Endometriosis is associated with central sensitization: a psychophysical controlled study.

Endometriosis is a pain syndrome representing a major cause of pelvic pain in women of reproductive age. The aim of this study was to test the hypothesis that persistent nociceptive input from endometriotic tissues leads to central sensitization manifested by somatic hyperalgesia and increased referred pain areas to experimental saline-induced muscle pain in patients with endometriosis, compared to healthy control subjects. Ten women with laparoscopically confirmed endometriosis and 10 healthy, age-matched women participated in the study. Hypertonic saline (0.5 mL, 5.8%) was injected intramuscularly, in random succession, into 1 site of menstrual pain referral (the multifidus muscle at the low back) and into 1 non-pain control site (first dorsal interosseous muscle [FDI] of the hand). The post-saline pain intensity and pain areas at the FDI were significantly greater in patients with endometriosis than in control subjects (P <.05) but were not different between the groups for the back. An absence of enhancement of post-saline pain responses at the back in the endometriosis group suggests that saline-induced pain at the back appears to activate segmental inhibitory systems in patients with endometriosis. Manifestation of central sensitization in women with endometriosis is demonstrated by increased muscle nociceptor input in the form of increased post-saline pain intensity, pain areas at the FDI, and hypersensitivity to pressure stimulation. These findings provide new insights into the complex pain mechanisms associated with endometriosis.     

Remembering the dynamic changes in pain intensity and unpleasantness: A psychophysical study

This study investigated the short-term memory of dynamic changes in acute pain using psychophysical methods. Pain intensity or unpleasantness induced by painful contact-heat stimuli of 8, 9, or 10 s was rated continuously during the stimulus or after a 14-s delay using an electronic visual analog scale in 10 healthy volunteers. Because the continuous visual analog scale time courses contained large amounts of redundant information, a principal component analysis was applied to characterize the main features inherent to both the concurrent rating and retrospective evaluations. Three components explained about 90% of the total variance across all trials and subjects, with the first component reflecting the global perceptual profile, and the second and third components explaining finer perceptual aspects (eg, changes in slope at onset and offset and shifts in peak latency). We postulate that these 3 principal components may provide some information about the structure of the mental representations of what one perceives, stores, and remembers during the course of few seconds. Analysis performed on the components confirmed significant memory distortions and revealed that the discriminative information about pain dimensions in concurrent ratings was partly or completely lost in retrospective ratings. Importantly, our results highlight individual differences affecting these memory processes. These results provide further evidence of the important transformations underlying the processing of pain in explicit memory and raise fundamental questions about the conversion of dynamic nociceptive signals into a mental representation of pain in perception and memory.     

Referred pain from the trochlear region in tension-type headache: a myofascial trigger point from the superior oblique muscle

BACKGROUND: Tension-type headache (TTH) is a prototypical headache in which myofascial trigger points (MTrPs) can play an important role. To our knowledge, MTrPs in the muscle tissues of the trochlear region, ie, the superior oblique muscle (SOM), have not been previously mentioned, and a referred pain pattern from this region has never been reported. OBJECTIVE: To describe the referred pain from the trochlear area based on the examination of MTrPs in the SOM in patients with episodic and chronic TTH (CTTH). DESIGN: A blinded, controlled study. METHODS: The trochlear region was examined in 15 patients with CTTH, 15 patients with episodic TTH (ETTH), and 15 control subjects. Referred pain elicited by different maneuvers performed during manual palpation, ie, maintained pressure, active muscle contraction, and stretching of the muscle, was assessed with a visual analogue scale. Patients with ETTH were examined on days when they were headache-free, whereas CTTH patients were examined on days in which headache intensity was less than 4 points on a 10-cm horizontal visual analogue scale. RESULTS: Eighty-six percent of patients with CTTH and 60% with ETTH had referred pain that originated from MTrPs in the SOM, while only 27% of the controls reported referred pain. This pain was perceived as a deep ache located at the retro-orbital region, sometimes extending to the supra-orbital region or the homo-lateral forehead. Pain intensity was greater in CTTH patients than in ETTH patients or control subjects (P < .001). CONCLUSIONS: MTrPs in the SOM may evoke a typical referred pain pattern in patients with TTH. The presence of a myofascial disorder in the trochlear region might contribute to the pathogenesis of TTH.     

Referred pain from amputation stump trigger points into the phantom limb

OBJECTIVES: The aim of the study was to examine whether/how myofascial stump trigger points (TPs) after lower leg amputations are able to produce stump pain (SP), phantom pain (PP), and sensations (PS) in the phantom limb. METHODS: Palpation of the 5 most striking stump TPs of 30 leg amputees (12 transfemoral, 18 transtibial) was documented in a standardized manner. Patients were asked to localize SP, PP, and PS. RESULTS: Of 150 TPs, 14 produced involuntary stump movements and 10 stump fasciculations. Dorsal PP after ventral TP palpation occurred as well as PP in the toes from TPs near the hip. Of 30 patients, 20 reported PS and 8 PP; 60 of 150 TPs produced PS and 17 PP. Phantom phenomena were localized in 62.8% in the toes (1st toe 19.8%, toes 2-5 about 10% each), 17.9% midfoot, and the rest were more proximal. TPs were localized more in the lateral/dorsal stump than medial/ventral. About 70% of the TPs were found between 3 and 7 cm from the stump end, those with toe projections more distal than those with tibial projections. CONCLUSIONS: Myofascial TPs in amputation stumps are common and able to produce sensations and pain in the phantom limb. Most reported experiences were localized in the toes, as phantom pain usually is. There seems to be a "stump representation" and it seems possible that "referred TP pain" and "phantom pain" may develop from similar origin.     

Cold-evoked pain varies with skin type and cooling rate: a psychophysical study in humans.

The psychophysical responses to noxious cold stimulation of the skin in normal human subjects are not well understood. Continuous pain ratings with the visual analogue scale is an important method to assess these responses. In this study, we addressed several important issues about the parameters with which stimuli are delivered: the type of skin stimulated, the rate with which the stimulus temperature decreases, and the dimension of the pain rated by subjects. Cold stimuli were delivered to the thenar eminence (glabrous skin) and the dorso-lateral hand (hairy skin) via a 4 cm(2) Peltier-type stimulator. Cold and pain thresholds were determined by the method of limits (MOL). A computerized visual analogue scale (VAS) was used to obtain continuous ratings of pain intensity and affect. The McGill Pain Questionnaire (MPQ) was used to assess the quality of cold-evoked pain. Supra-threshold stimuli (34 degrees C base) were delivered at 0.5, 1 or 2 degrees C/s to 2 degrees C, held for 20s and returned to baseline at 9 degrees C/s. These studies revealed: (1) Cold thresholds, measured with MOL, were lower (i.e. occurred at higher absolute temperatures) for the hairy skin of the dorso-lateral hand compared to the glabrous skin of the thenar eminence. (2) A similar pattern was evident for cold induced pain thresholds with MOL at 1.5 degrees C/s and with intensity and affect VAS scales at 0.5 and 1 degrees C/s. (3) Exponents for supra-threshold ratings fit to power functions were larger for the glabrous skin site than the hairy skin site regardless of cooling rate or dimension of pain measured. (4) All pain indices were higher for slower cooling rates. (5) No significant differences were found in the pain indices for pain ratings of intensity and affect. (6) A substantial proportion of subjects chose words representing paradoxical heat with the MPQ. (7) Painful paradoxical heat sensations occurred most often during cooling, while innocuous warm sensations mainly occurred during the rewarming phase.     

Referred pain from intraneural stimulation of muscle fascicles in the median nerve

Microelectrode recordings were obtained from 118 cutaneous and 26 muscle fascicles in the intact median nerves of healthy human subjects. The exploring electrodes were also used for painful electrical stimulation of the identified fascicles. Cutaneous pain was accurately projected to fields within the median innervation territory. Deep pain was projected to muscles innervated by the median nerve, but in 7 experiments it was also segmentally referred to muscles in the ipsilateral upper arm, axilla or chest. Reaction time measurements indicated that referred pain was conveyed by afferent group III fibres from muscle, but did not exclude a possible contribution by group IV fibres. Referred pain was influenced by temporal and spatial summation of the afferent inflow. The magnitude of referred pain was positively correlated to the stimulation frequency of deep nociceptive fibres. The results from this study on experimentally induced pain confirm clinical observations of proximal referral of pain in patients with median nerve entrapment, and prompt consideration of possible involvement of nerve fascicles supplying deep structures in the forearm or hand in the differential diagnosis of pain in the chest and upper arm.     

Serotonin infusions inhibit sensory input from the dural vasculature.

Intravenous infusions of serotonin (5-hydroxtryptamine creatinine sulphate, 5HT, 50-300 microg/kg/min) in cats reversibly inhibited the responses of cervical spinal cord neurons to electrical stimulation of the superior sagittal sinus. Inhibition developed over 20-30 min and resolved over the same time course, suggesting a dependence on accumulation of 5HT in the central nervous system. Inhibition was suppressed by prior intravenous injection of the 5HT antagonists methysergide (1 mg/kg) and methiothepin (1 mg/kg). Infusions of 5HT (50 microg/kg/min) caused a rise in whole blood levels of 5HT by a factor of 1.5 of control values. 5HT levels in platelet-free plasma rose by a factor of 50. Levels of 5HT and 5 hydroxyindole acetic acid released into the cerebrospinal fluid rose significantly. The results suggest that earlier clinical observations that 5HT infusions can ameliorate the pain of migraine may not have been due to cranial vasoconstriction alone, but could have involved a central action of 5HT.     

Dynamic adjustments of walking behavior dependent on noxious input in experimental low back pain

The aim of this study was to explore whether accelerations of the lower back during walking are temporarily attenuated by experimentally-induced low back pain, as compared with normal walking. Transient low back pain was induced by injection of 1 ml 6% hypertonic saline in the longissimus dorsi muscle in 20 healthy subjects. Acceleration was measured during walking at self-selected speeds before and repeatedly after the injection by a portable, triaxial accelerometer positioned over the L3 region. Data were subsequently adjusted for differences in walking speeds between trials and subjects. Pain was reported on a 0-10 point scale during walking until pain was no longer present. Lumbar acceleration sample mean was attenuated for the anteroposterior (P=0.002) and mediolateral (P=0.002) sensing axes as well as for the vector sum (P=0.005) at maximal pain compared to pretest values. The vertical axis showed no significant changes. Values returned to pretest level when pain was no longer present. Regardless of the initial increase and subsequent decrease in pain after injection, there was a linear relationship between pain and acceleration in 15 of the 20 subjects (0.89>/=R(2)>/=0.36, P相似文献   

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.     

Thermal and tactile sensory deficits and allodynia in a nerve-injured patient: a multimodal psychophysical and functional magnetic resonance imaging study

OBJECTIVE: A case study was conducted to examine a patient with chronic neuropathic pain of the right foot following peripheral nerve injury and characterize associated sensory abnormalities. METHODS: Multimodal psychophysical examination of the patient's affected and nonaffected foot included thermal sensibility, dynamic touch, and directional sensibility. In addition, we used functional magnetic resonance imaging to study cortical representation of brush-evoked allodynia. RESULTS: Detailed psychophysical examination revealed substantial deficits in warm, cool, and tactile perception on the injured foot. These findings indicated severe dysfunction of perceptual processes mediated by A beta, A delta, and C fibers. Despite reduced tactile perception, light touch evoked a deep burning pain in the foot. Functional magnetic resonance imaging during brushing of the patient's injured foot showed that tactile allodynia led to activation of several cortical regions including secondary somatosensory cortex, anterior and posterior insular cortex, and anterior cingulate cortex. Brushing of the patient's nonaffected foot led to fewer activated regions. DISCUSSION: The profound sensory disturbances suggest a possible deafferentation type of tactile allodynia mediated by changes within the central nervous system, such as a disruption of normal tactile or thermal inhibition of nociception. The functional magnetic resonance imaging data suggest that tactile allodynia is represented in similar brain regions as experimental pain.     

Sex differences in the associations among psychological factors and pain report: a novel psychophysical study of patients with chronic low back pain.

Previous studies have consistently suggested that there are sex differences in pain report, but there is no consensus regarding sex differences in the associations among psychological factors and pain report. This cross-sectional study used a novel, clinically relevant, psychophysical pain-induction technique to examine sex differences between sensory and affective pain report and sex differences in the association of depression, pain related anxiety, and catastrophizing with pain report. Patients with chronic low back pain (N = 53) were recruited from an outpatient spine clinic, and those consenting completed self-report measures of pain-related anxiety, depression, pain catastrophizing, and pain. A measure of induced low back pain was obtained by having study participants perform a protocol on the MedXtrade mark Low-Back Exercise Apparatus. Our results indicated that no sex differences were detected in psychological factors and self-reported or induced low back pain. However, the relationships between pain related anxiety and self-report of low back pain (z = 2.51, P < .05) and between pain-related anxiety and induced low back pain (z = 3.00, P < .05) were significantly stronger in men than women. These findings suggest that anxiety was linked to self-reported and induced low back pain for men, but not for women. PERSPECTIVE: Results of this study suggest that pain-related anxiety has a stronger association with psychophysical and clinical reports of low back pain for men.     

The late whiplash syndrome: a psychophysical study.

Some patients who have sustained whiplash injuries present with chronic widespread pain and mechanical allodynia. This single-blind, case control matched study of 43 chronic whiplash patients sought to examine psychophysical responses to non-noxious stimuli and their relationship to psychological profiles. Symptom Check List 90-R (SCL-90-R), Neck Disability Index and Shortform McGill Questionnaire were completed prior to testing. Qualitative stimuli comprised light touch, punctate pressure, moderate heat and cold. Additionally, sustained vibration was administered using a vibrameter which allowed ramping of either frequency or amplitude. Twenty-eight patients reported vibration-induced pain. No control subject experienced pain in response to vibration. No significant differences in perception threshold to vibration were noted between patients and control group. Twenty-three patients and ten control subjects reported painful responses to cold. Eleven patients and nine control subjects experienced pain in response to moderate heat. Four patients rated punctate pressure and one patient rated light touch as painful. SCL-90-R profiles revealed an overall elevated level of distress in the whiplash group. No significant difference was found between patients with and without vibration-induced pain for any dimension of the SCL-90-R. Pain in response to non-noxious stimulation over presumably healthy tissues suggests that central mechanisms are responsible for ongoing pain in at least some whiplash patients. The additional findings of pain on punctate pressure and hyperalgesic responses to heat and cold stimuli are consistent with enhanced central responsiveness to nociceptor input. These results have important therapeutic and prognostic implications.     

Persistent idiopathic facial pain exists independent of somatosensory input from the painful region: findings from quantitative sensory functions and somatotopy of the primary somatosensory cortex

In 14 patients with unilateral persistent idiopathic facial pain (PIFP), classified according to the criteria of the International Headache Society, and 16 age-matched control subjects sensory functions were examined on the face by quantitative sensory testing (QST). Additionally, the somatotopy of the primary somatosensory cortex (SI) to tactile input from the pain area was evaluated by means of magnetoencephalography. Previously reported abnormalities in PIFP as a dishabituation of the R2 component of the blink reflex and psychiatric disturbances were co-evaluated. Psychiatric evaluation included a Structured Clinical Interview for axis-I DSM IV disorders (SCID-I) and employment of the SCL-90-R and a depression scale (ADS). Thresholds to touch, pin prick, warm, cold, heat and pressure pain as well as the pain ratings to single and repetitive (perceptual wind up) painful pin prick stimuli did not indicate a significant sensory deficit or hyperactivity in the pain area when compared with the asymptomatic side nor when compared with the values of healthy control subjects. QST results were not significantly altered in patients (n=4) that showed an abnormal dishabituation of the R2 component of the blink reflex. The interhemispheric difference in distance between the cortical representation of the lip and the index finger did not differ between patients and control subjects. Psychiatric evaluation did not disclose significant abnormalities at a group level. It is concluded that PIFP is maintained by mechanisms which do not involve somatosensory processing of stimuli from the pain area.     

Corticospinal excitability is dependent on the parameters of peripheral electric stimulation: a preliminary study

Chipchase LS, Schabrun SM, Hodges PW. Corticospinal excitability is dependent on the parameters of peripheral electric stimulation: a preliminary study.

Objective

To evaluate the effect of 6 electric stimulation paradigms on corticospinal excitability.

Design

Using a same subject pre-post test design, transcranial magnetic stimulation (TMS) was used to measure the responsiveness of corticomotor pathway to biceps and triceps brachii muscles before and after 30 minutes of electric stimulation over the biceps brachii. Six different electric stimulation paradigms were applied in random order, at least 3 days apart.

Setting

Motor control research laboratory.

Participants

Healthy subjects (N=10; 5 women, 5 men; mean age ± SD, 26±3.6y).

Interventions

Six different electric stimulation paradigms with varied stimulus amplitude, frequency, and ramp settings.

Main Outcome Measure

Amplitudes of TMS-induced motor evoked potentials at biceps and triceps brachii normalized to maximal M-wave amplitudes.

Results

Electric stimulation delivered at stimulus amplitude sufficient to evoke a sensory response at both 10Hz and 100Hz, and stimulus amplitude to create a noxious response at 10Hz decreased corticomotor responsiveness (all P<0.01). Stimulation sufficient to induce a motor contraction (30Hz) applied in a ramped pattern to mimic a voluntary activation increased corticomotor responsiveness (P=0.002), whereas constant low- and high-intensity motor stimulation at 10Hz did not. Corticomotor excitability changes were similar for both the stimulated muscle and its antagonist.

Conclusions

Stimulus amplitude (intensity) and the nature (muscle flicker vs contraction) of motor stimulation have a significant impact on changes in corticospinal excitability induced by electric stimulation. Here, we demonstrate that peripheral electric stimulation at stimulus amplitude to create a sensory response reduces corticomotor responsiveness. Conversely, stimulus amplitude to create a motor response increases corticomotor responsiveness, but only the parameters that create a motor response that mimics a voluntary muscle contraction.     

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.     

Cervical spinal cord neurons receiving sensory input from the cranial vasculature

The superior sagittal sinus, middle meningeal artery or superficial temporal artery was stimulated electrically in anaesthetized cats. Field potential recordings were used to locate areas of maximum responses in the upper cervical cord, which were then further examined for responsive single units. Short latency units responded to stimulation of the superior sagittal sinus with a mean latency of 11.9 ms. Some units also responded at longer latencies in the 200-250 ms range. Spontaneous discharge rates of some units in a dorsolateral area of the cervical cord were accelerated by iontophoretic application of glutamic or homocysteic acid to these same units. Evoked action potentials were commonly multiphasic. Dorsolateral area units commonly received convergent input from two vessels and often had receptive fields on the face and limbs. Spontaneously active cells which respond to electrical stimulation were accelerated by the local application of bradykinin to the sinus and responses of dorsolateral area units could be reversibly blocked by local application of lignocaine to the sinus. It was concluded that the dorsolateral area is a relay area for the perception of pain from cranial vessels.     

A psychophysical study of endogenous analgesia: The role of the conditioning pain in the induction and magnitude of conditioned pain modulation

Endogenous analgesia (EA) can be examined experimentally using a conditioned pain modulation (CPM) paradigm. While noxious conditioning stimulation intensities (CSIs) are mainly used, it has not been fully investigated in the same experimental design whether the experienced conditioning pain level affects CPM responses. The principal goal of the present study was to characterize CPM induction and magnitudes evoked by various conditioning pain levels. Furthermore, we explored associations between conditioning pain reports and CPM responses across various CSIs. Thirty healthy, young, right‐handed males were tested with a parallel CPM paradigm. Three different CSIs (hand water‐immersion) induced mild, moderate and intense pain levels, rated 12.41±7.85, 31.57±9.56 and 58.1±11.43, respectively (0–100 numerical pain scale) (P<0.0001). Contact‐heat ‘test‐stimulus’ levels were compared before and during conditioning. Within the group, (i) CPM was induced only by the moderate and intense CSIs (Ps≤0.001); (ii) no difference was demonstrated between the magnitudes of these CPM responses. Regression analysis revealed that CPM induction was independent of the perceived conditioning pain level, but associated with the absolute CSI (P<0.0001). Conditioning pain levels were correlated across all CSIs, as were CPM magnitudes (Ps≤0.01). We conclude that among males, (i) once a CPM response is evoked by a required conditioning pain experience, its magnitude is not further affected by increasing conditioning pain and (ii) CPM magnitudes are inter‐correlated, but unrelated to conditioning pain reports. These observations may suggest that CPM responses represent an intrinsic element of an individual's EA processes, which are not significantly affected by the experienced conditioning pain.     

Chronic pain and surgery: a review of new insights from sensory testing

Chronic pain is increasingly recognized as an undesirable outcome after surgery. Predicting risk of postoperative chronic pain, as well as chronic pain prevention or treatment, requires understanding of the processes underlying its development. Quantitative sensory testing research over the last decade has made it possible to start understanding the alterations in central pain processing associated with chronic pain and its development. Chronic pain syndromes are typically characterized by a pronociceptive state of pain processing, e.g., generalized hyperalgesia as a sign of supraspinal central sensitization and poor inhibitory or even facilitatory descending modulation. In the perioperative context, development and progression of chronic pain are accompanied by signs congruent with a shift towards a pronociceptive state. Preoperatively, hyperalgesia and poor descending inhibitory modulation appear to increase the risk of subsequent chronic pain. Postoperatively, abnormal persistence and spread of hyperalgesia, compatible with rostral neuraxial spread of central sensitization, are increasingly linked to the development and progression of chronic pain. These findings, which need further confirmation, suggest that perioperative quantitative sensory testing of pain sensitivity and pain modulation has the potential to become a valuable clinical tool for assessing risk of chronic pain development and for managing its prevention and treatment.     

Visual cortical inhibitory function in migraine is not generally impaired: evidence from a combined psychophysical test with an fMRI study

A robust, visual masking test that was developed to be feasible with functional magnetic resonance imaging (fMRI) was used to examine the visual cortical inhibitory function in migraine patients with visual aura at both psychophysical and cortical levels. The study showed that the decreased visibility of a visual target was associated with a reduction in cortical activation in the primary visual cortex. The suppression of the transient on-response and after-discharge of neurons to the target was most likely to be responsible for reducing cortical activation, rendering the target less visible or invisible. The migraine patients were equally susceptible to visual masking and showed no difference in cortical activation when compared with age- and sex-matched non-headache controls, demonstrating that visual cortical inhibitory function was not impaired under the experimental conditions. Although these results are not in conflict with the general cortical hyperexcitability theory in migraine, they provide evidence to show the limitation to the theory.