Multiple mechanisms of secondary hyperalgesia

Publisher Summary This chapter discusses the multiple mechanisms of secondary hyperalgesia. The chapter defines the minimal conditions of complexity that must be fulfilled by a model of plasticity of spinal nociceptive transmission in order to explain clinical and psychophysical observations in humans. Secondary hyperalgesia is characterized by a leftward shift of the stimulus-response function for noxious mechanical stimuli. In order to define the afferent pathways involved in inducing central sensitization and in mediating the hyperalgesia to noxious mechanical stimuli, several psychophysical experiments using selective nerve block techniques is performed. Secondary hyperalgesia is likely…

389 HIGH-FREQUENCY STIMULATION-INDUCED LONG-TERM POTENTIATION (LTP) AND LOW-FREQUENCY STIMULATION-INDUCED DEPOTENTIATION (DE-LTP) OF PAIN PERCEPTION IN HUMANS

Secondary tactile hypoesthesia: a novel type of pain-induced somatosensory plasticity in human subjects

Quantitative sensory testing revealed that pain induced by intracutaneous capsaicin injection elicited secondary hyperalgesia coexisting with secondary tactile hypoesthesia. Mapping the areas of altered mechanical sensations adjacent to the capsaicin injection disclosed that the area of secondary hyperalgesia was always nested in a larger area of secondary hypoesthesia easily detected as numbness by most subjects. Psychometric functions revealed a twofold rightward shift of tactile detection (hypoesthesia), which coexisted with a more than fourfold leftward shift of pricking pain detection (hyperalgesia) in the same skin area. As a mechanism we propose a functional switch at the spinal leve…

204 PINPRICK-EVOKED POTENTIALS (PEPS): A NOVEL TOOL TO ASSESS CENTRAL SENSITISATION IN HUMANS

Corrigendum to “Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values” [Pain 123 (2006) 231–243]

a Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, Mainz, Germany b Department of Neurology, Johannes Gutenberg-University, Mainz, Germany c Division of Neurological Pain Research and Therapy, Department of Neurology, University of Kiel, Germany d Department of Pain Management, BG Kliniken Bergmannsheil, Ruhr University Bochum, Germany e Department of Neurology, Technische Universitat Munchen, Germany f Department of Anaesthesiology, Ludwig-Maximilians-Universitat Munchen, Germany g Institute of Medical Psychology and Behavioural Neurobiology, University of Tubingen, Germany h Department of Neurology, University of Freiburg, Germany i Department of Clinical and Co…

416 POTENTIATION AND DEPOTENTIATION OF PAIN PERCEPTION IN A HUMAN SURROGATE MODEL OF NOCICEPTIVE LTP

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia.

Age- and gender-matched reference values are essential for the clinical use of quantitative sensory testing (QST). To extend the standard test sites for QST-according to the German Research Network on Neuropathic Pain-to the trunk, we collected QST profiles on the back in 162 healthy subjects. Sensory profiles for standard test sites were within normal interlaboratory differences. QST revealed lower sensitivity on the upper back than the hand, and higher sensitivity on the lower back than the foot, but no systematic differences between these trunk sites. Age effects were significant for most parameters. Females exhibited lower pressure pain thresholds (PPT) than males, which was the only si…

Asymmetry in the human primary somatosensory cortex and handedness.

Brain asymmetry is a phenomenon well known for handedness and language specialization and has also been studied in motor cortex. Less is known about hemispheric asymmetries in the somatosensory cortex. In the present study, we systematically investigated the representation of somatosensory function analyzing early subcortical and cortical somatosensory-evoked potentials (SEP) after electrical stimulation of the right and left median nerve. In 16 subjects, we compared thresholds, the peripheral neurogram at Erb point, and, using MRI-based EEG source analysis, the P14 brainstem component as well as N20 and P22, the earliest cortical responses from the primary sensorimotor cortex. Handedness w…

The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria

Refereed/Peer-reviewed The new IASP diagnostic criteria for complex regional pain syndrome (CRPS) (aka “the Budapest Criteria”3; Table 1) have improved the diagnostic specificity for CRPS while maintaining good sensitivity. Internationally, these criteria are now in common use. The IASP CRPS Special Interest Group convened a workshop of CRPS experts in Valencia/Spain in September 2019 to review perceived ambiguities in the diagnostic text and issues identified in applying these criteria in both the research and clinical contexts. After this review, workshop attendees discussed and reached a consensus regarding adaptations to the diagnostic taxonomy text. This process resulted in pragmatic u…

Generalized hyperalgesia in patients with chronic tension-type headache.

Increased pain sensitivity in the central nervous system may play an important role in the pathophysiology of chronic tension-type headache (CTTH). Previous studies using pain thresholds as a measure of central pain sensitivity have yielded inconsistent results and only a few studies have examined perception of muscle pain without involvement of adjacent tissues. It has been suggested that suprathreshold testing might be more sensitive than threshold measurements in evaluation of central hyperexcitability in CTTH. The aim of the study was to compare pain ratings to suprathreshold single and repetitive (2 Hz) electrical stimulation of muscle and skin in cephalic (temporal and trapezius) and…

Basal opioid receptor binding is associated with differences in sensory perception in healthy human subjects: a [18F]diprenorphine PET study.

The endogenous opioid system is involved in many body functions including pain processing and analgesia. To determine the role of basal opioid receptor availability in the brain in pain perception, twenty-three healthy subjects underwent positron emission tomography (PET) utilizing the subtype-nonselective opioid antagonist [(18)F]diprenorphine, quantitative sensory testing (QST) and the cold pressor test. Binding potentials (BPs) were calculated using a non-invasive reference tissue model and statistical parametric mapping was applied for t-statistical analysis on a voxelwise basis. We found that cold pain-sensitive subjects present a significantly lower BP in regions including the bilater…

Explicit episodic memory for sensory-discriminative components of capsaicin-induced pain: Immediate and delayed ratings

Pain memory is thought to affect future pain sensitivity and thus contribute to clinical pain conditions. Systematic investigations of the human capacity to remember sensory features of experimental pain are sparse. In order to address long-term pain memory, nine healthy male volunteers received intrader- mal injections of three doses of capsaicin (0.05, 1 and 20 lg, separated by 15 min breaks), each given three times in a balanced design across three sessions at one week intervals. Pain rating was performed using a computerized visual analogue scale (0-100) digitized at 1/s, either immediately online or one hour or one day after injection. Subjects also recalled their pains one week later.…

The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization.

The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB-irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24h after irradiation with UVB at 3-fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror-image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P=.01), profound generalized hyperalgesia to heat (P.001), cold (P.05), pinprick and pressure (P.001), and mild dynamic mechanical allodynia (…

34. The impact of partial sleep deprivation on the modulation of pain: Psychophysical and neurophysiological correlates

Pain elicited by blunt pressure: neurobiological basis and clinical relevance.

Laser-evoked potentials for assessment of nociceptive pathways in humans

I n their Focus article, Chen, Arendt-Nielsen, and Plaghki [8] provide a comprehensive review of the . literature o~ human evoked potentials that ~re elicited by noxious heat, usually generated by Infrared laser stimulators. From this review, we identified four issues that may deserve a comment: (1) Standardize the experiment or its scientific report? (2) Nociception and pain. (3) What do laser-evoked potentials (LEPs) really measure? (4) Rational clinical use. For the sake of brevity, we do not attempt to quote all relevant literature; a complete literature survey can be found in a recent review paper by Bromm and Lorenz [4].

Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system

We recently reported perceptual correlates of long-term potentiation (LTP) of synaptic strength within the nociceptive system demonstrating the functional relevance of LTP for human pain sensation. LTP is generally classified as NMDA-receptor dependent or independent. Here we show that low doses of the NMDA-receptor antagonist ketamine (0.25 mg/kg) prevented the long-term increase in perceived pain to electrical test stimuli, which was induced by high-frequency electrical stimulation (HFS) of nociceptive afferents. Whereas in a control experiment HFS led to a stable increase in perceived pain by 51% for the entire observation period of 1 h HFS given 4 min after i.v. ketamine was ineffective…

112 Workshop Summary: DOPAMINERGIC MECHANISMS OF PAIN CONTROL

Perceptual Correlate of Nociceptive Long-Term Potentiation (LTP) in Humans Shares the Time Course of Early-LTP

As in neocortex and hippocampus, neurons in the dorsal horn of the spinal cord develop long-term potentiation of synaptic efficacy (LTP) on high-frequency stimulation (HFS) of their afferent input, although how long LTP lasts in this nociceptive relay nucleus has not yet been addressed. Here we studied neurogenic hyperalgesia, a perceptual correlate of nociceptive LTP, in 13 healthy subjects, after HFS (5 × 1 s at 100 Hz) of superficial cutaneous afferents. HFS led to a mean upward shift of the stimulus–response function for pinprick-evoked pain (punctate mechanical hyperalgesia) in all subjects by a factor of 2.5 ( P < 0.001) that lasted undiminished for the initial 1-h observation per…

Association between pain, central sensitization and anxiety in postherpetic neuralgia

Background In postherpetic neuralgia (PHN), dorsal root ganglia neurons are damaged. According to the proposed models, PHN pain might be associated with nociceptive deafferentation, and peripheral (heat hyperalgesia) or central sensitization (allodynia). Methods In 36 PHN patients, afferent nerve fibre function was characterized using quantitative sensory testing and histamine-induced flare analysis. Psychological factors were evaluated with the Hospital Anxiety and Depression Scale (HADS), disease-related quality of life (QoL) with SF-36 and pain with the McGill questionnaire [pain rating index (PRI)]. The patients were also divided into subgroups according to the presence or absence of br…

Persistent antinociception through repeated self-injury in patients with borderline personality disorder.

Abstract Patients with borderline personality disorder, mostly female, exhibit severe autoaggressive behavior, namely an intentionally performed, nonsuicidal self-injury and severe blunting of pain perception, the mechanism of which is hitherto not understood. Because the nociceptive system displays a high degree of plasticity, the aim of this study was to analyze the relationship of pain perception to self-injurious behavior. Pain perception of mechanical and chemical noxious stimuli was studied by quantitative sensory testing in 22 patients (15 female, 7 male) with borderline personality disorder (BPD) according to DSM-IV and 22 age- and gender-matched controls. BPD patients exhibited a s…

High opiate receptor binding potential in the human lateral pain system

To determine how opiate receptor distribution is co-localized with the distribution of nociceptive areas in the human brain, eleven male healthy volunteers underwent one PET scan with the subtype-nonselective opioidergic radioligand [(18)F]fluoroethyl-diprenorphine under resting conditions. The binding potential (BP), a parameter for the regional cerebral opioid receptor availability, was computed using the occipital cortex as reference region. The following regions of interest (ROIs) were defined on individual MR images: thalamus, sensory motor strip (SI/MI area), frontal operculum, parietal operculum, anterior insular cortex, posterior insular cortex, anterior cingulate cortex (ACC; peri-…

Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia.

Polymodal nociceptors respond to mechanical, thermal and chemical stimuli. Whereas sensitivities to heat and to the irritant substance capsaicin have recently been linked via the properties of the vanilloid receptor type 1 receptor ion channel, sensitivity to noxious mechanical stimuli such as the pinpricks used in clinical neurology seems to be unrelated. We investigated the peripheral neural basis of pinprick pain using quantitative psychophysical techniques combined with selective conduction block by nerve compression and selective desensitization by topical capsaicin treatment. Complete A-fibre block by compression of the superficial radial nerve (criterion: loss of first pain sensation…

Secondary hyperalgesia to punctate mechanical stimuli

Tissue injury induces enhanced pain sensation to light touch and punctate stimuli in adjacent, uninjured skin (secondary hyperalgesia). Whereas hyperalgesia to light touch (allodynia) is mediated by A-fibre low-threshold mechanoreceptors, hyperalgesia to punctate stimuli may be mediated by A- or C-fibre nociceptors. To disclose the relative contributions of A- and C-fibres to the hyperalgesia to punctate stimuli, the superficial radial nerve was blocked by pressure at the wrist in nine healthy subjects. Secondary hyperalgesia was induced by intradermal injection of 40 microg capsaicin, and pain sensitivity in adjacent skin was tested with 200 micron diameter probes (35-407 mN). The progress…

The autonomic response pattern to experimental pain is not compatible with the concept of pain as a stress event

Increased muscular and cutaneous pain sensitivity in cephalic region in patients with chronic tension-type headache

Increased excitability of the central nervous system generated by repetitive and sustained pericranial myofascial nociception may be responsible for transformation of episodic tension-type headache into chronic form. We aimed to compare mechanical and electrical (intramuscular and cutaneous) pain thresholds in trapezius and anterior tibial regions between 20 patients with chronic tension type headache and 20 healthy controls. Pain thresholds to three types of electrical stimulation (single pulse, 2 and 100 Hz) were significantly lower in patients than in controls in trapezius muscle (P < 0.02) and in skin overlying the trapezius muscle (P < 0.05), whilst electrical pain thresholds did not d…

Spatial discrimination thresholds for pain and touch in human hairy skin

The traditional concept that pain is poorly localized has been challenged by recent studies, where subjects were able to point to the stimulated spot on the skin with an accuracy of 10-20 mm. Pointing movements themselves, however, have errors of about 15 mm. To determine the limits of sensory performance of the nociceptive system independent of motor performance, point localization of heat pain (540 mJ punctate laser stimuli, 5 mm diameter), mechanical pain (256 mN punctate probe, 200 microm diameter), and touch (16 mN von Frey probe, 1.1 mm diameter) were tested in a two-alternative forced-choice paradigm in 12 healthy subjects. Stimuli were applied in randomized order to two parallel lin…

Erratum to “Human surrogate models of neuropathic pain” [Pain 115 (2005) 227–233]☆

Antihyperalgesic and analgesic properties of the N-methyl-d-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia

Abstract NMDA-receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti-hyperalgesic (prevention of central sensitization) properties of the NMDA-receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40 mg p.o.), flupirtine (100 m…

Response to letter by Werner et al.

C- and Aδ-fiber components of heat-evoked cerebral potentials in healthy human subjects

Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated…

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values

The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 …

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1mm). Thresholds and stimulus-response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2mm). Allodynia was tested by light stroking with a brush, Q-tip, and…

Psychophysical evidence for long-term potentiation of C-fiber and Adelta-fiber pathways in humans by analysis of pain descriptors.

Long-term potentiation of human pain perception (nociceptive LTP) to single electrical test stimuli was induced by high-frequency stimulation (HFS) of cutaneous nociceptive afferents. Numerical pain ratings and a list of sensory pain descriptors disclosed the same magnitude of nociceptive LTP (23% increase for &gt;60 min, P &lt; 0.001), whereas affective pain descriptors were not significantly enhanced. Factor analysis of the sensory pain descriptors showed that facilitation was restricted to two factors characterized by hot and burning (+41%) and piercing and stinging (+21%, both P &lt; 0.01), whereas a factor represented by throbbing and beating was not significantly increased (+9%, P = …

Human surrogate models of neuropathic pain.

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994). Current efforts to refine this definition focus on the terms ‘dysfunction’ and ‘nervous system’ with the intention to clarify that there has to be an identifiable lesion or disease process affecting the somatosensory system. Experimental models of neuropathic pain according to either one of these definitions are expected to imitate mechanisms of nerve damage within the peripheral or central parts of the somatosensory system and the ensuing processes of degeneration and regeneration. Whereas this approach to model the etiology and pathophysiology of the…

Transcranial direct current stimulation of the motor cortex induces distinct changes in thermal and mechanical sensory percepts

Abstract Objective The aim of this single-blinded, complete crossover study was to evaluate the effects of tDCS on thermal and mechanical perception, as assessed by quantitative sensory testing (QST). Methods QST was performed upon the radial part of both hands of eight healthy subjects (3 female, 5 male, 25–41 years of age). These subjects were examined before and after cathodal, anodal or sham tDCS, applied in a random order. TDCS was administered for 15 min at a 1 mA current intensity, with the active electrode placed over the left primary motor cortex and the reference electrode above the right orbit. Results After cathodal tDCS, cold detection thresholds (CDT), mechanical detection thr…

114 NEUROPATHIC PAIN IN RESTLESS LEGS SYNDROME - A DISORDER OF PAIN CONTROL

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up…

200 TEST/RETEST- AND INTEROBSERVER-RELIABILITIY IN QUANTITATIVE SENSORY TESTING ACCORDING TO THE PROTOCOL OF THE GERMAN NETWORK ON NEUROPATHIC PAIN (DFNS)

Differential nociceptive deficits in patients with borderline personality disorder and self-injurious behavior: laser-evoked potentials, spatial discrimination of noxious stimuli, and pain ratings.

Approximately 70-80% of women meeting criteria for borderline personality disorder (BPD) report attenuated pain perception or analgesia during non-suicidal, intentional self-mutilation. The aim of this study was to use laser-evoked potentials (LEPs) and psychophysical methods to differentiate the factors that may underlie this analgesic state. Ten unmedicated female patients with BPD (according to DSM-IV) and 14 healthy female control subjects were investigated using brief radiant heat pulses generated by a thulium laser and five-channel LEP recording. Heat pulses were applied as part of a spatial discrimination task (two levels of difficulty) and during a mental arithmetic task. BPD patien…

Deep pain thresholds in the distal limbs of healthy human subjects.

Pressure pain thresholds (PPTs) in distal limbs have been under-investigated despite their potential clinical importance. Therefore, we compared PPTs over nail bed, bony prominences, and muscle in distal parts of upper and lower limbs. We investigated 12 healthy subjects using three handheld devices: a spring-loaded, analogue pressure threshold meter (PTM) with two operating ranges, and an electronic Algometer. PPTs were determined with three series of ascending stimulus intensities with a ramp of about 50 kPa/s. PPTs were normally distributed in logarithmic space. PPTs over different tissues varied significantly (ANOVA, p0.001): mean thresholds and 95% confidence intervals were 615 kPa (26…

Mechanisms and predictors of chronic facial pain in lateral medullary infarction

The purpose of this study was to identify clinical predictors and anatomical structures involved in patients with pain after dorsolateral medullary infarction. Eight out of 12 patients (67%) developed poststroke pain within 12 days to 24 months after infarction. The pain occurred in the ipsilateral face (6 patients) and/or the contralateral limbs and trunk (5 patients, 3 of whom also had facial pain). Ipsilateral facial pain was significantly correlated with lower medullary lesions, including those of the spinal trigeminal tract and/or nucleus, as documented by magnetic resonance imaging. The R2 blink reflex component was abnormal only in patients with facial pain. Likewise, pain and temper…

451 SPATIAL AND TEMPORAL STIMULUS PARAMETERS OF CONDITIONING STIMULATION AFFECT THE MAGNITUDE AND DIRECTION OF HUMAN PAIN PLASTICITY

High opiate receptor binding potential in the human lateral pain system: A (FEDPN)PET study

Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans.

Wind-up and secondary hyperalgesia both are related to central sensitization, but whereas the former is explained by homosynaptic facilitation, the latter is due to heterosynaptic facilitation. To investigate possible interactions between both types of facilitation, we tested for alterations of perceptual wind-up in the secondary hyperalgesic skin zone adjacent to a capsaicin injection with light touch (by a cotton wisp) and punctate stimuli (calibrated von Frey hairs and pin pricks). Temporal summation of pain sensation (perceptual wind-up) was only observed with a clearly noxious stimulus (pin prick) presented at a repetition frequency of 0.6 s(-1), but not 0.2 s(-1). Pain ratings to trai…

Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex.

Pain perception comprises sensory and emotional dimensions. While the emotional experience is thought to be represented in the right hemisphere, we here report a left-hemisphere dominance for the early sensory component of pain perception using brain electrical source analysis of laser-evoked potentials. Ten right-handed subjects underwent several series of laser radiant heat stimuli to pairs of parallel lines on the dorsum of the left or right hand. Stimulus location and intensity were randomised independently. The sensory-discriminative aspects of pain were emphasised by asking the subjects to perform either a spatial or an intensity discrimination task and were contrasted with active dis…

Numbness in clinical and experimental pain – A cross-sectional study exploring the mechanisms of reduced tactile function

Pain patients often report distinct numbness of the painful skin although no structural peripheral or central nerve lesion is obvious. In this cross-sectional study we assessed the reduction of tactile function and studied underlying mechanisms in patients with chronic pain and in healthy participants exposed to phasic and tonic experimental nociceptive stimulation. Mechanical detection (MDT) and pain thresholds (MPT) were assessed in the painful area and the non-painful contralateral side in 10 patients with unilateral musculoskeletal pain. Additionally, 10 healthy participants were exposed to nociceptive stimulation applied to the volar forearms (capsaicin; electrical stimulation, twice e…

Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically ch…

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 × 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for &gt;3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 μm diameter) in skin adjacent to the HFS–LFS con…

Forget about your chronic pain

Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways.

The impact of long-term potentiation (LTP) in nociceptive pathways on somatosensory perception was examined by means of quantitative sensory testing (QST) in the ventral forearm of 12 healthy human subjects. Electrical high-frequency stimulation of the forearm skin (HFS; 5 x 1 s at 100 Hz and 10 x detection threshold) led to an abrupt increase of pain to single electrical test stimuli, which were applied through the same electrode (perceptual LTP +72%, p0.01). Perceptual LTP outlasted the 1-h observation period. The effects of HFS on somatosensory perception of natural test stimuli in the conditioned skin area were restricted to mechanical submodalities. Subjects exhibited a significant dec…

Interaction of hyperalgesia and sensory loss in complex regional pain syndrome type I (CRPS I).

Background: Sensory abnormalities are a key feature of Complex Regional Pain Syndrome (CRPS). In order to characterise these changes in patients suffering from acute or chronic CRPS I, we used Quantitative Sensory Testing (QST) in comparison to an age and gender matched control group. Methods: 61 patients presenting with CRPS I of the upper extremity and 56 healthy subjects were prospectively assessed using QST. The patients’ warm and cold detection thresholds (WDT; CDT), the heat and cold pain thresholds (HPT; CPT) and the occurrence of paradoxical heat sensation (PHS) were observed. Results: In acute CRPS I, patients showed warm and cold hyperalgesia, indicated by significant changes in H…

Chapter 33 Experimental human models of neuropathic pain

Publisher Summary This chapter reviews human surrogate models of neuropathic pain that focus on the mechanisms of symptom generation. A vast array of human surrogate models exists for ongoing symptoms, for positive sensory symptoms, and for sensory loss. The chapter discusses that by design, human surrogate models of neuropathic pain involve a reversible modulation of the properties of the nociceptive system such as its acute plasticity (phase 2). They usually do not create a long-lasting and potentially irreversible modification (phase 3). The denervation and ectopic activity of phase 3 can be modeled to a certain extent by transient nerve compression–ischemia and by topical capsaicin. By …

Warm and cold complex regional pain syndromes: Differences beyond skin temperature?

Objective: To investigate clinical differences in warm and cold complex regional pain syndrome (CRPS) phenotypes. Background: CRPS represents inhomogeneous chronic pain conditions; approximately 70% patients with CRPS have “warm” affected limbs and 30% have “cold” affected limbs. Methods: We examined 50 patients with “cold” and “warm” CRPS (n 25 in each group). Both groups were matched regarding age, sex, affected limb, duration of CRPS, and CRPS I and II to assure comparability. Detailed medical history and neurologic status were assessed. Moreover, quantitative sensory testing (QST) was performed on the affected ipsilateral and clinically unaffected contralateral limbs. Results: Compared …

Quantitative sensory testing: a comprehensive protocol for clinical trials.

We have compiled a comprehensive QST protocol as part of the German Research Network on Neuropathic Pain (DFNS) using well established tests for nearly all aspects of somatosensation. This protocol encompasses thermal as well as mechanical testing procedures. Our rationale was to test for patterns of sensory loss (small and large nerve fiber functions) or gain (hyperalgesia, allodynia, hyperpathia), and to assess both cutaneous and deep pain sensitivity. The practicality of the QST protocol was tested in 18 healthy subjects, 21-58 years, half of them female. All subjects were tested bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test fo…

The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation

Long-term potentiation (LTP) of nociceptive synaptic transmission induced by high-frequency electrical stimulation (HFS) predominantly modulates natural somatosensory perceptions mediated by Adelta- and Abeta-fibers in humans at the site of conditioning stimulation. The relative contribution of homo- and heterosynaptic mechanisms underlying those perceptual changes remained unclear. We therefore compared changes of the somatosensory profile between a conditioned skin site (homotopic zone) and an area adjacent to conditioning HFS (heterotopic zone). HFS of the ventral forearm in 24 healthy subjects (mean pain 41/100) led to an abrupt increase of pain to single electrical test stimuli (pain a…

Heat-evoked vasodilatation in human hairy skin: axon reflexes due to low-level activity of nociceptive afferents.

1. Spreading vasodilatation of the axon reflex type was evoked by contact heat stimulation of the hairy skin in the human forearm (13.3 cm2 stimulus area) and was detected by laser Doppler flowmetry at 8, 19 and 30 mm distance. 2. From a base temperature of 35 degrees C, rapidly rising short heat stimuli (4 degrees C s-1, 2 s plateau) elicited vasodilatation at an average threshold of 39.4 degrees C. For slowly rising sustained heat stimuli (64 s duration) the average threshold was 39.6 degrees C (n.s.) Laser Doppler flowmetry revealed a rapid onset within about 4 s, a long duration of several minutes beyond the end of the stimulus, and a rapid spread of vasodilatation to remote skin areas.…

A family-based investigation of cold pain tolerance

In the present study the question was addressed whether sensitivity to experimental pain stimuli differs between families, which are previously characterized by the degree of cold tolerance (very insensitive or very sensitive) of one family member. A total of 232 healthy medical students were screened for cold pain tolerance employing a cold pressor test. Subsequently 50 of them were investigated in detail under laboratory conditions. The water temperature was 1 degrees C, the maximum time in water 3 min, cold pain was rated on a 101 step numerical rating scale every 10s. Two of the most cold pain sensitive (shortest time in ice water) and insensitive (lowest ratings) students were selected…