[D.G.S.S. President's corner].
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Germany↗
Biomedical subjects
R D Treede
Publications and source records attributed to R D Treede.
Withdrawal reflex organisation to electrical stimulation of the dorsal foot in humans.
The present study investigated excitatory reflex receptive fields for various muscle reflex responses and reflex mediated ankle joint movements using randomised electrical stimulation of the dorsal and plantar surface of the foot in 12 healthy subjects. Eleven electrodes (0.5-cm2 cathodes) were mounted on the dorsal side and three on the plantar side of the foot. A low (1.5 times pain threshold) and a high (2.3 times pain threshold) stimulus intensity were used to elicit the reflexes. EMG signals were recorded from tibialis anterior (TA), gastrocnemius medialis (GM), soleus (SO), biceps femoris (BF), and rectus femoris (RF) muscles together with the ankle movement measured by a goniometer. The withdrawal pattern evoked from the dorsal side consisted of two separate responses with different receptive fields: (1) early EMG responses in GM and BF (50-120 ms) evoking knee flexion, probably of purely spinal origin, and (2) a late response in GM and SO (120-200 ms) that may be under supraspinal control. The ankle flexor TA was significantly activated in both time windows, but in 11 of 12 subjects its contraction was too small to cause significant dorsal flexion. In the ankle joint inversion was the most dominant movement. Stimulation of the plantar side resulted in activation of TA when stimulating the forefoot and in activation of triceps surae when stimulating the heel. These observations show that painful stimuli activate appropriate muscles depending on stimulus location to initiate the adequate withdrawal. For proximal muscles (e.g. knee flexors) the receptive field covers almost the entire foot (dorsal and plantar sides) while more distal muscles have a smaller receptive field covering only a part of the foot. This adequate withdrawal movement suggests a more refined withdrawal reflex organisation than a stereotyped flexion of all joints to avoid tissue damage.
Adult↗
Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies.
The aim of this study was to identify the functional cerebral network involved in the central processing of itch and to detect analogies and differences to previously identified cerebral activation patterns triggered by painful noxious stimuli. Repeated positron emission tomography regional cerebral blood flow (rCBF) measurements using O15-labeled water were performed in six healthy right-handed male subjects (mean age 32 +/- 2 years). Each subject underwent 12 sequential rCBF measurements. In all subjects a standardized skin prick test was performed on the right forearm 2 min before each rCBF measurement. For activation, histamine was applied in nine tests in logarithmically increasing concentrations from 0.03 to 8%. Three tests were performed with isotonic saline solution serving as a control condition. Itch intensity and unpleasantness were registered with a visual analogue scale during each test. Subtraction analysis between activation and control conditions as well as correlation analysis with covariates were performed. Itch induced a significant activation in the predominantly contralateral somatosensory cortex and in the ipsilateral and contralateral motor areas (supplementary motor area (SMA), premotor cortex, primary motor cortex). Additional significant activations were found in the prefrontal cortex and the cingulate gyrus, but not in subcortical structures nor in the secondary somatosensory cortex. In correlation analyses, several cortical areas showed a graded increase in rCBF with the logarithm of the histamine concentration (bilateral sensorimotor areas and cingulate cortex; contralateral insula, superior temporal cortex and prefrontal cortex) and with itch unpleasantness (contralateral sensorimotor cortex, prefrontal cortex and posterior insula; ipsilateral SMA). Induction of itch results in the activation of a distributed cerebral network. Itch and pain seem to share common pathways (a medial and a lateral processing pathway and a strong projection to the motor system). In contrast to pain activation studies, no subcortical (i.e. thalamic) activations were detected and correlation analyses suggest differences in subjective processing of the two sensations.
Adult↗
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) lowered the stimulus-response function for pinprick pain (-82 +/- 6% versus baseline). Topical pretreatment of the skin with a 10% capsaicin cream also lowered the pinprick stimulus-response function (-32 +/- 10%), whereas laser-evoked heat pain was eliminated completely (-96 +/- 2%). Under combined capsaicin desensitization and A-fibre blockade, pinprick pain was eliminated completely (-98 +/- 1%). Intradermal injection of 40 microg capsaicin into normal skin between two skin areas that had been pretreated with either capsaicin cream or vehicle produced secondary hyperalgesia with a 260% enhancement of the stimulus-response function for pinprick pain in both areas. In contrast, axon reflexive flare spread only into the vehicle-treated area. These results suggest that capsaicin-sensitive afferents, including polymodal A-fibre and C-fibre nociceptors, make a small contribution to pinprick pain and that capsaicin-insensitive C-fibres do not contribute significantly to either mechanical or heat pain. Pinprick pain is mediated primarily by capsaicin-insensitive A-fibre nociceptors, which include high-threshold mechanoreceptors and type I mechano-heat nociceptors. In addition, central sensitization to input from these A-fibre nociceptors is the primary mechanism that accounts for the enhanced pain in response to punctate mechanical stimuli in the zone of secondary hyperalgesia. These capsaicin-insensitive A-fibre nociceptors may also mediate hyperalgesia in neuropathic pain.
Adult↗
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 temperature sensation in the ipsilateral face was decreased in all patients with facial pain but not in patients without pain. Ipsilateral touch sensation in the face was also decreased in all patients with facial pain, but the lesions revealed on magnetic resonance imaging did not involve the principal sensory nucleus of the fifth cranial nerve, and the R1 blink reflex latencies were normal. Although facial pain was correlated with lesions of the spinal trigeminal tract and/or nucleus, none of the lesions involved the subnucleus caudalis, which contains most nociceptive neurons. These findings suggest that facial pain after medullary infarction is due to lesions of the lower spinal trigeminal tract (axons of primary afferent neurons), leading to deafferentation of spinal trigeminal nucleus neurons.
Aged↗
Inactivation and tachyphylaxis of heat-evoked inward currents in nociceptive primary sensory neurones of rats.
Membrane currents evoked by repeated noxious heat stimuli (43-47 degrees C) of 3 s duration were investigated in acutely dissociated dorsal root ganglion (DRG) neurones of adult rats. The heat stimuli generated by a fast solution exchanger had a rise time of 114 +/- 6 ms and a fall time of 146 +/- 13 ms. When heat stimuli were applied to heat-sensitive small (< or = 32.5 microm) DRG neurones, an inward membrane current (I(heat)) with a mean peak of 2430 +/- 550 pA was observed (n = 19). This current started to activate and deactivate with no significant latency with respect to the heat stimulus. The peak of I(heat) was reached with a rise time of 625 +/- 115 ms. When the heat stimulus was switched off I(heat) deactivated with a fall time of 263 +/- 17 ms. During constant heat stimulation I(heat) decreased with time constants of 4-5 s (inactivation). At the end of a 3 s heat stimulus the peak current was reduced by 44 +/- 5 % (n = 19). Current-voltage curves revealed outward rectifying properties of I(heat) and a reversal potential of -6.3 +/- 2.2 mV (n = 6). Inactivation was observed at all membrane potentials investigated (-80 to 60 mV); however, inactivation was more pronounced for inward currents (37 +/- 5 %) than for outward currents (23 +/- 6 %, P < 0.05). When neurones were investigated with repeated heat stimuli (3 to 5 times) of the same temperature, the peak current relative to the first I(heat) declined by 48 +/- 6 % at the 3rd stimulus (n = 19) and by 54 +/- 18 % at the 5th stimulus (n = 4; tachyphylaxis). In the absence of extracellular Ca2+ (buffered with 10 mM EGTA) inactivation (by 53 +/- 6 %) and tachyphylaxis (by 42 +/- 7 % across three stimuli) were still observed (n = 8). The same was true when intracellular Ca2+ was buffered by 10 mM BAPTA (inactivation by 49 +/- 4 %, tachyphylaxis by 52 +/- 7 % across three stimuli; n = 13). Thus, inactivation and tachyphylaxis were mainly independent of intra- and extracellular Ca2+. These results indicate that inactivation and tachyphylaxis of heat-evoked inward currents can be observed in vitro, similar to adaptation and suppression of action potential discharges elicited by comparably fast heat stimuli in vivo. Whereas the voltage dependence of I(heat) resembles that of capsaicin-induced membrane currents (I(Caps)), the independence of inactivation and tachyphylaxis of I(heat) from calcium is in clear contrast to I(Caps). A similar difference in calcium dependence of inactivation has been reported between heat-evoked and capsaicin-induced currents through the cloned capsaicin receptor channel VR1. Thus, the properties of I(heat) and of VR1 largely account for the adaptation and suppression of heat-evoked nociceptor discharges.
Animals↗
Differential effects of pain and spatial attention on digit representation in the human primary somatosensory cortex.
Reorganization of primary somatosensory cortex subsequent to either reduced or enhanced peripheral input is well established. Recently, plastic changes following arm amputation in humans were shown to correlate with phantom limb pain. This raised the question whether spatial attention and pain may cause cortical reorganization in the absence of deafferentation. Using non-invasive neuroelectric imaging to study the digit representation in the human primary somatosensory cortex, we report a delayed shift of the representation of digits 2-3 due to pain on the digits 4-5, which outlasted the pain by several minutes. In contrast, reorganization during spatial attention was less pronounced, was seen almost immediately and only during the condition. These data indicate that spatial attention and pain without peripheral deafferentation cause cortical reorganization by different mechanisms. The differential time course of reorganizational effects observed at the cortex may be due to modulation of the lemniscal pathways by nociceptive input from the spinal cord dorsal horn.
Adult↗
Different generators in human temporal-parasylvian cortex account for subdural laser-evoked potentials, auditory-evoked potentials, and event-related potentials.
In order to localize cortical areas mediating pain we now report subdural cortical potentials evoked by auditory stimulation (auditory-evoked potentials - AEPs) and by cutaneous stimulation with a laser (laser-evoked potentials - LEPs). Stimulation with the laser evokes a pure pain sensation by selective activation of nociceptors. LEPs were maximal over the inferior aspect of the central sulcus and had the same polarity on either side of the sylvian fissure. AEPs were maximal posterior to the LEP maximum and had opposite polarity on opposite sides of the sylvian fissure, consistent with the location of a known generator in the temporal operculum. Auditory P3 (event-related) potentials were maximal over the temporal base. These findings demonstrate that the LEP generator is not in secondary somatosensory cortex on the parietal operculum and is different from the P3 generator.
Adult↗
Multiple mechanisms of secondary hyperalgesia.
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Animals↗
Clinical evaluation criteria for the assessment of impaired pain sensitivity by thulium-laser evoked potentials.
OBJECTIVES: Cortical potentials evoked by carbon dioxide laser pulses have been applied in clinical practice to study nociceptive pathways for several years. In this study, we evaluate the properties of an infrared laser (thulium-YAG) with a penetration depth in the skin that matches the intracutaneous depth of nociceptors. METHODS: Temperature measurements and modelling showed that the thulium laser generates painful intracutaneous temperatures with less surface heating than the carbon dioxide laser and with no side effects (up to 600 mJ pulse energy). To develop clinical evaluation criteria, laser-evoked potentials (LEPs) were recorded from 3 midline positions (Fz, Cz, Pz) versus linked earlobes in 23 healthy subjects. Within a session, two skin areas were studied twice in a balanced sequence using randomized interstimulus intervals and two intensities in randomized order. RESULTS: After hand and foot stimulation with 540 mJ pulses, all subjects showed reproducible biphasic vertex potential, consisting of a negativity (hand: 210 ms, foot: 250 ms) and a positivity (hand: 330 ms, foot: 380 ms). Mean habituation of the vertex potential amplitude across runs was 25% (hand) or 16% (foot); due to the balanced sequence it did not affect the other comparisons. Following foot stimulation, peak latencies were significantly longer (by 40-50 ms) and amplitudes were significantly smaller than following hand stimulation (22.5+/-6.7 vs. 30.3+/-10.9 microV, mean+/-SD). Using 2. 5 standard deviations from the mean as a cut-off, absolute normative values were determined for peak latencies and amplitudes. In addition, relative normative values were determined for paired comparisons (hand-hand, foot-foot, hand-foot). CONCLUSIONS: The thulium-YAG laser is a useful tool for assessment of impaired pain sensitivity. Representative case reports illustrate that unlike for early SEP components, the most frequent LEP abnormalities were amplitude differences.
Adult↗
Abolished laser-evoked potentials and normal blink reflex in midlateral medullary infarction.
We investigated two patients presenting with the rare finding of almost isolated hemianalgesia with a sensory level on the contralateral side sparing the face. Clinical findings, electrophysiological studies (absent laser-evoked pain-related somatosensory potentials, normal electrically evoked somatosensory potentials, magnetically evoked potentials, and blink reflexes), and magnetic resonance imaging showed the ventrolateral medullar tegmentum containing the spinothalamic tract to be affected by lacunar infarction. The blink reflex R2 component was unimpaired in both patients.
Adult↗
Functional MRI of human primary somatosensory and motor cortex during median nerve stimulation.
OBJECTIVES: Somatosensory evoked potential (SEP) studies suggested that some early cortical SEP components may be generated in the primary motor cortex (M1) rather than the primary somatosensory cortex (S1). METHODS: We now used functional magnetic resonance imaging (fMRI) to study activation of S1 and M1 by electrical median nerve stimulation in healthy volunteers. RESULTS: The hand areas of both S1 and M1 showed significant activation (correlation coefficients >0.45) in 7 of 9 subjects (activated volume S1 > M1). For comparison, a sequential finger opposition task significantly activated S1 in 7 and M1 in all 9 subjects (activated volume M1 > S1). CONCLUSIONS: These data show that the electrical stimuli used for SEP recording lead to a functional activation of S1 as well as M1.
Adult↗
The cortical representation of pain.
Anatomical and physiological studies in animals, as well as functional imaging studies in humans have shown that multiple cortical areas are activated by painful stimuli. The view that pain is perceived only as a result of thalamic processing has, therefore, been abandoned, and has been replaced by the question of what functions can be assigned to individual cortical areas. The following cortical areas have been shown to be involved in the processing of painful stimuli: primary somatosensory cortex, secondary somatosensory cortex and its vicinity in the parietal operculum, insula, anterior cingulate cortex and prefrontal cortex. These areas probably process different aspects of pain in parallel. Previous psychophysical research has emphasized the importance of separating pain experience into sensory-discriminative and affective-motivational components. The sensory-discriminative component of pain can be considered a sensory modality similar to vision or olfaction; it becomes more and more evident that it is subserved by its own apparatus up to the cortical level. The affective-motivational component is close to what may be considered 'suffering from pain'; it is clearly related to aspects of emotion, arousal and the programming of behaviour. This dichotomy, however, has turned out to be too simple to explain the functional significance of nociceptive cortical networks. Recent progress in imaging technology has, therefore, provided a new impetus to study the multiple dimensions of pain.
Animals↗
Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input.
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 of conduction blockade was monitored by touch, cold, warm and first pain detection and by compound sensory nerve action potential. When A-fibre conduction was blocked completely but C-fibre conduction was fully intact, pricking pain to punctate stimuli was reduced by 75%, but burning pain to capsaicin injection remained unchanged. In normal skin without A-fibre blockade, pain ratings to the punctate probes increased significantly by a factor of two after adjacent capsaicin injection. In contrast, pain ratings to the punctate probes were not increased after capsaicin injection when A-fibre conduction was selectively blocked. However, hyperalgesia to punctate stimuli was detectable immediately after block release, when A-fibre conduction returned to normal. In conclusion, the pricking pain to punctate stimuli is predominantly mediated by A-fibre nociceptors. In secondary hyperalgesia, this pathway is heterosynaptically facilitated by conditioning C-fibre input. Thus, secondary hyperalgesia to punctate stimuli is induced by nociceptive C-fibre discharge but mediated by nociceptive A-fibres.
Adult↗
Inhibition of rapid heat responses in nociceptive primary sensory neurons of rats by vanilloid receptor antagonists.
Recent studies demonstrated that heat-sensitive nociceptive primary sensory neurons respond to the vanilloid receptor (VR) agonist capsaicin, and the first cloned VR is a heat-sensitive ion channel. Therefore we studied to what extent heat-evoked currents in nociceptive dorsal root ganglion (DRG) neurons can be attributed to the activation of native vanilloid receptors. Heat-evoked currents were investigated in 89 neurons acutely dissociated from adult rat DRGs as models for their own terminals using the whole cell patch-clamp technique. Locally applied heated extracellular solution (effective temperature approximately 53 degrees C) rapidly activated reversible and reproducible inward currents in 80% (62/80) of small neurons (< or = 32.5 microm), but in none of nine large neurons (P < 0.001, chi(2) test). Heat and capsaicin sensitivity were significantly coexpressed in this subpopulation of small DRG neurons (P < 0.001, chi(2) test). Heat-evoked currents were accompanied by an increase of membrane conductance (320 +/- 115%; mean +/- SE, n = 7), had a reversal potential of 5 +/- 2 mV (n = 5), which did not differ from that of capsaicin-induced currents in the same neurons (4 +/- 3 mV), and were carried at least by Na(+) and Ca(2+) (pCa(2+) > pNa(+)). These observations are consistent with the opening of temperature-operated nonselective cation channels. The duration of action potentials was significantly higher in heat-sensitive (10-90% decay time: 4.45 +/- 0.39 ms, n = 12) compared with heat-insensitive neurons (2.18 +/- 0.19 ms, n = 6; P < 0.005, Student's t-test), due to an inflection in the repolarizing phase. This property as well as capsaicin sensitivity and small cell size are characteristics of nociceptive DRG neurons. When coadministered with heat stimuli, the competitive VR antagonist capsazepine (1 microM to 1 mM) significantly reduced heat-evoked currents in a dose-dependent manner (IC(50) 13 microM, Hill slope -0.58, maximum effect 75%). Preincubation for 12-15 s shifted the IC(50) by approximately 0.5 log(10) units to an estimated IC(50) of approximately 4 microM. The noncompetitive VR antagonist ruthenium red (5 microM) significantly reduced heat-evoked currents by 33 +/- 6%. The effects of both VR antagonists were rapidly reversible. Our results provide evidence for a specific activation of native VRs in nociceptive primary sensory neurons by noxious heat. The major proportion of the rapid heat-evoked currents can be attributed to the activation of these temperature-operated channels, and noxious heat may be the signal detected by VRs under physiological conditions.
Animals↗
Transduction and transmission properties of primary nociceptive afferents.
The prototypical primary nociceptive afferent is the polymodal C-fiber nociceptor, which responds to noxious thermal, mechanical, and chemical stimuli. C-fiber nociceptors are peripheral terminals of small neurons in the dorsal root ganglia (DRG). DRG neurons must therefore supply their peripheral terminals with the molecular machinery for the encoding of noxious stimuli into trains of action potentials. The following phenomena are known for this encoding process in vivo: 1) adaptation: for a constant stimulus intensity the action potential discharge decreases slowly within 2-3 seconds, 2) fatigue: recovery from adaptation may take ten minutes or more, 3) sensitization: preceding tissue damage enhances the response, particularly to heat stimuli. Recent studies in vitro have provided important clues about the molecular mechanisms underlying these phenomena. Several membrane receptors and channels are specifically expressed in small nociceptive neurons, such as vanilloid receptors (VR1), purinergic receptors (P2X3), acid sensing ion channels (ASIC), and TTX-resistant Na-channels. In the near future, we may therefore expect major advances in our understanding of the transduction of noxious stimuli into generator potentials and transformation into trains of action potentials. Along the axon that leads from the innervated tissue to the spinal cord, primary nociceptive afferents have a limited capacity to transmit high impulse rates, suggesting a different composition of voltage-gated channels than in other primary afferents (low-threshold mechanoreceptors and thermoreceptors). Finally, the DRG neuron also supplies its central terminals with the molecular machinery for synaptic transmission and its presynaptic modulation. Progress in understanding the cellular mechanisms at both ends of the primary nociceptive neuron promises to lead to new analgesic treatment modalities for both acute and chronic pain.
Action Potentials↗
Pain-related evoked potentials from parasylvian cortex in humans.
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Evoked Potentials, Somatosensory↗
Convergence of nociceptive and non-nociceptive input onto the medullary dorsal horn in man.
Referred pain arising in orofacial pain states is probably due to convergence of different somatosensory input onto the medullary dorsal horn (MDH). To examine convergence between nociceptive and non-nociceptive input onto the MDH, the blink reflex (BR) was applied. R1- and R2-components can be evoked by innocuous stimuli, but only the R2 is elicited by painful heat. The BR was elicited by innocuous electrical stimuli applied to the supraorbital nerve. A conditioning painful heat pulse which did not evoke any BR was homotopically applied to the left forehead preceding the electrical stimulus by 75 ms. While R1 remained unchanged, the R2 was facilitated by about 30%. This study demonstrates a convergence of low-threshold mechanoreceptive and nociceptive inputs onto interneurons of the MDH in man.
Adult↗