Vertex-recorded, rather than primary somatosensory cortex-recorded, somatosensory-evoked potentials signal unpleasantness of noxious stimuli in the rat

In the present study, we investigated in the rat whether vertex- or primary somatosensory cortex-recorded somatosensory-evoked potentials (Vx-SEP/SI-SEP, respectively) signal unpleasantness of noxious stimuli. Therefore, initially we characterised fentanyl effects (0, 20, 40 or 50 microg/kg/h) on somatosensory and auditory processing by recording Vx-/SI-SEPs and vertex- and primary auditory cortex-recorded auditory-evoked potentials (Vx-/AI-AEPs, respectively). Subsequently, in a separate experiment, the animals were subjected to a Pavlovian fear-conditioning paradigm. The noxious stimuli applied to evoke Vx-/SI-SEPs (unconditioned stimulus (US)) were paired to a tone (conditioned stimulus (CS)) under 'steady state' conditions of 0, 20, 40 or 50 microg/kg/h fentanyl. Vx-/SI-SEPs were recorded simultaneously during these trials. After CS-US presentation, CS-induced fear-conditioned behaviour was analysed in relation to the SEPs recorded during CS-US presentation and the AEPs recorded in the first experiment. While the SI-SEP and AI-AEP were minimally but significantly affected, fentanyl dose-dependently decreased the Vx-SEP and Vx-AEP. The decrease of the Vx-SEP and Vx-AEP was parallelled by the dose-dependent decrease of the amount of CS-induced fear-conditioned behaviour. These results suggest that the dose-dependent decrease of the Vx-SEP amplitude, rather than of the SI-SEP, indicates that the US was experienced as less unpleasant. Next to an altered US processing, altered CS processing contributed to the decrease of the amount of CS-induced fear-conditioned behaviour as indicated by the dose-dependent decrease of the Vx-AEP.     

Prognostic value of somatosensory- and motor-evoked potentials in patients with a non-traumatic coma

Summary A total of 28 patients with non-traumatic coma were studied both with somatosensory- and motor-evoked potentials. While somatosensory-evoked potentials (SEP) have proved to be useful in predicting the outcome in patients with severe brain damage, the aim of this study was to find out whether the additional evaluation of motor-evoked potentials (MEP) could contribute to a better prediction of the outcome than SEP alone. Our results clearly indicate that in terms of prognostic value, SEP are superior to MEP. Nine patients with bilaterally preserved MEP died, while all of the patients with bilaterally preserved SEP and a central conduction time 6.5 ms survived, with a Glasgow outcome score of 1 to 3. Therefore, we cannot recommend the inclusion of MEP in the prognostic evaluation of patients with non-traumatic coma.     

The organization of motor responses to noxious stimuli

Withdrawal reflexes are the simplest centrally organized responses to painful stimuli, making them popular models for the study of nociception. Until recently, it was believed that withdrawal was a single reflex response involving excitation of all flexor muscles in a limb with concomitant inhibition of extensors. However, recent findings suggest that withdrawal reflexes are tailored to produce the most appropriate movement according the site at which the stimulus is applied, which could require extensors to act as the primary movers. This idea is supported by new evidence obtained from the direct measurement of limb movements, although these data indicate that differentiation of withdrawal reflexes is most readily seen from stimuli applied to the plantar surface of the foot. Injurious stimuli augment the protective function of reflexes by enhancing (sensitizing) reflexes that protect the injured site and inhibiting those reflexes that might exacerbate the insult. The areas from which a reflex can be sensitized closely match those from which the reflex itself can be evoked, provided that the spinal cord is intact. If descending pathways are interrupted, sensitization can be evoked from a much wider area. Thus, the exact movement made in a withdrawal reflex is determined by the location of the evoking stimulus and whether the reflex sensitized or inhibited after an injury depends on the relationship between the site of the injury and the movement made by the reflex. The factors should be borne in mind when designing experiments in which reflexes are used as the end point in studies of nociception.     

Effects of motor response expectancy on cortical processing of noxious laser stimuli

Previous studies have shown pain reductions during motor cortex stimulation or voluntary movements. To shed more light on cortical changes associated with decreases in pain during heightened level of motor preparedness in absence of movement, we decided to analyse the effects of motor readiness on EEG laser-evoked potentials (LEPs) by manipulating the expectancy of motor responses. Noxious laser stimuli were administered to the right hand in absence of any movements during periods associated with either high or no expectancy of motor response (HMRE or NMRE, respectively).Subjects reported greater pain intensity during NMRE than HMRE trials. The N1 component of LEPs, peaking at 141 ms and generated in the contralateral operculo-insular cortex, was larger during HMRE than NMRE periods. The amplitude of the N1 component during NMRE correlated with pain intensity. The P2 component peaked earlier during HMRE (336 ± 30 ms) than NMRE (356 ± 29 ms, P < 0.05) condition and its amplitude showed statistically significant positive correlation with subjective pain intensity.Results suggest that pain reduction during high motor expectancy may be related to summation of effects of motor readiness and nociceptive processing in operculo-insular cortex. Subjective pain intensity appears to be formed at an early, sensory stage of processing of laser stimulus in the absence of motor task and only later, during the period in which multiple behavioural challenges are evaluated, if motor readiness is heightened.     

Adelta nociceptor response to laser stimuli: selective effect of stimulus duration on skin temperature, brain potentials and pain perception.

OBJECTIVE: To disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception. METHODS: We used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature. RESULTS: Stimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1. CONCLUSIONS AND SIGNIFICANCE: The shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.     

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut–brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 ± 5.9 years), a 5 mm stainless-steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 μs) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two-dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 ± 1.2 vs 1.4 ± 0.3* μV, N2/P2: 17.2 ± 1.7 vs 4.6 ± 0.4* μV, P2/N3: 6.9 ± 0.7 vs 4.2 ± 0.5* μV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1–1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1,N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centro-parietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.     

Further studies of the effects of intranigral morphine on behavioral responses to noxious stimuli

Bilateral intranigral microinjection of morphine produces dose-related and naloxone reversible analgesic-like effects on the hot-plate and tail-flick tests. The main objectives of the present studies were to further characterize the analgesic-like effects of intranigral morphine, to determine whether these effects were related to a general impairment of sensory or motor function, and to assess their anatomical specificity. The principal findings are: (1) intranigral morphine (10 micrograms) suppresses pain-related behavior without altering responses to a variety of non-noxious auditory, visual, and somatic stimuli, and without producing motor impairment; (2) movement of injector needles approximately 1 mm rostral, dorsal, or medial to the active nigral site significantly reduces the analgesic-like effect of morphine on the tail-flick test; and (3) electrolytic lesions confined to the nigra significantly reduced the analgesic-like effect of morphine on the hot-plate test. It is concluded that the analgesic-like effects of intranigral morphine are mediated by the substantia nigra and that these effects are specifically related to pain.     

Effects of stimulating the subcoeruleus-parabrachial region on the non-noxious and noxious responses of T1-T5 spinothalamic tract neurons in the primate

The effects of electrical stimulation of the subcoeruleus-parabrachial (SC-PB) region on the discharge rate of upper thoracic spinothalamic tract (STT) neurons were investigated in 21 monkeys anesthetized with alpha-chloralose. STT cells were antidromically activated from the medial thalamus (MT) and the ventral posterior lateral nucleus (VPL) and received viscerosomatic convergent input from the cardiopulmonary sympathetic afferents and the left chest-forearm region. Stimulation of the SC-PB region inhibited the activity of all 30 STT neurons studied in the T1-T5 regions of the spinal cord. The minimum average current required to decrease the discharge rate of 22 cells exhibiting spontaneous activity was 89 +/- 10 microA (100 Hz, 100 microseconds duration). Currents as high as 300 microA completely inhibited the activity of most cells. Examination of the importance of frequency of stimulation from the SC-PB area on 8 cells revealed that impulses of at least 40 Hz (208 +/- 37 microA, 100 microseconds duration) were necessary to inhibit the spontaneous activity by 60%. Higher frequencies produced greater degrees of inhibition. Stimulation of the SC-PB region also inhibited the response of 23 of 23 neurons excited by noxious pinch and 11 of 11 wide dynamic range cells stimulated by innocuous input such as blowing or brushing hair. No differences in the inhibition produced by SC-PB stimulation on cells projecting to VPL (n = 20), MT (n = 5), or both VPL and MT (n = 5) were observed. These results demonstrate that the SC-PB region may be an important brainstem site for descending inhibition of both noxious and innocuous somatic input to upper thoracic STT cells in the primate.     

Effects of morphine and midazolam on reactivity to peripheral noxious and central aversive stimuli

Electrical stimulation of the mesencephalic tectum elicits behavioral and autonomic responses similar to those following peripheral noxious stimulation. Benzodiazepine and opioid compounds attenuate escape behavior induced by electrical stimulation of the dorsal periaqueductal gray (PAG) and deep layers of the superior colliculus (SC). The present study determines if microinjections of midazolam and morphine applied to these PAG-SC sites affect both responsiveness to peripheral noxious stimulation and to aversive PAG-SC stimulation. Both aversive brain stimulation or foot-shocks applied at threshold intensities caused running or jumps concomitant with increases in mean arterial blood pressure (MBP) and heart rate (HR). Microinjection of both drugs attenuated the behavioral reaction and increases in MBP and HR induced by mesencephalic tectum stimulation, while attenuating only the increase in heart rate induced by peripheral painful stimulation. These results suggest that the neural substrates of the behavioral and autonomic effects of stimulating the mesencephalic tectum and peripheral nociceptors are different although they may partially overlap.     

Characterization of responses of primary somatosensory cerebral cortex neurons to noxious visceral stimulation in the rat

In pentobarbital-anesthetized rats, responses of single neurons in primary somatosensory cortex (SI) to graded noxious visceral (colorectal distention, CRD) and cutaneous stimulation were recorded. One-hundred fifteen SI neurons were identified on the basis of spontaneous activity, 66 of which responded to CRD. CRD resulted in facilitation of neuronal activity in 33% and inhibition of activity in 52% of these cells. Fifteen percent had mixed facilitated/inhibited responses to varying CRD pressures. Cutaneous receptive fields were identified in 71% of CRD-responsive neurons, with low-threshold or wide dynamic range responses in most cases. Nearly all cutaneous receptive fields were small contralateral sites. Responses to CRD were independent of neuronal depth within the cortex. These data support a role of primary somatosensory cerebral cortical neurons in visceral nociception.     

Responses in the CA1 region of the rat hippocampus to a noxious stimulus.

We report here some physiological and pharmacological characteristics of noxious stimuli-induced changes in the hippocampal CA1 pyramidal cell synaptic excitability to field CA3 stimulation. A noxious heat stimulus applied to the left hind paw (LHP) produced a persistent depression of the CA1 population spike (PS) which habituated to a repetition of the stimulus. Interestingly, exposure of the tail to a noxious stimulus following habituation of the LHP produced a depression of the CA1 PS. This finding suggested that persistent depression and habituation are topographically represented. In separate experiments we determined that while the persistent depression of the CA1 population spike was accompanied by, in most cases, a prolonged increase in the amplitude of the CA1 antidromic field potential, there was a concurrent persistent depression and habituation of the CA1 PS and the corresponding apical dendritic field excitatory postsynaptic potential (dfEPSP). This suggested that noxious stimulus-induced CA1 synaptic depression is mediated at the apical dendritic region, perhaps postsynaptically at the dendrites and/or presynaptically on CA3 afferent terminals. Furthermore, atropine sulfate (40 mg/kg ip), which prevented the depression of the CA1 PS, also blocked the depression of dfEPSP when iontophoresed at the apical dendritic recording site. In addition atropine antagonized the depression of the dfEPSP produced by iontophoretic acetylcholine (Ach) but not gamma-aminobutyric acid. However, iontophoretic atropine at the cell body recording site did not prevent the depression of the CA1 PS. These results are consistent with the notion that Ach release in the apical dendrites of CA1 pyramidal cells following a noxious stimulus depresses CA1 synaptic excitability.     

Event-related potentials in response to 3-D auditory stimuli

To evaluate auditory spatial cognitive function, age correlations for event-related potentials (ERPs) in response to auditory stimuli with a Doppler effect were studied in normal children. A sound with a Doppler effect is perceived as a moving audio image. A total of 99 normal subjects (age range, 4–21 years) were tested. In the task-relevant oddball paradigm, P300 and key-press reaction time were elicited using auditory stimuli (1000 Hz fixed and enlarged tones with a Doppler effect). From the age of 4 years, the P300 latency for the enlarged tone with a Doppler effect shortened more rapidly with age than did the P300 latency for tone-pips, and the latencies for the different conditions became similar towards the late teens. The P300 of auditory stimuli with a Doppler effect may be used to evaluate auditory spatial cognitive function in children.     

Increased reactivity to chemical but not to heat noxious stimuli in mice producing anti-idiotypic antibodies for substance P

Mice immunized against anti-substance P (anti-SP) monoclonal antibodies produced anti-SP anti-idiotypic antibodies (SPAb2). In a previous report. SPAb2 antibodies were found to have in vitro biological activity i.e. to behave either as agonists or as antagonists for substance P (SP) depending on the biological test. In this study, the involvement of SPAb2 in vivo biological activity has been tested. Because of the possible implication of SP in the generation and transmission of nociceptive information, we have tested the responsiveness of SPAb2 responding mice in behavioral nociceptive tests. SPAb2 mice showed very small behavioral variations in the hot plate test as compared with a control group of mice immunized against an unrelated monoclonal antibody. In the formalin test, however, SPAb2 mice displayed a significant increase in paw licking time, which was significantly correleted with SPAb2 serum concentration. These results are discussed in terms of the use of SPAb2 as pharmacological tools for studying the biological properties of SP receptors and more generally of auto anti-idiotypic antibodies in modulating behavior responses.     

Involvement of the dorsolateral funiculi in the spinal release of Met-enkephalin-like material triggered by heterosegmental noxious mechanical stimuli

The lumbar spinal cord was superfused with artificial CSF at a rate of 0.1 ml/min in halothane anaesthetized rats. Under resting conditions, Met-enkephalin-like material (MELM) found in superfusates corresponded to a spinal release of 4.2 +/- 1.4 pg Met-enkephalin equivalents per 5 min. During a 30-min period in which pinches were applied to the muzzle, the MELM content in the superfusates increased markedly (by 120.5 +/- 32.9%). This effect was totally suppressed following bilateral lesions of the dorsolateral funiculi (DLF), under both chronic and acute conditions. It is concluded that strong mechanical stimuli applied in the trigeminal region can induce the release of MELM within the lumbar spinal cord via mechanisms involving the DLF. This heterosegmental release of Met-enkephalin may participate in the management of pain by methods involving high intensity stimulation.     

接触性热痛诱发电位的临床研究

目的 进一步完善接触性热痛诱发电位(CHEP)的检测方法 和检测痛觉传导通路上段脊髓丘脑束和周围段神经传导时间及周围段神经传导速度. 方法 受检者取卧位,应用CHEP刺激器,于54.5℃应用可调节脉冲,刺激部位为手背、前臂的掌侧面和C7水平皮肤.以Keypoint.net仪器记录,记录点为Cz和Pz,测定CHEP主要波形及外周神经传导速度. 结果 于记录点记录到2个主要成分;Cz/N550、Cz/P750;刺激手背、前臂掌侧面和C7水平皮肤所得CHEP起始波潜伏期男性女性间比较差异无统计学意义(P0.05);介导此诱发电位的外周神经传导速度为(12.9±7.5)m/s,与A8纤维传导速度相对应. 结论 主观疼痛能够进行客观测定,C7点刺激进行CHEP测定有助于判断脊髓丘脑束中枢段和周围段的损害.     

The effect of chronic pain upon the response to noxious stimuli by psychiatric patients

The literature on the experimental response to noxious stimuli in patients with chronic pain has been reviewed and it has been shown that there are very few studies in this field either of “psychogenic” or “organic” pain. The results are then reported of investigations of the response to pin-prick, of thresholds obtained with the pressure algometer and of the response to electric shock measured by electronic recording of finger-movement.

The pressure algometer was the most sensitive test-instrument employed. It showed a tendency for females to react more than males and for normal subjects to react less than patients. A special group of very hypochondriacal patients reacted earliest and most. There was a tendency for anxious patients without pain to react more than depressed patients without pain, and in fact depressed patients without pain reacted relatively late. On the other hand anxious patients with pain responded late to the algometer and depressed patients with pain responded to it relatively early. Patients with hysteria and pain occupied an intermediate position between other diagnostic groups.

A test of finger-movement in response to electric shock gave clear evidence that part of the response was related to anxiety in the test situation and part to the unpleasant nature of the stimulus. It did not distinguish well between groups but did indicate that normal subjects reacted less than patients with anxiety or with pain. Whilst the algometer was the most effective indicator of differences between groups in the response to noxious stimuli there were several significant intercorrelations with other test measures. Thus the two algometer measures of P.P.T. and S.P.T. were both significantly correlated with the response to pin prick. Further, the finger-movement test showed a significant correlation with the P.P.T., so that it seems as if these tests measured a common parameter of response.

Lastly, when the responses associated with a particular site were considered it was shown that psychiatric patients without headache were inclined to react slightly less than those with headache. However, there was no significant difference between them and other psychiatric patients with pain—even with the algometer tests which involved pain on the forehead. Thus, in at least this instance, there was no significant effect of local psychogenic pain upon the response to trauma at the same site.     

Spinal cord metabolic response to noxious radiant heat stimulation of the cat hind footpad

The 2-deoxy[¹⁴C]glucose (2-DG) method was used to study glucose utilization in the cat lumbar spinal cord during noxious thermal stimulation to the hind footpad. Spinal cord glucose utilization in stimulated cats was twice that of control animals. Diffusely increased metabolic activity was seen in the ipsilateral dorsal horn. The highest levels of 2-DG were seen in the ipsilateral ventral horn, while a moderate increase was seen in the contralateral ventral horn.     

Pharmacological differentiation between responses of rat medullary dorsal horn neurons to noxious mechanical and noxious thermal cutaneous stimuli

Responses of lamina V medullary dorsal horn neurons to noxious thermal and noxious mechanical facial stimuli were challenged with iontophoretically appliedcis-2,3-piperidine dicarboxlic acid, a broad spectrum excitatory amino acid antagonist. This antagonist reduced neuronal responses to noxious mechanical stimuli but not responses to noxious thermal stimuli. These results suggest that different neural mechanisms underlie the responses of lamina V neurons to different noxious stimuli, and that responses to noxious mechanical stimuli appear to involve excitatory amino acid receptors.     

Naloxone-reversible analgesia induced by electrical stimulation of the habenula in the rat

During a previous study of the nucleus parafascicularis (Pf), cells were recorded in the lateral habenula (HbL) which exhibited response patterns to peripheral noxious stimuli similar to those recorded in the Pf. In order to study the possible role of the habenular complex (Hb) in pain processing, we investigated the effect of electrical stimulation of the Hb on the tail-flick latency. For each series of experiments, the Hb of 15 female rats was implanted unilaterally, with bipolar electrodes, on either the right or left side. A week later, the animals were submitted to measurements of tail-flick latency, every 10 min, for a period of 3 h. The amount of analgesia was estimated by the percentage increase in latency. Five intensities of current (50, 100, 200, 300 and 400 microA) were used for stimulation during 60 s, at 50 Hz and 0.5-ms pulse width. A group of animals were given naloxone i.p. (1 mg/kg) 40 min after Hb stimulation at 200 microA to study the reversibility of the analgesia. A second group had their Hb destroyed by coagulation and the effect on tail-flick latency was checked once a week for 4 weeks. The results of these experiments clearly demonstrate Hb stimulation-induced analgesia, the maximum of which occurs 60-80 min after stimulation and then decreases slowly. The maximal amount of analgesia increases with the intensity of current up to 200 microA, without any behavioral side effects. At 300 microA, the analgesia is not significantly different from the one induced at 200 microA. However at 400 microA, behavioral side effects (fear, escape) appear and the analgesia is weaker. Two-hundred microA appears to be the most efficient current intensity and induces an average of 80% increase in tail-flick latency. The group which was given naloxone exhibited a dramatic and complete reversal of analgesia. The group which had their Hb destroyed did not show any difference from the control group a week after surgery. During the following weeks, both lesioned animals and controls exhibited a habituation-like analgesia, without any significant difference (the index of analgesia was 45.73 +/- 23.65% for the lesioned rats and 51.82 +/- 29.18% for the controls), which was not naloxone reversible. A review of the literature does not provide an explantation for Hb-induced analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)