Phenobarbital induces slow recovery from sodium inactivation at the nodal membrane.

Voltage-clamp experiments were performed on single myelinated nerve fibres of Rana esculenta at 20 degrees C in Ringer's solution and in solutions containing phenobarbital-sodium ([PB] less than or equal to 5 mM). The reduction of the sodium current under phenobarbital could be explained by an increase in the resting sodium inactivation; h infinity (E) was shifted towards more negative membrane potentials. The recovery from sodium inactivation proceeded with two time constants. The fast process could be described with the same time constant as in Ringer's solution, whereas the slow process had a time constant approx. 40 times larger. The slow process was also potential-dependent and could be described by 1/(0.025 alpha h + beta h), where alpha h and beta h denoted the rate constants in Ringer's solution. With the measured blockage of sodium channels by phenobarbital, both the shift of h infinity (E) and the slow recovery from sodium inactivation could be explained.

A three-state model for inactivation of sodium permeability.

The inactivation of Na+ permeability in single myelinated motor nerve fibres of Rana esculenta was investigated under voltage and current clamp conditions at 20 degrees C in Ringer's solution and under blocked K+ currents. Development of inactivation and its recovery was described by two potential-dependent time constants: The smaller time constant followed the usual bell-shaped function of membrane potential, whereas the larger one was monotone-increasing with more negative potentials. Several three-state models for inactivation were investigated. The experiments could best be approximated by a model with two open and one closed state for inactivation following: open in equilibrium closed in equilibrium open. Rate constants were determined for all transitions shown from the voltage clamp experiments. The action potentials computed by means of the proposed model were in good agreement with those measured, both in Ringer's solution and under blocked K+ current conditions.

The influence of tilidine and prazepam on withdrawal reflex, skin resistance reaction and pain rating in man.

Pain rating, withdrawal reflex and skin resistance reaction upon electrical skin stimuli were studied on 15 male volunteers under placebo, tilidine and prazepam. Tilidine (Valoron) is an orally applicable narcotic analgesic, with a mode of pain relief presumably similar to morphine; the tranquilizer prazepam (Demetrin) belongs to the benzodiazepine group. Significant reduction in all measured reaction amplitudes was found under tilidine, whereas prazepam reduced significantly only the skin resistance reaction. The relative drug-induced changes in reaction amplitudes, related to the corresponding placebo value, were independent of stimulus intensity for all investigated reactions. Therefore, fitted power functions re = a . Sn between reaction amplitudes re and stimulus intensity S showed a decrease in parameter a under the investigated drugs, whereas the exponent n remained constant. High correlations between parameters a and corresponding reciprocal threshold currents could be shown for all reactions measured. Furthermore the drug-induced changes of withdrawal reflex amplitude and of subjective estimation were found to be correlated over subjects. In contrast, no correlations were found between variations in skin resistance reaction and magnitude estimation due to the selected drugs, i.e., the influence of the drugs on the sensory component of pain sensation and on the skin resistance reaction were independent effects.

Imipramine reduces experimental pain.

In a homogeneous sample of 20 healthy male students, the analgesic effects of the tricyclic antidepressant imipramine (100 mg) were compared to those of the narcotic meperidine (150 mg) and a further tricyclic compound with assumed analgesic properties (fluradoline, 450 mg). Drugs were orally administered, using a placebo controlled, double-blind repeated measures Latin Square design. Phasic pain was induced by intracutaneous electrical shocks with random intensities and interstimulus intervals. Each stimulus block consisted of 80 stimuli and lasted for 20 min. Pain estimates, somatosensory evoked cerebral potentials (SSEPs) and power spectral density of the electroencephalogram (EEG) were measured under each drug condition. Under placebo, pain ratings and SSEP amplitudes were constant within the entire session lasting for approximately 4 h. Meperidine analgesia was evident within 30 min of drug application, reaching a maximum after about 90 min. Imipramine produced a comparable degree of pain reduction, however, with a delay of 2 h. Under both drugs, the decrease in pain ratings was accompanied by decreased amplitudes of the late components of the SSEP, as well as by a reduction in alpha activity and an enhancement of slow EEG waves. Effects of fluradoline on experimental pain could not be affirmed. These findings are discussed in terms of pain relief and decrease in vigilance.

Withdrawal reflex, skin resistance reaction and pain ratings due to electrical stimuli in man.

Simultaneous measurements of pain rating, withdrawal reflex, and skin resistance reaction with non-painful and painful electrical stimuli were performed on 15 healthy male volunteers. Eight different intensities were delivered in standardized randomized order. Each intensity appeared 10 times. There was no influence on the preceding stimulus on responses to the following stimulus. Neither skin resistance reaction nor withdrawal reflex were specific for pain in the sense that they appeared solely when pain was reported; the two reaction threshold currents were significantly smaller than the pain threshold. The reaction amplitudes, however, showed a close correlation to the intensity of sensation. The relations between all reactions measured and stimulus strength could be described best by power functions, with an exponent less than or equal to 1 if least square fits in linear scales were performed. Graphical evaluation in double logarithmic scales led to systematic errors causing higher exponents. Compound relations, like skin resistance reaction or withdrawal reflex amplitude as function of subjective estimation, could also be approximated by power functions, with parameters predictable from stimulus-reaction functions. No change in exponent was observed when subjective estimation turned from pre-pain to pain.

Hypnotic hypo- and hyperalgesia: divergent effects on pain ratings and pain-related cerebral potentials.

Pain ratings and pain-related cerebral potentials in response to noxious stimuli were investigated under hypnotic hypo- or hyperalgesia. Out of a sample of 50 subjects the 10 most highly hypnotizable were selected using the Stanford Hypnotic Susceptibility Scale. Phasic pain was induced by brief electrical stimuli intracutaneously applied to the subject's left middle finger. The subjects took part in three experimental sessions. The first session was without hypnosis for familiarization with the experimental surroundings. In the two other sessions, the subjects were hypnotized and given a suggestion of analgesia or hyperalgesia with respect to pain sensation in the left hand. The sequence of hypnosis was matched within and between sessions. Pain ratings and late cerebral somatosensory evoked potentials (SEP) were used to quantify pain reactions. In addition, auditory evoked potentials (AEP) and spontaneous EEG were evaluated to differentiate between pain-specific and unspecific effects of hypnosis. Only the subjects' verbal reports of pain were drastically influenced by hypnosis: suggestion of analgesia diminished the mean pain ratings, suggestion of hyperalgesia enhanced them (P < 0.001). In contrast, the amplitudes of the late somatosensory potentials evoked by the pain-inducing stimuli were not modified in either of the suggestive states. Furthermore, no effects of hypnosis were found on AEPs and on the power spectra of the spontaneous EEG. The results are discussed on the basis of a dissociation of sensory and affective components of pain under hypnosis.

Effects of acetaminophen and antipyrine on non-inflammatory pain and EEG activity.

Antinociceptive effects of the 2 (each 1000 mg, orally) non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen (paracetamol) and antipyrine (phenazone) were investigated with a non-inflammatory experimental pain model in 32 healthy volunteers. Phasic pain was induced by intracutaneously applied brief electrical pulses (20 msec). Pain ratings, cerebral potentials and the EEG delta power were measured in response to the stimuli. Unspecific effects upon the vigilance system were evaluated by spontaneous EEG, auditory evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind crossover study. Blood samples were taken to monitor the plasma concentrations of the active agents. Ninety minutes after medication the 2 NSAIDs produced similar effects upon all pain-relevant target variables, although the mean plasma concentration of antipyrine (15 micrograms/ml) was approximately twice that of acetaminophen (7.5 microgram/ml). Both NSAIDs reduced pain ratings by 6%, late cerebral potentials by 19%, and stimulus-induced delta power of the EEG by 21%. The antipyrine effects emerged earlier, in agreement with its faster kinetics. Both NSAIDs could be differentiated by their effects upon spontaneous EEG activity. Whereas acetaminophen mainly enhanced the power in the theta range, antipyrine predominantly depressed the alpha frequencies. None of the drugs influenced auditory evoked potentials and reaction times. The central effects of acetaminophen and antipyrine are discussed with respect to antinociception and decrease in vigilance.

Subcortical structures involved in pain processing: evidence from single-trial fMRI.

Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single-trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium-YAG (yttrium-aluminum-granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right- and left-sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.

Differentiation of conversive sensory loss and malingering by P300 in a modified oddball task.

We applied the methodology of evoked potentials (EP) to reveal the functional level of abnormality in a patient with circumscribed complete anaesthesia due to conversion disorder. EP components related to sensory and perceptual processing of both innocuous electrical and noxious laser stimuli were normal. However, a P300 component indicating cognitive processing failed to appear when using a modified oddball task with rare stimuli applied to the anaesthetic right hand. P300 was present with this paradigm stimulating the healthy left hand, as well as in a 'malingerer' - a healthy subject who was instructed to feign the same deficit. These results suggest cognitive deficits underlying sensory loss as conversion symptom which can be differentiated from malingering by use of P300.

Abeta-fiber mediated activation of cingulate cortex as correlate of central post-stroke pain.

A patient is presented who suffered a lateral brainstem infarction which selectively abolished pain and temperature sensitivity in the lower right limb. One year later central post-stroke pain had developed in the affected limb with touch and cold allodynia. P40m dipoles calculated from magnetoencephalographic fields after electrical stimulation of both tibial nerves were localized in SI as is seen in normal subjects. However, stimulation of the affected side caused deep pain sensations and elicited a large N80m component, best explained by an additionally active dipole in cingulate cortex. This early co-activation in a limbic structure suggests peripheral Abeta-fiber mediation and lemniscal projection. Abnormal link to the pain system may be due to sensitization and reorganization above the level of nociceptive deafferentation.

The pain inhibiting pain effect: an electrophysiological study in humans.

This study examines the counterirritation phenomenon of experimental pain in human subjects. Phasic pain induced by intracutaneous electrical stimuli was simultaneously applied with tonic pain induced by ischemic muscle work. Pain ratings, spontaneous EEG and evoked potentials were measured. We found a significant reduction of phasic pain ratings during and 10 min after tonic pain. The late somatosensory evoked potentials as neurophysiological correlates of phasic pain sensation were attenuated until 20 min after tonic pain offset. The extent of phasic pain relief due to concomitant tonic pain was small but significant, comparable to the effect of a regular systemic dose of a narco-analgesic drug in this experimental pain model. On the other hand, no modulations in the late components of the auditory evoked potential and the power spectrum of the spontaneous EEG were observed. These variables reflect the attention and vigilance of the subject and are well-known to be affected by opioids. The only exception was an increase of beta power, which might reflect hyperarousal during tonic pain. These results support the suggestion, that the analgesic effect of heterotopic noxious stimulation in humans is based on the activation of a specific inhibitory pain control system. Systemic release of endogenous opioids is unlikely to be involved, because the typical effects of opioids on the EEG were not observed.

Isoflurane induces dose-dependent changes of thalamic somatosensory information transfer.

In spite of several reports about suppressive effects of volatile anesthetics on somatosensation, their neuronal mechanisms are largely unknown. The present study investigates somatosensory impulse transmission at the thalamic level in rats under varied concentrations of isoflurane by recordings of neuronal responses to mechanical stimulation of the body surface. Single-unit recordings of thalamo-cortical relay neurons (TCNs, third order neurons; n=28) and presumed trigemino-thalamic fibers (TTFs, second order neurons; n=7) were performed in the ventral posteromedial nucleus. Functional response characteristics were quantified following defined tactile stimulation (trapezoidal or vibratory deflection of sinus hairs or fur) applied to the neuronal receptive fields. End-tidal isoflurane concentration was increased in steps of 0.2% between 0.6% (baseline) and 2.0%. The response activity in all TCNs studied was suppressed in a dose-dependent manner (2.0% isoflurane decreased responses to 3. 5+/-1.1% of baseline; mean+/-S.E.M.); the response activity in TTFs was much less affected (decrease to 55.0+/-8.2%). Suppression of ongoing activity, however, was similar for both, TCNs and TTFs. Furthermore, in TCNs, the response characteristics changed with increasing isoflurane between 1.0% and 1.8%: tonic and sustained responses were converted to phasic on-responses. In contrast, the tonic and sustained response characteristics of TTFs were preserved even at higher isoflurane concentrations. The results indicate that isoflurane attenuates the output of somatosensory signals in the specific nucleus of the rat's thalamus, while its input is only marginally affected. The observed changes of thalamic neuronal response characteristics, at least in part, may cause the loss in sensory discrimination observed during general anesthesia.

Antagonism between tilidine and naloxone on cerebral potentials and pain ratings in man.

The effects of the opioid tilidine and the opiate antagonist naloxone on somatosensory evoked potentials (SSEP) and pain ratings (E), elicited by electrical skin stimuli with randomized intensities, were investigated for different, orally administered tilidine and naloxone combinations in a double-blind Latin square design in 15 healthy humans. A high correlation between SSEP amplitudes and E was found for all treatments investigated. Tilidine (100 mg) decreased both SSEP amplitudes and E by about 25% compared to the placebo. No significant differences were found between the analgesic effects of tilidine and TN8 (tilidine 100 mg; naloxone 8 mg). The effects of both treatments were significantly different from those of the naloxone, placebo and TN32 treatments (tilidine 100 mg; naloxone 32 mg), indicating a marked naloxone-induced reversal of tilidine analgesia. Naloxone (32 mg) increased the SSEP amplitudes. No naloxone-induced hyperalgesia was seen in the pain ratings.

Effects of menthol and cold on histamine-induced itch and skin reactions in man.

The effects of cooling and topical application of menthol on histamine-induced itch, wheal and flare reactions of the left lower arm were investigated in a threefold cross-over design with 15 healthy male volunteers. Lowering skin temperature by cooling from 32.8 +/- 0.3 degrees C to 29.7 +/- 0.5 degrees C reduced itch intensity from 260 +/- 47 units to 55 +/- 12 units (visual analogue scale) and flare diameters from 39.0 +/- 2.0 mm to 30.2 +/- 1.8 mm; wheal reactions were not affected. A similar reduction in itch was found under menthol (42 +/- 14 units) although skin temperature was not decreased. These findings suggest a central inhibitory effect of cold sensitive A-delta fibre activation on itch.

Oscillating repolarization in action potentials of frog sensory myelinated nerve fibres.

Current and voltage clamp experiments were performed in single myelinated sensory nerve fibres of Rana esculenta. The K current was blocked by external tetraethylammonium-chloride and internal CsCl. Negative prepotentials led to the formation of a plateau in the repolarization phase of the action potential, and further regenerative depolarizations emerged from this plateau. A three-state model for Na inactivation based on voltage clamp data was sufficient to simulate these observations.

Evoked cerebral potential correlates of C-fibre activity in man.

CO2 laser emitted radiant heat pulses of 20 ms duration were used to activate predominantly slowly conducting nociceptive cutaneous afferents in man. Stimuli of two-fold individual pain threshold caused stinging and burning pain and elicited cerebral potentials with latencies consistent with A delta-fibre activity. After preferential block of the myelinated nerve fibres by pressure only the burning pain remained with significantly increased reaction time (about 1433 ms). The A delta-fibre-induced evoked potential components disappeared, and a marked ultralate positive component became visible with mean peak latency of 1260 ms, consistent with C-fibre activity.

Recovery from brain-stem lesions involving the nociceptive pathways: comparison of clinical findings with laser-evoked potentials.

Dissociated sensory impairment in brain-stem disorders suggests a lateral lesion involving the spinothalamic tract. Evoked potential studies of the somatosensory system with standard electrical stimulation (SEP) generally fail to establish objective correlates of such sensory deficits, because electrical stimuli predominantly activate large myelinated fibers that project into the medial lemniscal system. In contrast, laser-evoked potentials (LEPs), in response to brief radiant heat pulses, stimulate nociceptive afferents of the superficial skin and allow evaluation of thin fiber and spinothalamic tract function. We describe the recovery of deficits in pain sensitivity in five patients with isolated lateral brain-stem lesions that could be successfully monitored by LEP recordings in the acute stage and after intervals ranging from 7 months to 4 years. Upon first examination, LEPs were abnormal on the affected body side in all five cases of lateral medullary syndrome, irrespective of whether the etiology was vascular or inflammatory. The degree of recovery of pain sensitivity upon reexamination was reflected by the extent of normalization of the LEP. A control patient with vascular pontine lacunar stroke had normal LEPs on both sides, suggesting preserved spinothalamic conduction. The peak-to-peak amplitude of the main LEP component (N250-P400) correlated significantly with clinical pain sensitivity scored by standardized sensory testing (r = 0.76, p < 0.01). In contrast, early and late SEPs, after standard electrical median or tibial nerve stimulation, were normal in all patients, consistent with their intact mechanosensitivity. In conclusion, LEP studies allow the status of nociceptive function to be objectively and reliably documented on repeated examinations and therefore provide a useful supplement to multimodal sensory assessment in brain-stem disorders.

Response plasticity of pain evoked reactions in man.

Pain estimation (E), evoked cerebral potential (EP), electrooculogram (EOG), electromyogram of withdrawal reflex activity (EMG) and skin conductance reaction (SCR) were measured in response to electrical skin stimuli in 11 male volunteers (age 21-31 years). Constant current stimuli (20 msec; 2, 3, 6, 10 mA) were applied to a finger tip (averaged pain threshold at 5.1 mA). Interstimulus intervals (20-40 sec) and stimulus intensities were delivered in quasi-randomized order, each intensity appearing 40 times per session. Four sessions were repeated with intervals of two days between sessions. With randomized stimulus intensities, power spectral density functions of the prestimulus EEG indicated a stable non-specific arousal level between and within sessions. Under these conditions no significant response plasticity was found for E and EP, not in the prepain or the pain range, and also not between or within sessions. In contrast, the amplitudes of EOG, EMG and SCR decreased drastically with time, especially between the first and second session, and between the first 10 and second 10 stimuli of equal intensity in each session. EP and E remained highly correlated in repeated sessions. A EOG-EP contamination could be ruled out because of their different time course to repeated stimuli.

Correlations between histamine-induced wheal, flare and itch.

Correlations between the skin reactions wheal and flare and the subjectively reported degree of itch were investigated in response to 1% histamine, intradermally applied by standardized skin prick and by iontophoresis. Experiments were performed with 15 male volunteers using a threefold repeated measures design (skin prick, and iontophoresis with 0.13 mA for 10 s and with 2.0 mA for 10 s). Skin reactions (perpendicular diameters) were determined at the time of their maximum (10 min). Itch was rated on a computerized visual analogue scale which was anchored upon the individual scratch threshold. Most effective in producing itch was the skin prick which caused strong sensations markedly above the scratch threshold during the entire period of measurement (30 min), whereas iontophoresis induced only transient itch sensations. On the other hand, the largest wheals were generated by iontophoresis of both intensities (mean 10 or 14 mm vs 6 mm with skin prick). The higher current induced higher itch, wheal and flare responses, but after eliminating this effect of stimulus intensity, no correlations were found. In contrast, skin prick-induced flare reactions varied with the degree of itch above the scratch threshold (r = 0.56; P < 0.01). Repeated measurements showed a higher stability for the itch reaction with skin prick compared with iontophoresis. It is hypothesized that in iontophoresis the brief (10-s) histamine bolus passed the most superficial pruritoceptive C fibres too quickly to induce long-lasting itch sensations, whereas the skin prick caused a deposit at the dermal-epidermal junction releasing histamine during the entire time of measurement. Consequently, both the C fibre-mediated itch and the axon reflex flare were more pronounced with the skin prick, and the wheal resulting from a permeability increase in the postcapillary venule walls was an independent phenomenon.

Tonic pain inhibits phasic pain: evoked cerebral potential correlates in man.

In a sample of 10 healthy volunteers phasic pain ratings and evoked cerebral potentials (EPs) elicited by brief electrical skin stimuli were investigated in periods before, during, and after contralateral tonic ischemia pain. In all subjects the phasic pain ratings and the late EP components P80-N150 and N150-P260 were depressed under concurrent tonic pain. The magnitude of the mean reduction (31%, 40%, and 26%) is comparable to morphine analgesia. The early EP components with latencies below 80 ms, which are considered to be correlates of mechanosensitivity, were not influenced. The findings of tonic pain inhibiting phasic pain are discussed on the basis of changes in attention as well as of pain-specific physiological mechanisms like diffuse noxious inhibitory control.