Pain Sensitivity Modifies Risk of Injury-Related Temporomandibular Disorder.

This study evaluates contributions of jaw injury and experimental pain sensitivity to risk of developing painful temporomandibular disorder (TMD). Data were from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) nested case-control study of incident painful TMD. Injury and subsequent onset of painful TMD were monitored prospectively for ≤5 y in a community-based sample of 409 US adults who did not have TMD when enrolled. At baseline, thermal-pressure and pinprick pain sensitivity, as potential effect modifiers, were measured using quantitative sensory testing. During follow-up, jaw injury from any of 9 types of potentially traumatic events was determined using quarterly (3-monthly) health update questionnaires. Study examiners classified incident painful TMD, yielding 233 incident cases and 176 matched controls. Logistic regression models, estimated incidence odds ratios (IORs), and 95% confidence limits (CLs) were used for the association between injury and subsequent onset of painful TMD. During follow-up, 38.2% of incident cases and 13.1% of controls reported 1 or more injuries that were 4 times as likely to be intrinsic (i.e., sustained mouth opening or yawning) as extrinsic (e.g., dental visits, whiplash). Injuries due to extrinsic events (IOR = 7.6; 95% CL, 1.6-36.2), sustained opening (IOR = 5.4; 95% CL, 2.4-12.2), and yawning (IOR = 3.4; 95% CL, 1.6-7.3) were associated with increased TMD incidence. Both a single injury (IOR = 6.0; 95% CL, 2.9-12.4) and multiple injuries (IOR = 9.4; 95% CL, 3.4,25.6) predicted greater incidence of painful TMD than events perceived as noninjurious (IOR = 1.9; 95% CL, 1.1-3.4). Injury-associated risk of painful TMD was elevated in people with high sensitivity to heat pain (IOR = 7.4; 95% CL, 3.1-18.0) compared to people with low sensitivity to heat pain (IOR = 3.9; 95% CL, 1.7-8.4). Jaw injury was strongly associated with elevated painful TMD risk, and the risk was amplified in subjects who had enhanced sensitivity to heat pain at enrollment. Commonly occurring but seemingly innocuous events, such as yawning injury, should not be overlooked when judging prognostic importance of jaw injury.

Vigilance behaviors and EEG activity in sustained attention may affect acute pain.

During Sustained Attention to stimuli across many modalities neural activity often decreases over time on task, while Errors in task performance increase (Vigilance Decrement). Sustained Attention to pain has rarely been investigated experimentally despite its clinical significance. We have employed a Sustained Attention protocol (Continuous Performance Task, CPT) in which the subject counts painful laser stimuli (targets) when they occur randomly in a prolonged train of nonpainful nontargets. We hypothesize that the magnitude of the poststimulus oscillatory power divided by baseline power (Event-Related Spectral Perturbation, ERSP - scalp EEG) over Frontoparietal structures will decrease at all frequencies with time on task, while Beta ERSP (14-30Hz) will be correlated with Error Rates in performance of the CPT. During the CPT with a painful target ERSP was found in four separate Windows, as defined by both their frequency band and the time after the stimulus. A Vigilance Decrement was found which confirms that Sustained Attention to pain was produced by this CPT. In addition, Error Rates was correlated inversely with laser energy, and with ratings of pain unpleasantness and salience. Error Rates also were related directly to the Beta ERSP Window at scalp EEG electrodes over the central sulcus. Over time on task, the ERSP magnitude decreased in Alpha (8-14Hz) Window, was unchanged in early and late Delta/Theta Windows (0-8Hz), and increased in the Beta Window. The increase in Beta ERSP and a decrease in the Alpha ERSP occurred at the same EEG electrode over the parietal lobe to a significant degree across subjects. Overall, Beta activity increases with time on task, and with higher Error Rates as in the case of other modalities. In the case of pain increased Errors correspond to misidentification of painful and nonpainful stimuli and so modulate the sensation of pain under the influence of Sustained Attention.

Painful Temporomandibular Disorder: Decade of Discovery from OPPERA Studies.

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a "symptom iceberg" when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA's separate case-control study. The puzzle was resolved in OPPERA's nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD's onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

COMT Diplotype Amplifies Effect of Stress on Risk of Temporomandibular Pain.

When measured once, psychological stress predicts development of painful temporomandibular disorder (TMD). However, a single measurement fails to characterize the dynamic nature of stress over time. Moreover, effects of stress on pain likely vary according to biological susceptibility. We hypothesized that temporal escalation in stress exacerbates risk for TMD, and the effect is amplified by allelic variants in a gene, catechol-O-methyltransferase (COMT), regulating catechol neurotransmitter catabolism. We used data from the Orofacial Pain: Prospective Evaluation and Risk Assessment prospective cohort study of 2,707 community-dwelling adults with no lifetime history of TMD on enrollment. At baseline and quarterly periods thereafter, the Perceived Stress Scale (PSS) measured psychological stress. Genotyped DNA from blood samples determined COMT diplotypes. During follow-up of 0.25 to 5.2 y, 248 adults developed examiner-verified incident TMD. PSS scores at baseline were 20% greater (P < 0.001) in adults who developed incident TMD compared with TMD-free controls. Baseline PSS scores increased by 9% (P = 0.003) during follow-up in cases but remained stable in controls. This stress escalation was limited to incident cases with COMT diplotypes coding for low-activity COMT, signifying impaired catabolism of catecholamines. Cox regression models confirmed significant effects on TMD hazard of both baseline PSS (P < 0.001), modeled as a time-constant covariate, and change in PSS (P < 0.001), modeled as a time-varying covariate. Furthermore, a significant (P = 0.04) interaction of COMT diplotype and time-varying stress showed that a postbaseline increase of 1.0 standard deviation in PSS more than doubled risk of TMD incidence in subjects with low-activity COMT diplotypes (hazard ratio = 2.35; 95% confidence limits: 1.66, 3.32), an effect not found in subjects with high-activity COMT diplotypes (hazard ratio = 1.42; 95% confidence limits: 0.96, 2.09). Findings provide novel insights into dynamic effects of psychological stress on TMD pain, highlighting that effects are most pronounced in individuals whose genetic susceptibility increases responsiveness to catecholamine neurotransmitters.

Sleep apnea symptoms and risk of temporomandibular disorder: OPPERA cohort.

The authors tested the hypothesis that obstructive sleep apnea (OSA) signs/symptoms are associated with the occurrence of temporomandibular disorder (TMD), using the OPPERA prospective cohort study of adults aged 18 to 44 years at enrollment (n = 2,604) and the OPPERA case-control study of chronic TMD (n = 1,716). In both the OPPERA cohort and case-control studies, TMD was examiner determined according to established research diagnostic criteria. People were considered to have high likelihood of OSA if they reported a history of sleep apnea or ≥ 2 hallmarks of OSA: loud snoring, daytime sleepiness, witnessed apnea, and hypertension. Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence limits (CL) for first-onset TMD. Logistic regression estimated odds ratios (OR) and 95% CL for chronic TMD. In the cohort, 248 individuals developed first-onset TMD during the median 2.8-year follow-up. High likelihood of OSA was associated with greater incidence of first-onset TMD (adjusted HR = 1.73; 95% CL, 1.14, 2.62). In the case-control study, high likelihood of OSA was associated with higher odds of chronic TMD (adjusted OR = 3.63; 95% CL, 2.03, 6.52). Both studies supported a significant association of OSA symptoms and TMD, with prospective cohort evidence finding that OSA symptoms preceded first-onset TMD.

Non-invasive electrical stimulation of the brain (ESB) modifies the resting-state network connectivity of the primary motor cortex: a proof of concept fMRI study.

An innovative method to obtain fMRI resting-state network maps during non-invasive electrical stimulation of the brain (ESB) was developed and tested. Five healthy volunteers participated in 2 fMRI sessions. In session one, a transcranial direct current stimulator (tDCS) was applied placing the positive electrode (31.5 cm(2)) over the right M1 of the cortex and the negative electrode (31.5 cm(2)) over the left supra-orbital area of the head. In session two, a monophasic pulsed current stimulator (tPCS) was applied using the identical electrode placement. Imaging was performed on a Siemens 3T Tim Trio scanner with a 12-channel head coil. At each session, five consecutive functional scans were obtained: 1) resting-state without stimulation (Rest-1), 2) a motor scan consisting of self-paced, bilateral finger-thumb opposition task, 3) resting-state with ESB (Stim-1), 4) resting-state without stimulation (Rest-2), and 5) resting-state with ESB, replicating Stim-1 (Stim-2). Data were analyzed using AFNI and MATLAB. For motor task fMRI analysis, a general linear model (GLM) determined the voxels in the right and left M1 that were significantly correlated with the motor task paradigm. The resting-state time series from the voxels in the R-M1 were averaged and the resulting time series used as a regressor in a GLM analysis to identify M1 connectivity maps. Connectivity maps were quantified as R(2) values, and then combined to give overlap maps for each of the experimental conditions. Fourier analysis determined the energy in the normalized signal average time courses extracted from L-M1 and R-M1 for each of the resting-state scans. Both tDCS and tPCS lowered the R(2) values and energy of the averaged time course in the right and left M1 ROI. The effect of the tPCS appeared more pronounced and less variable among subjects. Applying non-invasive ESB during fMRI scanning may down regulate the motor cortex's resting-state network connectivity.

Guidelines and recommendations for assessment of somatosensory function in oro-facial pain conditions--a taskforce report.

The goals of an international taskforce on somatosensory testing established by the Special Interest Group of Oro-facial Pain (SIG-OFP) under the International Association for the Study of Pain (IASP) were to (i) review the literature concerning assessment of somatosensory function in the oro-facial region in terms of techniques and test performance, (ii) provide guidelines for comprehensive and screening examination procedures, and (iii) give recommendations for future development of somatosensory testing specifically in the oro-facial region. Numerous qualitative and quantitative psychophysical techniques have been proposed and used in the description of oro-facial somatosensory function. The selection of technique includes time considerations because the most reliable and accurate methods require multiple repetitions of stimuli. Multiple-stimulus modalities (mechanical, thermal, electrical, chemical) have been applied to study oro-facial somatosensory function. A battery of different test stimuli is needed to obtain comprehensive information about the functional integrity of the various types of afferent nerve fibres. Based on the available literature, the German Neuropathic Pain Network test battery appears suitable for the study of somatosensory function within the oro-facial area as it is based on a wide variety of both qualitative and quantitative assessments of all cutaneous somatosensory modalities. Furthermore, these protocols have been thoroughly described and tested on multiple sites including the facial skin and intra-oral mucosa. Standardisation of both comprehensive and screening examination techniques is likely to improve the diagnostic accuracy and facilitate the understanding of neural mechanisms and somatosensory changes in different oro-facial pain conditions and may help to guide management.

Spatial attention to thermal pain stimuli in subjects with visual spatial hemi-neglect: extinction, mislocalization and misidentification of stimulus modality.

One approach to the study of disordered spatial attention is to carry out tests of extinction, in which stimuli are detected on the left when they are presented on the left alone, but not when both sides are stimulated simultaneously in a dual simultaneous stimulation (DSS) protocol. Extinction has been documented for multiple sensory modalities, but not for thermal pain stimuli, to our knowledge. We now test the hypothesis that subjects with visual spatial neglect (hemi-neglect) will have alterations in thermal pain sensation which are related to abnormal spatial attention. The results demonstrate that thermal pain extinction of hot and cold pain stimuli occurs in a proportion of subjects with hemi-neglect. In the subjects with visual spatial hemi-neglect but without thermal pain extinction, the sensation of the thermal pain stimulus on the affected (left) side was not extinguished but was often localized to the unaffected (right) side, and the submodality of the stimulus (cold or hot) was often misidentified. Ratios indicating the magnitude of extinction, mislocalization and misidentification were significantly larger on the left side of subjects with visual spatial neglect than in healthy controls or in controls with stroke but without hemineglect. The proportion of subjects with thermal pain extinction, mislocalization, or misidentification was significantly higher in subjects with hemi-neglect than those in either control group. These results demonstrate that disordered attention exerts a powerful effect upon the perception of both the location and the quality of thermal pain stimuli.

Altered pain and thermal sensation in subjects with isolated parietal and insular cortical lesions.

Studies of sensory function following cortical lesions have often included lesions which multiple cortical, white matter, and thalamic structures. We now test the hypothesis that lesions anatomically constrained to particular insular and parietal structures and their subjacent white matter are associated with different patterns of sensory loss. Sensory loss was measured by quantitative sensory testing (QST), and evaluated statistically within patients relative to normal values. All seven subjects with insular and/or parietal lesions demonstrated thermal hypoesthesia, although the etiology of the lesions was heterogeneous. Cold and heat hypoalgesia were only found in the subject with the most extensive parietal and insular lesion, which occurred in utero. Cold allodynia occurred clinically and by thresholds in two subjects with isolated ischemic lesions of the posterior insular/retroinsular cortex, and by thresholds in two subjects with a lesion of parietal cortex with little or no insular involvement. Central pain occurred in the two subjects with clinical allodynia secondary to isolated lesions of the posterior insular/retroinsular cortex, which spared the anterior and posterior parietal cortex. These results suggest that nonpainful cold and heat sensations are jointly mediated by parietal and insular cortical structures so that lesions anywhere in this system may diminish sensitivity. In contrast, thermal pain is more robust requiring larger cortical lesions of these same structures to produce hypoalgesia. In addition, cold allodynia can result from restricted lesions that also produce thermal hypoesthesia, but not from all such lesions.

Cold stimuli evoke potentials that can be recorded directly from parasylvian cortex in humans.

Anatomic, imaging, and lesion studies suggest that insular or parietal opercular cortical structures mediate the sensation of nonpainful cold. We have now tested the hypothesis that cold stimuli evoke electrical responses from these cortical structures in humans. We recorded the response to cold stimuli from electrodes implanted directly over parasylvian cortex for the investigation of intractable seizures. The results demonstrate that slow potentials can be evoked consistently over structures adjacent to the sylvian fissure in response to nonpainful cold. The polarity of these cold evoked potentials (EPs) for electrodes above the sylvian fissure is opposite to those below. These results suggest that the generator of cold EPs is close to the sylvian fissure in the parietal operculum or insula.

Regional intensive and temporal patterns of functional MRI activation distinguishing noxious and innocuous contact heat.

Cortical responses to painful and nonpainful heat were measured using functional magnetic resonance imaging (fMRI) region of interest analysis (ROI) of primary somatosensory cortex (S1), secondary somatosensory cortex (S2), anterior cingulate (ACC), supplementary motor area (SMA), insula, and inferior frontal gyrus (IFG). Previous studies indicated that innocuous and noxious stimuli of different modalities produce responses with different time courses in S1 and S2. The aim of this study was to 1) determine whether temporally distinct nociceptive blood oxygen level-dependent (BOLD) responses are evoked in multiple somatosensory processing cortical areas and 2) whether these responses discriminate small noxious stimulus intensity differences. Thirty-three subjects underwent fMRI scanning while receiving three intensities of thermal stimuli, ranging from innocuous warm (41 degrees C) to 1 degrees C below tolerance, applied to the dorsum of the left foot. Innocuous and noxious responses were distinguishable in contralateral S1, the mid-ACC, and SMA. The peak of the nociceptive response was temporally delayed from the innocuous response peak by 6-8 s. Responses to noxious but not to innocuous stimuli were observed in contralateral posterior insula. Responses to innocuous and noxious stimuli were not statistically different in contralateral S2. In contralateral S1 only, the nociceptive response could differentiate heat stimuli separated by 1 degrees C. These results show that 1) multiple cortical areas have temporally distinguishable innocuous and noxious responses evoked by a painfully hot thermode, 2) the nociceptive processing properties vary across cortical regions, and 3) nociceptive responses in S1 discriminate between painful temperatures at a level unmatched in other cortical areas.

Quantitative assessment of neuropathic pain.

Quantitative sensory testing (QST) refers to a group of protocols that allows for quantitative measures of somesthetic function. Several protocols evaluate perceptual threshold, whereas others evaluate perception of stimuli above threshold. Each protocol has its own advantages and disadvantages, but one must always weigh a trade-off between accuracy (with longer protocols) and expediency (with shorter protocols). In assessing patients with neuropathic pain, one is interested in both positive and negative sensory symptoms. QST studies, using either neuropathic pain patients or healthy volunteers who have been rendered temporarily hyperalgesic, have demonstrated that pain abnormalities can be modality specific. The fact that various pain abnormalities can exist independently of each other suggests that (at least partially) different neuropathologic processes are responsible for each one. Current research suggests that both peripheral sensitization and central sensitization play a role in these abnormal pain conditions, and identification of precise neuropathologic mechanisms is under active investigation.

Peripheral coding of tonic mechanical cutaneous pain: comparison of nociceptor activity in rat and human psychophysics.

These experiments investigated temporal summation mechanisms of tonic cutaneous mechanical pain. Human volunteers provided psychophysical estimates of pain intensity, which were compared with discharge patterns of rat cutaneous nociceptors tested with identical stimulus protocols. Human subjects made either intermittent or continuous ratings of pain intensity during stimulation of the skin between the thumb and first finger. Stimulus intensities of 25, 50, and 100 g were applied with a probe of contact area of 0.1 mm(2) for 2 min. Pain perception significantly increased during stimulation (temporal summation) for the 50- and 100-g stimulus intensities. Sequential conduction block of the myelinated fibers supplying the stimulated skin was used to investigate the role of A-fiber mechanoreceptors and nociceptors in this temporal summation. Conduction block of the Abeta fibers resulted in an increase in mechanically evoked pain estimates and an increase in temporal summation, consistent with loss of Abeta-mediated inhibition. When only conduction in the unmyelinated fibers remained, pain estimates were reduced to the preblock levels, but temporal summation was still present. Electrophysiological recordings were made from filaments of the sciatic nerve supplying receptors in the plantar skin of barbiturate-anesthetized rats. Forty units fulfilled the identification criteria for nociceptors: 20 A-fiber and 20 C-fiber nociceptors. Each unit was characterized by recording its responses to graded mechanical and heat stimuli. Nociceptors were also tested with stimuli identical to those applied to the human subjects. The responses of all units to sustained mechanical stimuli were adaptive-that is, they exhibited a gradual decline in response with time. However, the time course of adaptation varied among units. All the C-fiber nociceptors and one-half of the A-fiber nociceptors had rapidly adapting responses. The remainder of the A-fibers displayed slowly adapting responses. One-third of all units also showed short-duration increases in firing rate during stimulation. The latency after stimulus onset of this rate acceleration was inversely related to stimulus intensity. Despite the apparent disparity between perceptual temporal summation and nociceptor adaptation, central and peripheral mechanisms are proposed that can reconcile the relationship between nociceptor activity and pain perception.

Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat.

Tissue injuries commonly cause an increase in pain sensitivity, so that normally painful stimuli become more painful (hyperalgesia), and those usually associated with nonnoxious sensations evoke pain (allodynia). The neural bases for these sensory phenomena have been explored most extensively using heat injuries and experimental arthritis as models. Heat sensitization of cutaneous nociceptors is observed after burns, and sensitization of articular afferents to limb movements occurs after knee joint inflammation. These are likely to be peripheral mechanisms of hyperalgesia. Others, using different models of peripheral inflammation, have only rarely found mechanical sensitization of cutaneous nociceptors. In general these studies have failed to evaluate suprathreshold mechanical sensitivity, which has led to the concept of enhanced spinal cord processing ("central sensitization") serving as the neural substrate for mechanical hyperalgesia. In the current experiments, the mechanical and heat responses of cutaneous nociceptors supplying the glabrous skin of the rat hindpaw were studied 16-24 h after induction of acute inflammation with complete Freund's adjuvant. Single-fiber recordings were made from nociceptors in the sciatic nerve of barbiturate-anesthetized animals, and their responses compared with those obtained from nociceptors tested identically in normal animals. Nociceptors were characterized by the following: 1) graded mechanical stimuli (5-90 g) delivered with probes of tip area of 1 and 0.1 mm(2), 2) their adaptive responses to 2-min mechanical stimuli at three intensities, and 3) their responses to graded heat stimuli (40-50 degrees C). Forty-three nociceptors were studied in the inflamed state; 20 were A fibers, and the remainder were C fibers. Mechanical thresholds, determined with calibrated monofilaments, were not significantly different from controls. Sensitization to suprathreshold mechanical stimuli was observed for both A- and C-fiber nociceptors, although it was greater for the A fibers. Similarly, sensitization during testing of adaptive properties of A- and C-fiber nociceptors was seen, although it was limited to the dynamic (initial) and not the static (plateau) phase of the response. Heat sensitization was observed in 25% of A-fiber nociceptors, but the responses of C fibers to heat were depressed. Other indicators of neuronal sensitization, such as spontaneous activity and expanded receptive fields, were also observed. It was concluded that the mechanical hyperalgesia caused by peripheral inflammation could be explained by nociceptor sensitization. Central mechanisms cannot be completely ruled out as contributing to such hyperalgesia, although their role may be much smaller than previously envisaged.

Modality-specific hyper-responsivity of regenerated cat cutaneous nociceptors.

1. Experiments were performed on anaesthetized cats to investigate the receptive properties of regenerated cutaneous tibial nerve nociceptors, and to obtain evidence for coupling between them and other afferent fibres as being possible peripheral mechanisms involved in neuropathic pain. These properties were studied 6-7 months after nerve section and repair. 2. Recordings were made from 25 regenerated nociceptors; 14 were A fibres and the remainder were C fibres. Their receptive field sizes and conduction velocities were similar to controls. There was no significant difference between their mechanical thresholds and those of a control population of nociceptors. 3. Regenerated nociceptors were significantly more responsive to suprathreshold mechanical stimuli than were uninjured control fibres. This increase in mechanical sensitivity occurred in both A and C fibres, although A fibres showed a greater increase in mechano-sensitivity than C fibres. Over half of the regenerated nociceptors (13/25) showed after-discharge to mechanical stimuli which was never seen in controls; the mean firing rate during this period of after-discharge was significantly related to both stimulus intensity and stimulus area. 4. There was no significant difference between the heat encoding properties of regenerated nociceptors and control nociceptors. Cold sensitivity was similarly unchanged. Thus, abnormal peripheral sprouting was unlikely to account for the increased mechanical sensitivity of the regenerated fibres. None of the regenerated nociceptors were found to be coupled to other fibres. 5. These results suggest that the clinical observation of mechanical hyperalgesia in patients after nerve injury may have a peripheral basis. Based on this model, other signs of neuropathic pain (i.e. tactile or thermal allodynia) are more likely to be due to altered central processing.

A longitudinal study of somesthetic perceptual disorders in an individual with a unilateral thalamic lesion.

Several aspects of tactile, thermal and pain perception were evaluated in an individual (R.S.) with a hemorrhagic lesion centered in her left lateral thalamus. Over a 4-year period, psychophysical evaluations were undertaken every 6-8 months, and five magnetic resonance (MR) studies were conducted. Early tests (1991-1992) revealed large contralateral deficits in R.S.'s perception of touch, innocuous temperature, and mechanically evoked cutaneous pain--more so for the upper versus the lower extremity. R.S. showed a similar pattern for heat pain sensitivity, but a more modest deficit than for mechanically evoked pain. She showed a deficit for cold pain sensitivity on her foot, but not for her hand. Thresholds for all types of stimuli ipsilateral to the lesion were within a normative range. Late in 1993, R.S. demonstrated improvements in sensory capacity for touch and mechanically evoked pain contralaterally, although deficits were still evident. During the same period, heat pain sensitivity improved contralaterally, and strikingly, a permanent, ipsilateral hypersensitivity to heat pain developed in her hand. Throughout the entire testing period, R.S.'s ratings of perceived unpleasantness matched the patterns of perceived pain intensity. Thus, the discriminative and the affective dimensions of her pain would change in tandem. However, perceptible innocuous thermal stimuli evoked no affective response when applied contralaterally, despite being described as pleasant when presented ipsilaterally. Throughout the testing period, R.S. reported a persistent numbness on her right hemi-body. Only during a 3-month period in 1995 did she experience spontaneous pain, which was referred to her right foot. The only change in psychophysical performance related to her right foot was a transient but intense thermal allodynia several months prior to her spontaneous pain. The MR studies over this 4-year period showed changes in the extent of edema, gliosis and/or ischemia that could be related to perceptual changes. Thus, the conspicuous observations in this thalamic lesion case were: (i) differential effects upon the various pain modalities (mechanical, heat and cold); (ii) development of thermal allodynia without mechanical allodynia, including an ipsilateral effect; (iii) a deficit in positive affective responses to temperature; and (iv) the different time courses for changes in evoked somesthetic capacity versus spontaneous paresthesias and pathological pain.

Nociceptors and the peripheral nervous system's role in pain.

This article reviews the role that the peripheral nervous system plays in pain perception. The first section describes the functional properties of the primary sensory element-the nociceptor-and how its behavior is related to pain perception. The second section describes the current state of knowledge concerning the way our nociceptive sensing system changes as a result of tissue injury, including those changes related to sympathetic nervous system modulation of pain.

Spatial summation of perceived pressure, sharpness and mechanically evoked cutaneous pain.

Psychophysically, spatial summation can be demonstrated as a decrease in threshold accompanying an increased field of stimulation. The present study examined to what extent different mechanically evoked percepts (pressure, sharpness, and pain) show spatial summation. Various probes were used to apply prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The threshold for three perceptual qualities showed differing degrees of spatial summation: sharpness showed no statistically significant spatial summation; pain demonstrated some significant summation (46% on average); pressure showed the greatest degree of spatial summation (76% on average). The lack of significant spatial summation for sharpness threshold is consistent with the theory that perceived sharpness can be evoked by near threshold activity of a single nociceptor. The modest amount of spatial summation for pain implies that distinctly suprathreshold activation of nociceptors is required for mechanically evoked pain perception, and such input summates centrally, but not completely. The greater spatial summation observed for pressure vs. pain thresholds implies a greater degree of central summation for slowly adapting mechanoreceptors vs. nociceptors.

Mechanical response properties of nociceptors innervating feline hairy skin.

1. The responses of feline cutaneous nociceptors were examined in vivo by systematically manipulating the intensive and spatial dimensions of mechanical stimulation. A computer-controlled motor was used to apply prescribed forces (5-90 g) to a nociceptor's receptive field, with flat-tipped, cylindrical probes of various sizes (contact areas: 0.1-5.0 mm2). The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing for comparisons of the two data sets. 2. With a ramp-and-hold stimulus of controlled force, most nociceptors showed a slowly adapting (SA) response throughout the stimulus. In this way, nociceptors resembled low-threshold SA mechanoreceptors. However, in contrast to SA mechanoreceptors, nociceptors failed to exhibit an onset burst of activity associated with the stimulus ramp. Nineteen percent (6 of 31) of the nociceptors often showed the opposite trend during the stimulus, e.g., a gradually increasing firing rate. Most of these nociceptors (5 of 6) had particularly high mechanical thresholds. 3. With 30 stimuli repeated at short intervals (6-8 s), response rates tended to decrease across trials. This phenomenon was most evident with more intense stimuli. When two series of stimuli were separated by 4-5 min, there was no apparent trend of reduced responsiveness between series. 4. Overall, nociceptors responded in an orderly way to variations in force and probe size. For a given probe size, larger forces produced greater responses; for a given force, smaller probes produced greater responses. The relationship between probe size and force was best described as an even tradeoff between force and a linear dimension of the probe (i.e., probe perimeter), rather than the area of the probe. Thus a given pressure (force/area) did not evoke the same response from nociceptors as probe size was varied. 5. There were two significant differences in the mechanical responsiveness between A fiber and C fiber nociceptors. First, for a given set of stimuli, A fiber nociceptors exhibited a greater response rate than the C fiber nociceptors. Second, the A fiber nociceptors exhibited a greater differential response related to probe size than the C fiber nociceptors. On the basis of these two features, the A fiber nociceptors' response profiles showed a closer parallel with previously reported human pain thresholds than the C fiber nociceptors did. 6. When the nociceptors were subdivided as to their mechanical threshold, those with lower thresholds [mechanically sensitive afferents (MSAs)] showed a response saturation with the more intense stimuli. On average, the stimulus levels at which saturation occurred were close to human pain threshold. Those nociceptors with higher thresholds [mechanically insensitive afferents (MIAs)] did not show such saturation. Thus only the MIAs appeared to have the capacity to unambiguously encode mechanical stimulus intensities above pain threshold. The MSAs, on the other hand, exhibited their greatest dynamic response range near the threshold for nonpainful sharpness. Thus the group of afferents commonly defined as nociceptors exhibit a heterogeneity of mechanical response properties, which may serve functionally different roles for perception.