pr = 0.32, p = .023, respectively). Greater increases in NE during the experimental task were significantly related to greater maximum flares and flare AUC (pr = 0.34, p = .024; pr = 0.37, p = .014, respectively). There were no significant relationships between changes in DBP, cortisol, ACTH, or changes in self-perceived relaxation during the task and flare size. There were no significant relationships between the maximum changes in any of these measures after capsaicin and the size of the maximum flare or total flare.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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These results extend previous findings by suggesting that relaxation inhibits the neurogenic flare response compared with both stress and neutral conditions. This result is consistent with findings that relaxation can inhibit the histamine-induced wheal, although an antigen-induced immunologic mechanism is more likely involved in the histamine wheal (7). In contrast to observations that stress enhances the antigenic inflammatory response (1, 42, 43), the stress condition did not exacerbate the neurogenic flare in this study.
Mechanisms responsible for these effects are not clear. The relationships of SBP, HR, and NE response during the experimental task with maximum and total flares suggest that sympathetic arousal may have contributed to flare size. These findings are consistent with the proinflammatory effects of sympathetic activity. For example, postganglionic sympathetic neurons can induce bradykinin and other mediators to elicit plasma extravasation (44), and sympathetic peptides such as neuropeptide Y can alter vascular permeability (45). Other data suggest that sympathetic products can directly activate sensory nerves (46). If relaxation is characterized by lowered sympathetic activity (47), such proinflammatory effects may be minimized in that condition. In future work, the exploration of cardiac activity in the frequency domain (spectral analysis of heart rate variability) might prove useful to document the influence of vagal activity on the heart in relation to the influences of stress and relaxation on the capsaicin flare (48). It is noteworthy that changes in cardiovascular measures and NE during the task (but not after capsaicin) were related to flare size. This suggests that the timing of modulation of stress with respect to capsaicin may be relevant to flare development.
There is evidence that peripherally-acting drugs such as lidocaine reduce hyperalgesia (49) and the flare response (50), whereas more centrally acting drugs such as ketamine seem to have little effect on capsaicin-induced pain (51). These findings suggest that the mechanism underlying the effects of relaxation on the flare response may involve a relaxation-induced decrease in sympathetic outflow and thus a decrease in the interaction of the sympathetic nervous system and sensory afferents at the peripheral level.
A potential alternative pathway may involve central mechanisms. Behavioral interventions used to modulate pain have been shown to depend partly on central mechanisms acting on spinal processes. For example, hypnotic analgesia modulates the spinal R-III nociceptive reflex (52). Central processes (reflected in relaxation ratings as well as autonomic and endocrine measures) may modulate the effects of the experimental manipulation on the flare through descending pathways acting on the spinal cord antidromic dorsal root reflex (DRR), which is thought to mediate the neurogenic flare response (53). In animal studies, stimulation of the pyramidal (motor) tract has been shown to modulate the DRR (54). The increase in subjective physical relaxation may reflect a decrease in pyramidal tract activity and in muscle tension. This decrease may translate into an attenuation of the DRR and, consequently, into a reduced flare response. Other descending pathways that are known to modulate spinal nociceptive processes (55) are likely to influence the DRR as well and are additional potential candidates for the influence of relaxation on the flare response.
A relationship between changes in cortisol level and flare size was not observed. These findings are consistent with a previous report that topical glucocorticoids do not inhibit the capsaicin-induced flare (27) and suggest that the antiinflammatory effects of cortisol may not be a major factor influencing the capsaicin-induced flare.
It is unclear why there was an inconsistency between these findings and those of our preliminary work, which used a crossover design to test a behavioral manipulation of stress precapsaicin and found smaller capsaicin-induced flares in the stress condition. Differences in the selection and training process in the two studies may have contributed to divergent results. The previous study included only participants who were "natural" relaxers, ie, subjects able to achieve a 2°F finger temperature increase on their first exposure to the relaxation tape, and who were then further trained in relaxation. In contrast, the current study included participants who were able to be trained to a criterion of a 2°F temperature increase over several sessions. It is possible that the selection of "natural" relaxers might have served to dampen the effect of the manipulation such that even stressed subjects might have been able to recover quickly from the capsaicin injection. In the absence of psychophysiological data from that study, we are unable to confirm these speculations. However, such inconsistencies suggest the importance of replication of the present results.
Limitations.
Limited sample size, particularly with respect to the NE samples, may have decreased the power to detect differences between groups. Limited time points of NE sampling may have also constrained the ability to detect group differences in NE. In addition, body mass index was not assessed; other than adjusting for sex in the flare findings, it is not known to what extent body mass contributed to the findings.
Nevertheless, these findings support a potential role for relaxation in the inhibition of the acute neurogenic inflammation induced by capsaicin. Whether relaxation would have similar effects in chronic conditions in which neurogenic inflammation contributes to pathophysiology such as asthma, interstitial cystitis, or rheumatoid arthritis is not known. However, the present findings suggest that examination of effects of relaxation on chronic conditions involving neurogenic inflammation warrants further investigation.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication July 19, 1999.
Revision received November 22, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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-adrenoreceptors are involved in the development of capsaicin induced stimulus evoked pain in humans. Pain 1997; 69: 79–85.[Medline]
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