Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia.

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.

Reduced paired pulse depression in the basal ganglia of dystonia patients.

Decreased inhibition and aberrant plasticity are key features in the pathophysiology of dystonia. Impaired short interval cortical inhibition and resultant increased excitability have been described for various forms of dystonia using paired pulse methods with transcranial magnetic stimulation of motor cortex. It is hypothesized that, in addition to cortical abnormalities, impairments in basal ganglia function may lead to dystonia but a deficit of inhibition within the basal ganglia has not been demonstrated to date. To examine the possibility that impaired inhibition and synaptic plasticity within the basal ganglia play a role in dystonia, the present study used a pair of microelectrodes to test paired pulse inhibition in the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) of dystonia and PD patients undergoing implantation of deep brain stimulating (DBS) electrodes. We found that there was less paired pulse depression of local field evoked potentials in the basal ganglia output nuclei of dystonia patients compared with Parkinson's disease patients on dopaminergic medication. Paired pulse depression could be restored following focal high frequency stimulation (HFS). These findings suggest that abnormalities exist in synaptic function of striatopallidal and/or striatonigral terminals in dystonia patients and that these abnormalities may contribute to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. These findings also suggest that HFS is capable of enhancing striatopallidal and striatonigral GABA release in basal ganglia output nuclei, indicating a possible mechanism for the therapeutic benefits of DBS in the GPi of dystonia patients.

Role of astrocytes in pain.

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.

Modulation of astroglial glutamine synthetase activity affects nociceptive behaviour and central sensitization of medullary dorsal horn nociceptive neurons in a rat model of chronic pulpitis.

Previous studies indicate that the astroglial glutamate-glutamine shuttle may be involved in acute pulpal inflammatory pain by influencing central sensitization induced in nociceptive neurons in the trigeminal subnucleus caudalis [the medullary dorsal horn (MDH)] by application of an inflammatory irritant to the rat tooth pulp. The aim of this study was to test if intrathecal application to the rat medulla of the astroglial glutamine synthetase inhibitor methionine sulfoximine (MSO) can influence the central sensitization of MDH nociceptive neurons and the animal's associated behaviour that are manifested in a model of chronic pulpitis pain induced by exposure of a mandibular molar pulp. This model was found to be associated with nocifensive behaviour and enhanced reflex activity evoked by mechanical stimulation of the rat's facial skin and with immunocytochemical evidence of astroglial activation in the MDH. These features were apparent for up to 28 days post-operatively. During this post-operative period, the nocifensive behaviour and enhanced reflex activity were significantly attenuated by intrathecal application of MSO (5 µL, 10 mM) but not by vehicle application. In electrophysiological recordings of nociceptive neuronal activity in the MDH, central sensitization was also evident in pulp-exposed rats but not in intact rats and could be significantly attenuated by MSO application but not by vehicle application. These behavioural and neuronal findings suggest that the astroglial glutamate-glutamine shuttle is responsible for the maintenance of inflammation-induced nocifensive behavioural changes and the accompanying central sensitization in MDH nociceptive neurons in this chronic pulpitis pain model.

Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms.

Studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in monkeys suggest that excessive inhibitory outflow from the internal segment of the globus pallidus (GPi) suppresses the motor thalamus, which reduces activation of the cerebral cortex motor system, resulting in the slowness and poverty of movement of Parkinson's disease (PD). This hypothesis is supported by reports of high rates of spontaneous neuronal discharges and hypermetabolism in GPi (ref. 4-7) and impaired activation of the supplementary motor area (SMA) and dorsolateral prefrontal regions in PD patients. Furthermore, lesion or chronic high-frequency electrical (likely inactivating) stimulation of GPi (ref. 10-14) is associated with marked improvements in akinesia and rigidity, and the impaired activation of SMA is reversed when the akinesia is treated with dopamine agonists. To test whether improvement in motor function with pallidal surgery can be attributed to increased activity in premotor cortical regions, we assessed the changes in regional cerebral blood flow (rCBF) and parkinsonian symptoms during disruption of GPi activity with high-frequency stimulation delivered through implanted brain electrodes. Positron emission tomography (PET) revealed an increase in rCBF in ipsilateral premotor cortical areas during GPi stimulation, which improved rigidity and bradykinesia. These results suggest that disrupting the excessive inhibitory output of the basal ganglia reverses parkinsonism, via a thalamic relay, by activation of brain areas involved in the initiation of movement.

Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.

Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

New developments in understanding the etiology of Parkinson's disease and in its treatment.

Important recent advances have been made in understanding the etiology and pathogenesis of Parkinson's disease, as well as in developing novel treatments. Two newly identified genes, alpha-synuclein and parkin, have been linked to parkinsonism. In addition, disturbances to the normal basal ganglia circuits in Parkinson's patients are being described at both anatomical and physiological levels. These developments provide a strong scientific basis for novel medical and surgical strategies to treat the profound motor disturbances in patients with Parkinson's disease.

Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp.

We have recently demonstrated that application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces central sensitization that is reflected in changes in spontaneous activity, mechanoreceptive field (RF) size, mechanical activation threshold, and responses to graded mechanical stimuli applied to the neuronal RF in trigeminal brainstem subnucleus caudalis and subnucleus oralis. The aim of this study was to test whether central sensitization can be induced in nociceptive neurons of the posterior thalamus by MO application to the pulp. Single unit neuronal activity was recorded in the ventroposterior medial nucleus (VPM) or posterior nuclear group (PO) of the thalamus in anesthetized rats, and nociceptive neurons were classified as wide dynamic range (WDR) or nociceptive-specific (NS). MO application to the pulp was studied in 47 thalamic nociceptive neurons and found to excite over 50% of the 35 VPM neurons tested and to produce significant long-lasting (over 40 min) increases in spontaneous activity, cutaneous pinch RF size and responses to graded mechanical stimuli, and a decrease in threshold in the 29 NS neurons tested; a smaller but statistically significant increase in mean spontaneous firing rate and decrease in activation threshold occurred following MO in the six WDR neurons tested. Vehicle application to the pulp did not produce any significant changes in six VPM NS neurons tested. MO application to the pulp produced pronounced increases in spontaneous activity, pinch RF size, and responses to mechanical stimuli, and a decrease in threshold in three of the six PO neurons. In conclusion, application of the inflammatory irritant MO to the tooth pulp results in central sensitization of thalamic nociceptive neurons and this neuronal hyperexcitability likely contributes to the behavioral consequences of peripheral inflammation manifesting as pain referral, hyperalgesia and allodynia.

Cortical involvement in the induction, but not expression, of thalamic plasticity.

The present study examined the role of the somatosensory cortex in the plasticity of thalamic sensory maps. Thalamic plasticity was induced by the disruption of hindlimb input by unilateral destruction of nucleus gracilis. Unilateral somatosensory cortex lesions were performed either on the same day as or a week after the removal of hindlimb input. Multiple electrode penetrations enabled us to measure the volume of somatosensory thalamus devoted to hindlimb, forepaw, and shoulder body regions. Cortical lesions alone did not change the volume of the shoulder, forepaw, or hindlimb representations in the thalamus relative to controls. However, these lesions blocked the increase in shoulder representation resulting from the nucleus gracilis lesion. In contrast, if thalamic reorganization caused by removal of hindlimb input was allowed to occur, subsequent somatosensory cortex lesions 1 week later did not prevent reorganization. Thus, an intact somatosensory cortex is necessary for the occurrence of sensory map reorganization at the thalamic level (induction) in response to nucleus gracilis lesions, but not for the maintenance of such changes once they are present (expression).

High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor.

It has been hypothesized that in Parkinson's disease (PD) there is increased synchronization of neuronal firing in the basal ganglia. This study examines the discharge activity of 121 pairs of subthalamic nucleus (STN) neurons in nine PD patients undergoing functional stereotactic mapping. Four patients had a previous pallidotomy. A double microelectrode setup was used to simultaneously record from two neurons separated by distances as small as 250 micrometer. In the six patients who had limb tremor during the recording session (n = 76 pairs), the discharge pattern of 12 pairs of tremor cells (TCs) was found to be coherent at the frequency of the limb tremor. Both in-phase and out-of-phase relationships were observed between TCs. Interestingly, in these six patients, 63/129 single neurons displayed 15-30 Hz oscillations, whereas 36/76 pairs were coherent in this frequency range. Although the oscillatory frequencies were variable between patients, they were highly clustered within a patient. The phase difference between these pairs was found to be close to 0. High-frequency synchronization was observed during periods of limb tremor as well as during intermittent periods with no apparent limb tremor. In contrast, in the three patients without limb tremor during the recording session, only 1/84 neurons had high-frequency oscillatory activity, and no TCs or synchronous high-frequency oscillatory activity was observed (n = 45 pairs). These findings demonstrate that in PD patients with limb tremor, many STN neurons display high-frequency oscillations with a high degree of in-phase synchrony. The results suggest that high-frequency synchronized oscillatory activity may be associated with the pathology that gives rise to tremor in PD patients.

Unique influence of stimulus duration and stimulation site (glabrous vs. hairy skin) on the thermal grill-induced percept.

BACKGROUND: The application to the skin of spatially interlaced innocuous warm (40 °C) and cool (20 °C) thermodes (termed a thermal grill--TG) can produce an unusual thermal percept, but the mechanisms remain unclear. METHODS: We compared the percept quality and intensity over a 120-s period evoked by each of three configurations of a 6-bar thermal stimulator (6 TS): all 40 °C(WARM); all 20 °C(COOL); alternating bars 40/20 °C (TG) at two body sites (forearm and palm). RESULTS: Both unpleasantness and pain were significantly greater for the TG-induced (vs. either COOL- or WARM-induced) percept. Unpleasantness ratings were significantly higher than pain intensity ratings. Several emotional qualitative descriptors were unique to the TG-induced percept. TG palmar (vs. forearm) stimulation produced a more intense percept and was perceived as painful in more subjects. Temporal profiles of intensities of TG-induced percepts differed from those induced by the COOL or WARM thermodes alone. For both unpleasantness and pain, the site differences in the temporal profile were also unique for TG versus the COOL- or WARM-evoked percepts. Qualitative characteristics of the TG-induced percept varied over time and between subjects. CONCLUSIONS: The TG percept intensity and temporal profile were different from those evoked by either of its component parts. The perceived quality is person-specific. These differences suggest that the classic 'TG illusion' results from complex central integration of several types of peripheral afferent inputs activated by the TG. Differing body site-related roles of thermosensory afferents in discrimination versus temperature homeostasis may explain site-related variations in the percept.

The afferent and efferent connections of the nucleus submedius in the rat.

The afferent and efferent connections of the nucleus submedius (Sm) in the medial thalamus of the rat were examined. Injections of wheat-germ agglutinin conjugated horseradish peroxidase (WGA-HRP) into the Sm resulted in dense terminal labeling in the middle layers of the ipsilateral ventrolateral orbital cortex (VLO). Less dense labeling was also observed in the superficial and deep layers of VLO and in the medial part of the lateral orbital cortex (LO) and in the contralateral VLO. Retrogradely labeled neurons were observed primarily in the deep layers of VLO and the dorsal peduncular cortex (DP). Labeled neurons were also observed bilaterally, in the nucleus of the horizontal limb of the diagonal band, the lateral hypothalamus, the thalamic reticular nucleus (Rt), medial parabrachial nucleus (MPB), and the laterodorsal tegmental nucleus (LDT). Many labeled neurons were also observed in the trigeminal brain-stem complex. Injections of Fluoro-Gold (FG) into Sm resulted in a very similar distribution of retrogradely labeled neurons. Injections of WGA-HRP and FG in the orbital cortex confirmed the ipsilateral Sm projection to VLO and suggested that the middle and deep layers of VLO receive a specific ipsilateral projection from the dorsal Sm and that the superficial layers receive a projection primarily from the ventral Sm. Injections of WGA-HRP into the lateral hypothalamus, LDT, and MPB confirmed the retrograde labeling findings; the lateral hypothalamus was found to send a projection to the medial Sm, the LDT region to the ventromedial Sm and the MPB to the medial and dorsal Sm. These findings confirm and extend the results of previous studies in cat and rat indicating that Sm has a major and specific reciprocal connection with VLO. This finding, in conjunction with previous studies showing direct spinal and trigeminal inputs and the existence of nociceptive neurons in Sm and VLO, provides further support for a role of Sm in nociception.

Trigeminal projections to the nucleus submedius of the thalamus in the rat.

Methods involving the anterograde and retrograde transport of wheat-germ agglutinin conjugated horseradish peroxidase and the retrograde transport of Fluoro-Gold were used in rats to examine the distribution within the spinal trigeminal nucleus of trigeminal neurons projecting to the nucleus submedius (Sm) of the thalamus, as well as the distribution of axon terminals within the Sm. Following injections into the trigeminal nucleus, axon terminals were seen in the dorsal part of the anterior Sm; the terminals occurred bilaterally but had an obvious contralateral dominance. To help determine the precise location of the Sm-petal neurons, the border between trigeminal subnuclei interpolaris and caudalis was examined by the use of immunohistochemical procedures for calcitonin gene-related peptide (CGRP). The Sm-petal neurons that were labeled retrogradely occurred only at the caudal interpolaris and rostral caudalis levels; the number of labeled neurons on the contralateral side was approximately six times that on the ipsilateral side. Most of these neurons were located in the ventral part of the caudal interpolaris and rostral caudalis and spinal trigeminal tract; in caudalis, the neurons were almost exclusively localized to its superficial layers. There were approximately three times more labeled neurons in interpolaris than in caudalis. In the experiments combined with immunohistochemistry for CGRP, many neurons (34%) were seen in proximity to CGRP-like immunopositive fibers. These results suggest that the Sm of the rat receives its orofacial afferent inputs from brainstem neurons that are localized to the caudal interpolaris and rostral caudalis. In view of previous studies that have implicated these three structures in somatosensory function, and in particular nociception, our data point to a role for this direct projection from interpolaris and caudalis to Sm in the central processing of pain.

Two major types of premotoneurons in the feline trigeminal nucleus oralis as demonstrated by intracellular staining with horseradish peroxidase.

Previous studies suggest that neurons in the dorsomedial subdivisions of trigeminal nucleus oralis (Vo) may contribute to reflex control of jaw movements and to modulation of sensory information. The present study has addressed this possibility by the use of intracellular staining with horseradish peroxidase of physiologically identified neurons in Vo to examine functional and morphological properties of these neurons. Of 14 labeled neurons, eight had axon collaterals terminating exclusively in the dorsolateral subdivision of the trigeminal motor nucleus (DL neurons) and four in its ventromedial subdivision (VM neurons); axon collaterals of two neurons were not traced. Both groups of neurons sent terminal arbors into other nuclei of the lower brainstem. The DL neurons were distinguishable from the VM neurons in their receptive field (RF) location, neuronal position, somadendritic architecture, and projections to other brainstem nuclei. All neurons, except for two that were exclusively activated by noxious stimuli applied to the tongue, were responsive to light mechanical stimulation of peri- and intraoral structures. The RFs of the DL neurons were located in more posterior oral structures than those of the VM neurons. The RF of nearly all low-threshold DL neurons was located in the maxillary region, and that of the VM neurons, in contrast, involved the mandibular region. The VM neurons were located medial or ventral to the DL neurons. The soma size of the VM neurons was significantly larger than that of the DL neurons. Dendritic arbors of both groups could be separated into medial and lateral components. The ratio of the dendritic transverse areas in the medial vs. lateral component was significantly higher in the VM neurons than in the DL neurons. The DL neurons also issued collaterals that terminated in larger brainstem areas than those of the VM neurons. These observations provide new evidence on the morphological and functional properties of Vo neurons that contribute to reflex control of jaw and facial movements and modulation of sensory information.

Responses of neurons in the rat thalamic nucleus submedius to cutaneous, muscle and visceral nociceptive stimuli.

The findings of recent studies have suggested that nucleus submedius (Sm) may be an important thalamic relay for nociceptive information. The aim of the present electrophysiological study was to examine in greater detail the activity and response properties of neurons in the rat Sm in order to further evaluate this hypothesis. Single unit extracellular recordings from neurons histologically verified to be in Sm were obtained in urethane/chloralose-anesthetized rats. Noxious but not innocuous mechanical stimulation elicited responses in 75% of the 204 neurons studied. Most (85%) of these neurons were excited, 10% were inhibited and a few neurons (5%) were excited by stimulation at some sites on the body and inhibited from other sites. The receptive fields were usually very large and bilateral. No marked differences were observed in the incidence, response type, or spontaneous activity of neurons located in dorsal, ventral, rostral or caudal parts of Sm. Most of these neurons (99 of 108, 92%) also responded to noxious heating and had a mean threshold of 47 degrees C. The majority of the neurons (19 of 21, 90%) also responded to subcutaneous, intramuscular or intraperitoneal injections of noxious chemicals (formalin or hypertonic saline). The responses elicited by pinching skin or squeezing muscle were frequently facilitated by the subcutaneous or intramuscular injections of formalin. Single electrical stimuli delivered to the cutaneous receptive field rarely produced responses. However, short trains (15-25 msec trains of 200 Hz, 3 msec pulses at 5-10 mA) delivered repetitively elicited responses in 90% (n = 73) of the neurons. These responses appearing after repetitive stimulation frequently resembled the 'wind-up' pattern observed in spinal cord dorsal horn. The conduction velocities of the primary afferents which elicited the Sm neuronal responses as estimated from the latency differences of responses elicited by stimulation at two points along the tail, were indicative of recruitment of A delta and C fibers. These findings provide further support for the proposed role of Sm in thalamic nociceptive mechanisms.

Effects of nucleus raphe magnus stimulation on jaw-opening reflex and trigeminal brain-stem neurone responses in normal and tooth pulp-deafferented cats.

Since we have recently shown that tooth pulp deafferentation results in changes in the receptive field properties and activity of brain-stem neurones in the adult cat's subnucleus oralis of the trigeminal (V) spinal tract nucleus, we wished to determine if these changes are associated with alterations in the powerful inhibitory influence that the nucleus raphe magnus (NRM) normally exerts on these neurones and on the related digastric jaw-opening reflex. In control cats or in cats that had undergone mandibular or maxillary tooth pulp deafferentation 7-140 days previously, the effects of NRM conditioning stimulation were tested on jaw-opening reflex responses or oralis neuronal responses evoked by stimulation of the maxillary or mandibular tooth pulp, facial skin, or oral mucosa. No statistically significant difference was noted between control and deafferented animals (n = 32) in the incidence, threshold or time course of NRM-induced inhibition of the reflex responses. Likewise, no difference was noted between control and deafferented animals in these features of the inhibition of oralis neuronal responses. In 276 neurones tested, the high incidence (92%), low threshold (0.08-0.15 mA) and prolonged time course (approximately 400 msec) of NRM-induced inhibition of responses evoked by electrical stimulation of the tooth pulp or by low-intensity electrical or mechanical stimulation of facial skin and oral mucosa were comparable in both groups of animals. These findings indicate that the alterations in properties or oralis neurones subsequent to tooth pulp deafferentation may not be associated with changes in the modulatory influence emanating from the NRM.

A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients.

Thalamic neurons are known to switch their firing from a tonic pattern during wakefulness to a bursting pattern during sleep. Several studies have described the existence of bursting activity in awake chronic pain patients and have suggested that this activity is abnormal and may be related to their pain. However, we have frequently observed bursting activity in awake non-pain patients suggesting that there may not be a causal relationship between thalamic bursting activity and chronic pain. To examine this issue more rigorously we compared the incidence and pattern of bursting activity of lateral thalamic neurons of both pain and non-pain patients in a state of wakefulness. Recordings were obtained from lateral thalamic areas of different groups of patients (n = 91) suffering from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal neuralgia, post-stroke pain) and motor disorders (e.g. Parkinson's disease, essential tremor) during stereotactic surgical procedures for the treatment of pain and movement disorders. Burst indices (the number of bursting cells per electrode track) were computed for all the explorations in the two groups. The burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16, respectively) were not significantly different from each other. The bursts were analyzed to see if they fulfilled the criteria of low-threshold calcium spike (LTS)-evoked bursts characterized by (i) a shortening of the first interspike interval with an increase in the number of interspike intervals in the burst and also (ii) a progressive prolongation of successive interspike intervals. LTS-evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and 15/32 (47%) cells in non-pain patients. These data demonstrate that the occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is prevalent in both pain and non-pain patients. This suggests that the bursting activity of thalamic neurons in pain patients is not necessarily related to the occurrence of their pain.

Ventrolateral orbital cortex and periaqueductal gray stimulation-induced effects on on- and off-cells in the rostral ventromedial medulla in the rat.

On- and off-cells of the rostral ventromedial medulla are thought to be involved in bulbospinal inhibition of ascending nociceptive information. Experiments were carried out in lightly anaesthetized rats to assess the effects of prefrontal cortex stimulation on the responses of neurons in the rostral ventromedial medulla. For comparison purposes, effects of periaqueductal gray stimulation were also investigated. Single unit activity was recorded in the rostral ventromedial medulla and on-, off- and neutral-cells were identified based on the tail nocifensor reflex to noxious heat. Short (0.1-1 s) and long (10-15 s) trains of bipolar electrical stimulation (100-300 Hz) were delivered to the ventrolateral orbital cortex of the rat forebrain and the periaqueductal gray. Short-train stimulation of the periaqueductal gray (including dorsolateral, ventrolateral and the dorsal raphé regions) excited 58% (25 of 43) of on-cells and 44% (seven of 16) of off-cells in the rostral ventromedial medulla. Long trains blocked the noxious stimulus-evoked pause of all seven off-cells tested and blocked the excitatory response of two, and enhanced one of three on-cells. Such stimulation also inhibited or abolished the tail-flick reflex at currents below 100 microA. Glutamate microinjections into the periaqueductal gray inhibited the noxious-evoked response of two off- and two on-cells and increased the tail-flick latency. Short-train stimulation of the ventrolateral orbital cortex (100-400 microA) excited eight of 25 on-cells and inhibited the ongoing activity of 10 of 14 off-cells. Long-train ventrolateral orbital cortex stimulation (5-15 s, 100-200 microA, 200-300 Hz) enhanced the noxious evoked responses of 10 of 11 on-cells, prolonged the noxious heat-evoked pause of all of four off-cells and decreased the tail-flick latency (pronociception). The results of this study support the proposed role of on- and off-cells in descending inhibition of nociception from the periaqueductal gray and implicate the ventrolateral orbital cortex in the control of this pathway.

Involvement of the periaqueductal grey matter and spinal 5-hydroxytryptaminergic pathways in morphine analgesia: effcts of lesions and 5-hydroxytryptamine depletion.

1 Electrolytic lesions of the periaqueductal grey matter (PAG) were made in rats. The analgesia produced by intraperitoneal injection of morphine (10 and 20 mg/kg), tested by the tail flick and hot plate methods, was substantially reduced in the lesioned rats. Baseline pain thresholds were unaffected by the lesions.2 The lesion effects were not due to damage to the dorsal raphé nucleus. The extent of histologically determined damage to the dorsal raphé and the resulting decrease in striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations did not correlate with the reduction in morphine analgesia produced by the lesion. Furthermore, microinjections of 5, 6-dihydroxytryptamine (5,6-DHT) into the dorsal raphé nucleus produced a similar fall in 5-HIAA levels but had no effect on morphine analgesia.3 Selective destruction of the periventricular catecholamine system produced by microinjection of 6-hydroxydopamine (6-OHDA) caused a slight decrease in morphine analgesia, thus raising the possibility that catecholamines may be involved in the action of morphine in the PAG.4 5,7-Dihydroxytryptamine-induced lesions of the spinal cord 5-hydroxytryptaminergic pathways reduced cord 5-HT concentration by 70% and markedly attenuated morphine analgesia as determined by the tail flick test.5 These experiments provide additional evidence that the PAG is a major site of action of opiates in producing analgesia. Furthermore, they have demonstrated the probable involvement of spinal 5-hydroxytryptaminergic pathways in the mediation of opiate analgesic effects.

Visceral pain evoked by thalamic microstimulation in humans.

Microstimulation within and below the ventrocaudal nucleus (Vc) in the human thalamus typically evokes non-painful, paraesthetic cutaneous sensations. We now describe cases in which thalamic microstimulation evoked visceral pains. Data were obtained during stereotactic thalamotomy procedures. Patient 211 had a history of essential tremor. At a site 0.5 mm ventroposterior to Vc, microstimulation elicited pain described as 'deep, internal, in a straight line like my appendix pain years ago'. Patient 153 had a history of post-stroke hemibody pain. In each of two trajectories, at sites approximately 2 mm ventroposterior to Vc, microstimulation evoked pain in the groin. At one of these sites, the pain was described as 'like having a baby'. These and additional observations suggest that stimulation ventroposterior to Vc can evoke visceral pain and may trigger pain 'memories'.