Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation.

Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. Although many rodent studies have examined the effects of exercise on persistent hypersensitivity, the most used forced exercise paradigms that are known to be highly stressful. Because stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress, and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces hypersensitivity as well as stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states. PERSPECTIVE: Modest levels of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent inflammatory pain, independently of the amount of exercise. As such, consistent, self-regulated activity levels may be more relevant to health improvement in persistent pain states than standardized exercise goals.

Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain.

BACKGROUND: In animal models, the impact of social and environmental manipulations on chronic pain have been investigated in short term studies where enrichment was implemented prior to or concurrently with the injury. The focus of this study was to evaluate the impact of environmental enrichment or impoverishment in mice three months after induction of chronic neuropathic pain. METHODS: Thirty-four CD-1 seven to eight week-old male mice were used. Mice underwent surgery on the left leg under isoflurane anesthesia to induce the spared nerve injury model of neuropathic pain or sham condition. Mice were then randomly assigned to one of four groups: nerve injury with enriched environment (n = 9), nerve injury with impoverished environment (n = 8), sham surgery with enriched environment (n = 9), or sham surgery with impoverished environment (n = 8). The effects of environmental manipulations on mechanical (von Frey filaments) heat (hot plate) and cold (acetone test) cutaneous hypersensitivities, motor impairment (Rotarod), spontaneous exploratory behavior (open field test), anxiety-like behavior (elevated plus maze) and depression-like phenotype (tail suspension test) were assessed in neuropathic and control mice 1 and 2 months post-environmental change. Finally, the effect of the environment on spinal expression of the pro-nociceptive neuropeptides substance P and CGRP form the lumbar spinal cord collected at the end of the study was evaluated by tandem liquid chromatography mass spectrometry. RESULTS: Environmental enrichment attenuated nerve injury-induced hypersensitivity to mechanical and cold stimuli. In contrast, an impoverished environment exacerbated mechanical hypersensitivity. No antidepressant effects of enrichment were observed in animals with chronic neuropathic pain. Finally, environmental enrichment resulted lower SP and CGRP concentrations in neuropathic animals compared to impoverishment. These effects were all observed in animals that had been neuropathic for several months prior to intervention. CONCLUSIONS: These results suggest that environmental factors could play an important role in the rehabilitation of chronic pain patients well after the establishment of chronic pain. Enrichment is a potentially inexpensive, safe and easily implemented non-pharmacological intervention for the treatment of chronic pain.

Altered C-tactile processing in human dynamic tactile allodynia.

Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aß afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aß but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aß afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aß signaling, at least under these experimental conditions.

Autonomic responses to heat pain: Heart rate, skin conductance, and their relation to verbal ratings and stimulus intensity.

In human pain experiments, as well as in clinical settings, subjects are often asked to assess pain using scales (eg, numeric rating scales). Although most subjects have little difficulty in using these tools, some lack the necessary basic cognitive or motor skills (eg, paralyzed patients). Thus, the identification of appropriate nonverbal measures of pain has significant clinical relevance. In this study, we assessed heart rate (HR), skin conductance (SC), and verbal ratings in 39 healthy male subjects during the application of twelve 6-s heat stimuli of different intensities on the subjects' left forearm. Both HR and SC increased with more intense painful stimulation. However, HR but not SC, significantly correlated with pain ratings at the group level, suggesting that HR may be a better predictor of between-subject differences in pain than is SC. Conversely, changes in SC better predicted variations in ratings within a given individual, suggesting that it is more sensitive to relative changes in perception. The differences in findings derived from between- and within-subject analyses may result from greater within-subject variability in HR. We conclude that at least for male subjects, HR provides a better predictor of pain perception than SC, but that data should be averaged over several stimulus presentations to achieve consistent results. Nevertheless, variability among studies, and the indication that gender of both the subject and experimenter could influence autonomic results, lead us to advise caution in using autonomic or any other surrogate measures to infer pain in individuals who cannot adequately report their perception. Skin conductance is more sensitive to detect within-subject perceptual changes, but heart rate appears to better predict pain ratings at the group level.

Unpleasant odors increase pain processing in a patient with neuropathic pain: psychophysical and fMRI investigation.

A 49-year old man with neuropathic pain in his right elbow, wrist and digits III-V of his hand reported that certain odors increased his pain by superimposing an electric shock-like pain to his already existing pain. Psychophysical testing revealed that the best predictor of pain exacerbation was odor unpleasantness. Functional magnetic resonance imaging (fMRI) showed increased activation following an unpleasant odor in pain related areas, including the thalamus, amygdala, insular and anterior cingulate cortices, with similar trends in primary somatosensory cortex hand/arm area. The increased pain and associated neural activations in response to unpleasant odors may be related to the phenomenon of synesthesia, to a rewiring of olfactory pathways onto pain pathways mimicking synesthesia or, to activation of the sympathetic nervous system.

The effects of racemic ketamine on painful stimulation of skin and viscera in human subjects.

Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral and somatic pain. Specifically, animal data indicate an analgesic role of NMDA-R antagonists in acute visceral but not acute somatic pain. In humans analgesic effects are documented in acute somatic pain, while the role of NMDA-R antagonists in acute visceral pain is still questionable. We, therefore, conducted a study in humans comparing the analgesic effects of ketamine in an experimental model of visceral and cutaneous pain. In a double-blind, randomized, cross-over study, 11 healthy volunteers (3M, 8F) participated in two experimental sessions in which they evaluated perceptions induced by balloon distention of the distal esophagus and contact heat on the upper chest during continuous computer-controlled i.v. infusion of either ketamine (60 and 120 ng/mL) or saline. Two stimulus intensities producing non-painful and painful sensation were used for each stimulus modality. Subjects reported maximum pain intensity and unpleasantness on visual analog scales (VAS). For noxious visceral stimulation, low dose ketamine produced significant attenuation of both pain intensity and unpleasantness. In contrast, for noxious cutaneous stimulation, ketamine reduced pain unpleasantness, but not perceived intensity. In addition, ketamine did not alter the perception of innocuous stimuli in either modality. Our results confirm the analgesic effects of low-dose ketamine, with minimal side effects, on acute visceral pain and indicate a similar but smaller effect on acute cutaneous pain. A decrease in the unpleasantness but not in the intensity of cutaneous pain may reflect the differential effect of NMDA-R antagonists for the two pain states observed in animal models.

Sex differences in pain perception and anxiety. A psychophysical study with topical capsaicin.

Much evidence indicates that women experience painful stimuli as more intense than men do. Nevertheless, some data suggest that sustained low-level pain may be more disturbing to men than to women. The current experiment evaluated the hypothesis that pain is more disturbing for men than for women by comparing across genders sensory and emotional aspects of pain evoked by capsaicin. Ten men and 10 women (aged 20-46 years) received topical capsaicin for 30 min on the face in one session and on the ankle in another. The subjects rated on visual analog scales pain intensity, unpleasantness and anxiety each minute during capsaicin application and for 30 min after its removal. During capsaicin application, females rated both pain intensity (P = 0.04) and unpleasantness (P = 0.05) higher than did males. Further, subjects rated pain intensity and unpleasantness higher on the face than on the ankle, although the physical stimulus was the same. Despite their lower pain ratings, men reported more pain-related anxiety than women (P = 0.02) Moreover, men showed a significant positive correlation between anxiety and pain intensity and unpleasantness, whereas women did not. After removing the capsaicin, there was no overall effect of sex on either intensity (P = 0.18) or unpleasantness (P = 0.37) of the residual sensation. However, men still showed a positive correlation between anxiety and the intensity and unpleasantness of the sensation. Our data confirm with the topical capsaicin model that women rate pain higher than men, but despite their lower pain ratings, males have more anxiety related to pain.

Analgesic and placebo effects of thalamic stimulation.

Numerous clinical studies have reported successful relief of chronic pain with sensory thalamic stimulation. However, even with the extensive use of sensory thalamic stimulation as a clinical tool in the relief of chronic pain, the results are still inconsistent. This discrepancy could probably be explained by the fact that the majority of these studies are case reports or retrospective analyses, which have often used imprecise pain measurements that do not allow a rigorous statistical evaluation of pain relief. None of these studies measured the effect of stimulation on clinical pain for longer than a few hours per day, which is an important aspect considering that clinical pain can vary over time. Moreover, placebo controls are seldom included. In the current study, we measured patients' pain perception at home over a 2-week period, both during days of normal stimulation of the sensory thalamus and during days without stimulation. Patients also came to the laboratory to assess the effects of thalamic and placebo stimulation on clinical pain, experimental heat pain, innocuous air puff and visual stimulation. A potential relation between the perceived paresthesia and analgesic efficacy during thalamic and placebo stimulation was also explored. We found that thalamic stimulation significantly affected clinical and experimental pain perception, but that an important placebo component also exists. On the other hand, neither thalamic nor placebo stimulation affected air puff and visual ratings, suggesting that the effect applies specifically to pain and hence is not caused by a general change in attention. The level of paresthesia elicited during the placebo manipulation was also directly correlated with the degree of placebo pain relief. These results suggest that thalamic stimulation produces a small but significant reduction in pain perception, but that a significant placebo effect also exists.

Psychophysical analysis of visceral and cutaneous pain in human subjects.

Clinical evidence suggests that cutaneous and visceral pain differ in sensory, affective, and motivational realms, yet there has been little comparative characterization of these types of pain. This study uses psychophysical measures to compare directly visceral and cutaneous pain and sensitivity. Healthy subjects (10 males, seven females, age 19-29) evaluated perceptions evoked by balloon distention of the distal esophagus and contact heat on the upper chest. Subjects gave continuous ratings of pain intensity using an on-line visual analog scale (VAS), reported maximum pain intensity and unpleasantness on printed VASs, chose phrases from the McGill Pain Questionnaire and Spielberger State-Trait Anxiety Inventory, and drew the area of perceived sensation. For esophageal distention, the threshold for pain intensity was higher than that observed for unpleasantness, whereas for contact heat, pain and unpleasantness thresholds did not differ for either phasic (10s) or tonic (36s) stimulus application. The relative unpleasantness, calculated as the difference between the unpleasantness and the intensity ratings, was higher during esophageal distention than during either phasic or tonic cutaneous heat; this difference in relative unpleasantness was seen at all intensities of esophageal stimulation. Subjects chose significantly more affective words and reported more anxiety during visceral pain than during phasic cutaneous heat pain. A similar tendency was observed when visceral pain was compared to tonic cutaneous heat pain. Subjects also chose a wider range of words to describe visceral than cutaneous pain. On-line VAS ratings revealed greater pain sensation after stimulus termination during visceral than during phasic cutaneous pain; likewise, a similar tendency was observed between visceral and tonic cutaneous pain. Finally, visceral pain led to a more spatially diffuse sensation and was referred to the entire chest and sometimes to the back. Our results show that visceral pain is more unpleasant, diffuse, and variable than cutaneous pain of similar intensity, independent of the duration of the presented stimuli. The data suggest the likelihood of both similarities and differences in the neural substrates underlying visceral and cutaneous pain.

Dissociation of sensory and affective dimensions of pain using hypnotic modulation.

Understanding the complex nature of pain perception requires the ability to separately analyze its psychological dimensions and their interaction, and relate them to specific variables and responses. The present study, therefore, attempted to selectively modulate the sensory and affective dimensions of pain, using a cognitive intervention, and to assess the possible relationship between these psychological dimensions of pain and changes in physiological responses to the noxious stimuli. In three experiments, normal subjects trained in hypnosis rated pain intensity and pain unpleasantness produced by a tonic heat-pain stimulus (1-min immersion of the hand in 45.0-47.5 degrees C water). Two experiments were designed to test hypnotic suggestions to decrease (Experiment one (Section 2.5.1)), or increase and decrease (Experiment two (Section 2.5.2)) pain affect. Suggestions in Experiment three (Section 2.5.3) were directed towards an increase or decrease in pain sensation. In Experiments one and two (Sections 2.5.1 and 2.5.2), the significant modulation in pain unpleasantness ratings was largely independent of variations in perceived pain intensity. Moreover, in Experiment two (Section 2.5.2), there was a significant correlation between the stimulus-evoked heart-rate increase and ratings of pain unpleasantness, but not of pain intensity, suggesting a direct functional interaction between pain affect and autonomic activation. In Experiment three (Section 2.5.3), suggestions to modulate the sensory aspect of pain produced significant modulation of pain intensity ratings, with secondary changes in pain unpleasantness ratings. Hypnotic susceptibility (Stanford Hypnotic Susceptibility Scale form A) was specifically correlated to pain unpleasantness modulation in Experiment two (Section 2.5.2) and to pain intensity modulation in Experiment three (Section 2.5.3), suggesting that this factor relates to the primary process toward which hypnotic suggestions are directed. The specific pain dimension on which hypnotic suggestions act depends on the content of the instructions and is not a characteristic of hypnosis itself. Results are consistent with a successive-stage model of pain perception (e.g. Wade JB, Dougherty LM, Archer CR, Price DD. Assessing the stages of pain processing: a multivariate analytical approach. Pain 1996;68:157-167) which provides a conceptual framework necessary to study the cerebral representation of pain perception.

Noxious and innocuous cold discrimination in humans: evidence for separate afferent channels.

The present study evaluated the ability of humans to discriminate temperature decreases in the noxious and innocuous cold range. Two groups of five subjects detected changes in cold stimuli applied to the maxillary face. For five subjects, adapting temperatures of 22 degrees, 16 degrees, 6 degrees and 0 degrees C were used, and thresholds for detecting temperature decreases were determined using an adaptive psychophysical paradigm. Visual analogue scale (VAS) ratings of cold and pain sensation were also recorded at 5-min intervals throughout each session. A second group of five subjects performed a similar detection task, but in this case using classical psychophysical techniques (method of constant stimuli) and adapting temperatures of 22 degrees, 16 degrees, 10 degrees and 6 degrees C. These subjects described the quality of the detected change in sensation, in addition to rating overall cold and pain sensation throughout the session. Detection thresholds were 0.27 degrees, 0.48 degrees, 4.8 degrees, 8.0 degrees and >10.0 degrees C for baselines of 22 degrees, 16 degrees, 10 degrees, 6 degrees and 0 degrees C, respectively, indicating that discrimination was better in the innocuous cool (22 degrees and 16 degrees C) than in the noxious and near-noxious cold (10-0 degrees C) range (P < 0.05). Tonic adapting temperatures of 22 degrees and 16 degrees C were always rated as cool but not painful, whereas adapting temperatures of 10 degrees and 6 degrees were sometimes and 0 degrees C usually rated as painful. Phasic temperature decreases from 22 degrees and 16 degrees C always produced cooling sensations, whereas decreases from baselines of 10 degrees and 6 degrees C produced primarily sensations of painful and non-painful prickle. These data suggest that different afferent channels mediate cool and noxious cold perception and add support to the hypothesis that noxious cold sensation is mediated by subdermal nociceptors.

Deep brain stimulation: a review of basic research and clinical studies.

Deep brain stimulation for pain control in humans was first used almost 30 years ago and has continued to receive considerable attention. Despite the large number of clinical reports describing pain relief, numerous studies have indicated that the results of these procedures vary considerably. In addition, many neurosurgeons find the procedures unpredictable, and considerable disagreement still exists regarding important issues related to the technique itself. This review gives an historical overview of the relevant basic and clinical literature and provides a critical examination of the clinical efficacy, choice of stimulation sites, parameters of stimulation, and effects on experimental pain. Finally, we give suggestions for future research that could more definitively determine the usefulness of deep brain stimulation for pain control.

Sex differences in the perception of noxious heat stimuli.

This study compared pain perception in young male and female subjects, using experimental noxious heat stimuli. During 2 sessions, each of 40 subjects rated the magnitude of 120 heat stimuli, ranging from 45 degrees C to 50 degrees C. The study included a comparison of visual analogue and magnitude matching rating procedures, as well as a test of simulated analgesia, in which the range of stimuli presented during the 2 experimental sessions was shifted by 1 degree C. We found that females rated noxious heat stimuli as more intense than did males, independent of the gender of the experimenter or the type of rating scale. In addition, the data suggest that females discriminate among the painful heat intensities better than males. For example, female subjects showed significant between-session discrimination of noxious heat stimuli, while male subjects did not, and females produced steeper within-session stimulus-response functions than did males. These observed differences in nociceptive discrimination between males and females indicate that the sex-related variation in pain perception is probably related to sensory factors rather than differences in attitude or emotional response.

Effects of attention on the intensity and unpleasantness of thermal pain.

Both experimental and clinical studies have shown that psychological manipulations, such as hypnosis, behavioral modification and cognitive-behavioral therapy, can reduce reports of pain. Although these are complex procedures, one important variable common to each is direction of attention. We have previously demonstrated in both humans and monkeys a method for monitoring and manipulating attention toward or away from a painful stimulus and have shown that changes in the direction of attention alter the ability to discriminate noxious heat stimuli. The present study assessed whether these changes in discrimination were accompanied by changes in the perception of pain intensity and/or unpleasantness. These data confirm that both the speed and accuracy of detecting changes in noxious heat stimuli are decreased when the subject attends to another stimulus modality. In addition, they show that direction of attention affects the perceived intensity and unpleasantness of painful stimuli in a similar manner. Our previous findings of attention-related modulation of nociceptive neuronal activity in the medullary dorsal horn suggest that these attention-dependent changes in sensory-discriminative and affective components of pain are mediated at early stages of sensory processing.

Comparison of verbal and visual analogue scales for measuring the intensity and unpleasantness of experimental pain.

Although the multidimensional nature of pain is now well recognized, there are, nevertheless, very few quantitative tests to measure the separate dimensions of pain and little data concerning their relative sensitivity. The present study compares 2 currently available methods, verbal descriptor and visual analogue scales. Eight subjects rated painful and near-painful heat stimuli by using visual analogue scales for intensity or unpleasantness and by choosing the most appropriate phrases from lists of intensity or unpleasantness descriptors. In the intensity dimension, the relationship between perception and stimulus temperature was essentially identical whether calculated from the visual analogue or verbal descriptor scales. However, data derived from the verbal descriptor scales revealed that subjects rated the painful temperatures as relatively more intense than unpleasant; this difference could not be detected using the visual analogue scales. These results confirm that both visual analogue and verbal descriptor techniques successfully quantify sensory intensity and affective aspects of pain, but that verbal descriptors may provide the more sensitive tool for separating intensity and unpleasantness.

Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception.

We have recently demonstrated that humans report heat stimuli as less painful when presented concurrently with a second noxious stimulus applied to another part of the body. Previous neurophysiological studies have shown that similar heterotopically applied noxious stimuli selectively and completely inhibit the activity of wide-dynamic-range (WDR) neurons in the dorsal horn - a phenomenon termed diffuse noxious inhibitory controls (DNICs). Taken together, these 2 lines of evidence suggest that activation of WDR cells may be necessary for normal perception of pain. Recent studies in the behaving monkey have additionally shown that WDR neurons respond to small changes in noxious heat stimuli better than do high threshold neurons, thus indicating a more specific role for WDR neurons in sensory-discriminative aspects of pain perception. If DNICs do indeed selectively and completely inhibit the activity of WDR neurons, then a heterotopically applied noxious stimulus should selectively interfere with a subject's ability to discriminate noxious stimuli. This hypothesis was tested using a noxious heat discrimination task and a cold water (5 degrees C) diffuse noxious stimulus. We found that the ability to detect small changes (0.4-0.8 degrees C) in painful heat stimuli applied to the face decreases when the person's hand is submerged in painfully cold water (P = 0.005) and that this effect persists, to a lesser extent, after the hand is removed from water. Control tasks, using visual stimuli, demonstrated that the modulation of nociceptive discrimination was not a generalized effect on sensory perception; other control measures indicated that the results could not be attributed to distraction, fatigue or changes in response bias.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffuse noxious inhibitory controls (DNICs): psychophysical evidence in man for intersegmental suppression of noxious heat perception by cold pressor pain.

Counterirritation, the phenomenon of one painful stimulus reducing pain caused by a second noxious stimulus, has been recognized clinically for decades. Recently a physiological mechanism to explain counterirritation was described and termed diffuse noxious inhibitory controls (DNICs). Nevertheless, few psychophysical studies have examined systematically the effects of a noxious conditioning stimulus on pain perception. The present study examined the perception of painful heat stimuli on the face before, during and after the subject submerged a hand in painfully cold water (5 degrees C) for 5 min (cold pressor pain). We found that the subjects' ratings of the heat stimuli were significantly, although not completely, reduced during the cold pressor pain; this attenuation of pain perception continued after the noxious conditioning stimulus was withdrawn. Similarly, the pain threshold was significantly increased from 45.7 degrees C to 47.3 degrees C while the hand was in cold water and this threshold remained elevated after the cold water was terminated. Since DNICs have been found to completely and selectively inhibit the activity of only one type of pain transmission neuron (wide dynamic range), our data suggest that these neurons are involved in the perception of pain intensity. However, the persistence of residual pain perception in the presence of noxious conditioning stimuli indicates the importance of other nociceptive pathways.