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Showing papers on "Summation published in 2003"


Journal ArticleDOI
01 Mar 2003-Pain
TL;DR: Temporal summation of pain and after‐sensations elicited by thermal stimulation of the skin are moderately enhanced for FMS subjects, and normal input from muscle nociceptors appears to underlie production of central sensitization in FMS that generalizes to input from cutaneous nocICEptors.
Abstract: Individuals diagnosed with fibromyalgia syndrome (FMS) report chronic pain that is frequently worsened by physical activity and improved by rest. Palpation of muscle and tendinous structures suggests that nociceptors in deep tissues are abnormally sensitive in FMS, but methods of controlled mechanical stimulation of muscles are needed to better characterize the sensitivity of deep tissues. Accordingly, force-controlled mechanical stimulation was applied to the flexor digitorum muscle of the forearm in a series of brief contacts (15 stimuli, each of 1s duration, at 3 or 5s interstimulus intervals). Repetitive stimulation was utilized to determine whether temporal summation of deep muscular pain would occur for normal subjects and would be enhanced for FMS subjects. Moderate temporal summation of deep pain was observed for normal controls (NC), and temporal summation was greatly exaggerated for FMS subjects. Temporal summation for FMS subjects occurred at substantially lower forces and at a lower frequency of stimulation. Furthermore, painful after-sensations were greater in amplitude and more prolonged for FMS subjects. These observations complement a previous demonstration that temporal summation of pain and after-sensations elicited by thermal stimulation of the skin are moderately enhanced for FMS subjects. Abnormal input from muscle nociceptors appears to underlie production of central sensitization in FMS that generalizes to input from cutaneous nociceptors.

371 citations


Journal ArticleDOI
01 Aug 2003-Pain
TL;DR: The increased temporal summation, and the slight decrease in mechanical pain thresholds, suggest that central nociceptive neurons do express activation‐dependent plasticity, a change that may hold a key to more effective prophylactic treatment.
Abstract: Recent clinical studies showed that acute migraine attacks are accompanied by increased periorbital and bodily skin sensitivity to touch, heat and cold. Parallel pre-clinical studies showed that the underlying mechanism is sensitization of primary nociceptors and central trigeminovascular neurons. The present study investigates the sensory state of neuronal pathways that mediate skin pain sensation in migraine patients in between attacks. The assessments of sensory perception included (a) mechanical and thermal pain thresholds of the periorbital area, electrical pain threshold of forearm skin, (b) pain scores to phasic supra-threshold stimuli in the same modalities and areas as above, and (c) temporal summation of pain induced by applying noxious tonic heat pain and brief trains of noxious mechanical and electrical pulses to the above skin areas. Thirty-four pain-free migraine patients and 28 age- and gender-matched controls were studied. Patients did not differ from controls in their pain thresholds for heat (44+/-2.6 vs. 44.6+/-1.9 degrees C), and electrical (4.8+/-1.6 vs. 4.3+/-1.6 mA) stimulation, and in their pain scores for supra-threshold phasic stimuli for all modalities. They did, however, differ in their pain threshold for mechanical stimulation, just by one von Frey filament (P=0.01) and in their pain scores of the temporal summation tests. Increased summation of pain was found in migraineurs for repeated mechanical stimuli (delta visual analog scale (VAS) +2.32+/-0.73 in patients vs. +0.16+/-0.83 in controls, P=0.05) and repeated electrical stimuli (delta VAS +3.83+/-1.91 vs -3.79+/-2.31, P=0.01). Increased summation corresponded with more severe clinical parameters of migraine and tended to depend on interval since last migraine attack. The absence of clinically or overt laboratory expressed allodynia suggests that pain pathways are not sensitized in the pain-free migraine patients. Nevertheless, the increased temporal summation, and the slight decrease in mechanical pain thresholds, suggest that central nociceptive neurons do express activation-dependent plasticity. These findings may point to an important pathophysiological change in membrane properties of nociceptive neurons of migraine patients; a change that may hold a key to more effective prophylactic treatment.

152 citations


Journal ArticleDOI
06 Feb 2003-Neuron
TL;DR: In CA1 pyramidal neurons of the hippocampus, a brief period of correlated pre- and postsynaptic activity, which induces long-term potentiation or long- term depression, results in a persistent increase or decrease in the linearity of spatial summation, respectively.

133 citations


Journal ArticleDOI
TL;DR: In this article, the properties and functional roles of voltage-dependent potassium channels in the dendrites of Purkinje neurons studied in rat cerebellar slices were characterized using outside-out patches formed 250m away from the soma.
Abstract: We characterized the properties and functional roles of voltage-dependent potassium channels in the dendrites of Purkinje neurons studied in rat cerebellar slices. Using outside-out patches formed250m away from the soma, we found that depolarization-activated potassium channels were present at high density throughout the dendritic tree. Currents required relatively large depolarizations for activation (midpoint, approximately 10 mV), had rapid activation and deactivation kinetics, and inactivated partially (20 ‐70% over 200 msec) with both fast (time constant, 15‐20 msec) and slow (300 ‐ 400 msec) components. Inactivating and noninactivating components were both blocked potently by external tetraethylammonium (half-block by 150M) and 4-aminopyridine (half-block by 110M). The voltage dependence, kinetics, and pharmacology suggest a predominant contribution by Kv3 family subunits, and immunocytochemical experiments showed staining for both Kv3.3 and Kv3.4 subunits in the dendritic tree. In the proximal dendrite, potassium channels were activated by passively spread sodium spikes recorded at the same position, and experiments using dual recordings showed that the channels serve to actively dampen back-propagation of somatic sodium spikes. In more distal dendrites, potassium currents were activated by voltage waveforms taken from climbing fiber responses, suggesting that they help shape these responses as well. The requirement for large depolarizations allows dendritic Kv3 channels to shape large depolarizing events while not disrupting spatial and temporal summation of smaller excitatory postsynaptic potentials.

128 citations


Journal ArticleDOI
01 Dec 2003-Pain
TL;DR: Both PPT and perceived pressure pain intensity are subject to a considerable spatial summation in all the regions tested, probably within the receptive field of single spinal nociceptive neurons.
Abstract: The characteristics of spatial summation of pressure pain are not clear. Pressure pain threshold (PPT) and perceived pressure pain intensity were measured in the hand, painfree back and myofascial trigger points (MTPs) in the back, using three different stimulus areas (0.5, 1 and 2 cm2). PPT decreased and perceived pain increased significantly with an increase in stimulation area in all the regions (e.g. PPT in the back, from 406±168 to 205±102 kPa, P<0.0001). The magnitude of spatial summation of pressure pain was not significantly different between the regions. However, PPT in the back was significantly higher compared to the hand and MTPs (e.g. for 2 cm2: mean of 205±102 vs 175±75 and 159±72 kPa, P<0.01, respectively). Irrespective of body region, the quality of pain evoked with the large areas (1 and 2 cm2) was of pressure whereas in the small area (0.5 cm2) it was perceived as a prick. In conclusion, both PPT and perceived pressure pain intensity are subject to a considerable spatial summation in all the regions tested. The quality of pressure-evoked pain is probably determined by this spatial summation. Body region significantly affects the PPT level for a fixed stimulation area but not the magnitude of its spatial summation for areas up to 2 cm2, which are probably within the receptive field of single spinal nociceptive neurons.

67 citations


Journal ArticleDOI
TL;DR: Temporal summation of heat pain was strongly influenced by the ISIs and cannot be explained by small increases in skin temperature between taps or by heat storage throughout a stimulus series, which appeared to be established primarily by peripheral factors.
Abstract: Temporal summation of heat pain during repetitive stimulation is dependent on C nociceptor activation of central N-methyl-d-aspartate (NMDA) receptor mechanisms. Moderate temporal summation is prod...

50 citations


Journal ArticleDOI
TL;DR: The results appear to provide new evidence for the existence of separate S-cone ON and OFF pathways, and are compared with known morphology of primate retina and assume that, if S- cone decrements are detected via separate OFF cells, these should differ in density and dendritic field size from the S- cones ON cells, but only in the retinal periphery.

39 citations


Journal ArticleDOI
TL;DR: It is found that muscle pain sensitivity was higher in the trapezius than in the anterior tibial muscle, and temporal summation, a clinical correlate of wind-up, is more pronounced in muscle than in skin, which may help explain why chronic muscle pain most frequently is located in the shoulder and neck regions.
Abstract: Chronic myofascial pain is very common in the general population. The pain is most frequently located in the shoulder and neck regions, and nociceptive input from these regions may play an important role for tension-type headache. The mechanisms leading to the frequent occurrence of muscle pain in the shoulder and neck regions are largely unknown. It is possible that the pain is caused by increased sensitivity of muscle nociceptors or by central sensitization induced by nociceptive input from muscle. The primary aim of the present study was to compare muscle pain sensitivity in the trapezius and anterior tibial muscles. The secondary aim was to investigate whether temporal summation, a clinical correlate of wind-up, is more pronounced in muscle than in skin and, if so, whether such a difference is more pronounced in the trapezius than in the anterior tibial region. Sixteen healthy subjects were included. Pressure-pain thresholds and electrical cutaneous and intramuscular pain thresholds were measured at standard anatomical points in the trapezius and anterior tibial regions. Temporal summation was assessed by repetitive electrical stimulation. Pressure-pain thresholds (P = 0.005) and intramuscular electrical pain thresholds (P = 0.006) were significantly lower in trapezius than in anterior tibial muscle. Temporal summation was present in skin and muscle of both regions (P < 0.001). The degree of temporal summation was significantly higher in muscle than in skin in the trapezius region (P = 0.02), but not in the anterior tibial region (P = 0.47). In conclusion, we found that muscle pain sensitivity was higher in the trapezius than in the anterior tibial muscle. We also demonstrated that temporal summation could be induced in both muscle and skin and, importantly, that temporal summation was significantly more pronounced in muscle than in skin in the trapezius but not in the anterior tibial region. These data may help to explain why chronic muscle pain most frequently is located in the shoulder and neck regions.

38 citations


Journal ArticleDOI
TL;DR: In this article, the authors assess the shunting effect of GABA(A) receptor activation and I(h) on the summative properties of pyramidal neurons in the rat somatosensory cortex.
Abstract: The timing and location of action potential initiation in layer V pyramidal cells of the rat somatosensory cortex depends on different ligand-gated and intrinsic conductances. In order to assess the shunting effect of GABA(A) receptor activation and I(h) on the summative properties of these neurons, we recorded simultaneously from their somata and dendrites and induced combined excitatory and inhibitory postsynaptic potentials using extracellular stimulation. Three major consequences of GABA(A) receptor activation on the integration properties were found: (i) the action potential could be initiated in the distal apical dendrite, if GABA(A) receptors were simultaneously activated in the soma; (ii) GABA(A) receptor activation narrowed the time window for suprathreshold summation of two coincident excitatory synaptic inputs by a factor of 3.4; and (iii) uneven weights of the GABAergic components between two inputs could lead to unbalanced shunting and consequently to a time shift in the peak of the coincidence detection window. Blockade of I(h) practically abolished coincidence detection within a time window of 30 ms. Location of spike initiation and summation of coincident inputs in pyramidal cells is determined by at least two shunting mechanisms: activation of the presynaptic inhibitory network and modulation of I(h) as a function of the postsynaptic membrane potential.

38 citations


Journal ArticleDOI
TL;DR: Increasing the duration or frequency of stimulation increases the concentration of isoflurane required to suppress movement by a 0.4 minimum alveolar concentration, a finding consistent with temporal summation (which requires intact N-methyl-d-aspartate receptor activity) at concentrations of up to 1 minimum alVEolar concentration isofLurane.
Abstract: Background: General anesthesia may delay the onset of movement in response to noxious stimulation. The authors hypothesized that the production of immobility could involve depression of time-related processes involved in the generation of movement. Methods: The delays (latencies) between onset of tail clamp (n 16) or 50-Hz continuous electrical stimulation (n 8) and movement were measured in rats equilibrated at 0.1– 0.2% increasing steps of isoflurane. In other rats (n 8), the isoflurane concentrations just permitting and preventing movement (crossover concentrations) in response to trains of 0.5-ms 50-V square-wave pulses of interstimulus intervals of 10, 3, 1, 0.3, or 0.1 s during the step increases were measured. These measures were again made during administration of intravenous MK801, an N-methyl-D-aspartate receptor antagonist that can block temporal summation (n 6). Temporal summation refers to the cumulative effect of repeated stimuli. Crossover concentrations to 10- and 0.1-s interstimulus interval pulses ranging in voltage from 0.25–50 V were also measured (n 4). Results: The increase in concentrations from 0.6 to nearly 1.0 minimum alveolar concentration progressively increased latency from less tha n1st o 58 s.Shortening the interstimulus interval (50 V) pulses from 10 to 0.1 s progressively increased crossover concentrations from 0.6 to 1.0 minimum alveolar concentration. In contrast, during MK801 administration shortening interstimulus intervals did not change crossover concentrations, producing a flat response to change in the interstimulus interval. Increasing the voltage of interstimulus interval pulses increased the crossover concentrations but did not change the response to change in interstimulus intervals for pulses greater than 1 V. Conclusions: Increasing the duration or frequency (interstimulus interval) of stimulation increases the concentration of isoflurane required to suppress movement by a 0.4 minimum alveolar concentration MK801 blocks this effect, a finding consistent with temporal summation (which requires intact N-methyl-D-aspartate receptor activity) at concentrations of up to 1 minimum alveolar concentration isoflurane. THE mechanical or electrical stimulation used to determine MAC (the minimum alveolar concentration producing immobility in 50% of subjects receiving noxious stimulation) is applied continuously for up to 1 min. 1–5 This period allows for a delay between the onset of stimulation and the beginning of movement. The delay seems to increase as the anesthetic concentration approaches MAC, suggesting that time-related processes underlie the generation of the movement and that increasing anesthetic concentrations are required to suppress the response to increasing durations of stimulation. Such processes may be assessed by application of temporally graded electrical stimuli of the type used to create neuronal windup. 6 –10 Typically, these stimuli are trains of brief (0.5 ms) high-intensity square-wave pulses with relatively large interstimulus intervals (ISI), often up to 3 s. Such stimuli delivered to spinal cord afferents of spinal cord-transected rats can produce a cumulative depolarization of dorsal and ventral horn neurons. After several seconds, this progressive depolarization can reach a threshold, triggering a sustained burst of action potentials, giving rise to the term “windup.” N-methyl-Daspartate (NMDA) receptor activity underlies at least part of the cumulative depolarization and subsequent windup. 11,12 We hypothesized that temporal summation, the cumulative effect of repeated stimulation, might govern part of the MAC for isoflurane anesthesia. Although electrophysiologic and electromyographic effects of temporal summation have been investigated during isoflurane and halothane anesthesia in humans and rodents, 13–16 the involvement of temporal summation in the generation of movement during anesthesia has not been investigated. To document the time-related dose-dependent effect of isoflurane on the generation of movement responses, we measured the latency to movement after tail clamp and 50-Hz continuous stimulation. To test for temporal summation, we measured the effect of the ISI on the latency to movement responses, on the concentrations required to achieve immobility, and on the observed buildup of muscle tone and hindlimb electromyogram. To determine if disruption of temporal summation impaired the generation of movement, we measured the effect of the NMDA antagonist, MK801, on isoflurane concentrations required to achieve immobility during the ISI pulses. To study the dose-dependent effect of isoflurane on temporal summation, we studied the effect of ISIs of increasing voltage and the corresponding increasing concentrations required to achieve immobility.

33 citations


Journal ArticleDOI
TL;DR: The findings suggest that a single lumbar epidural dose of fentanyl should be injected at the spinal interspace corresponding to the dermatomal site of pain, and could therefore contribute to prevention and treatment of central hypersensitivity states.
Abstract: Results. Fentanyl 100 mg, but not 50 mg, produced analgesia to heat stimulation only at L2. Surprisingly, no effect at S1 was detected. Both fentanyl doses significantly increased temporal summation threshold and decreased muscle pain intensity. Conclusions. The findings suggest that a single lumbar epidural dose of fentanyl should be injected at the spinal interspace corresponding to the dermatomal site of pain. Increased effect on L2 compared with S1 suggests that drug effect on spinal nerve roots and binding to opioid receptors on the dorsal root ganglia may be more important than traditionally believed for the segmental effect of epidurally injected fentanyl. Epidural fentanyl increases temporal summation threshold and could therefore contribute to prevention and treatment of central hypersensitivity states. I.M. injection of hypertonic saline is a sensitive technique for detecting the analgesic action of epidural opioids.

Journal ArticleDOI
TL;DR: Using a compartmental model derived from morphological recordings of hippocampal CA1 pyramidal neurons, the hypothesis that Ih was primarily responsible for normalization of temporal summation was examined and it was concluded that this hypothesis was incomplete.
Abstract: Recent experimental and theoretical studies have found that active dendritic ionic currents can compensate for the effects of electrotonic attenuation In particular, temporal summation, the percentage increase in peak somatic voltage responses invoked by a synaptic input train, is independent of location of the synaptic input in hippocampal CA1 pyramidal neurons under normal conditions This independence, known as normalization of temporal summation, is destroyed when the hyperpolarization-activated current, I h, is blocked [Magee JC (1999a), Nature Neurosci 2: 508–514] Using a compartmental model derived from morphological recordings of hippocampal CA1 pyramidal neurons, we examined the hypothesis that I h was primarily responsible for normalization of temporal summation We concluded that this hypothesis was incomplete With a model that included I h, the persistent Na+ current (I NaP), and the transient A-type K+ current (I A), however, we observed normalization of temporal summation across a wide range of synaptic input frequencies, in keeping with experimental observations

Journal ArticleDOI
TL;DR: The present in vitro modelling suggests that passive signal transmission in neurons will depend on type of signal conveyed, on directionality and on membrane state, particularly important for thalamic interneurons, whose presynaptic dendrites may either work independently or function in concert with each other and with the soma.
Abstract: Computer models were used to investigate passive properties of lateral geniculate nucleus thalamocortical cells and thalamic interneurons based on in vitro whole-cell study. Two neurons of each type were characterized physiologically and morphologically. Thalamocortical cells transmitted 37% of steady-state signal orthodromically (distal dendrite to soma) and 93% antidromically (soma to distal dendrite); interneurons transmitted 18% orthodromically and 53% antidromically. Lowering membrane resistance caused a dramatic drop in steady-state signal transmission. Simulation of brief signals such as orthodromically transmitted postsynaptic potentials and antidromically transmitted action potentials showed relatively poor transmission due to the low-pass filtering property of dendrites. This attenuation was particularly pronounced in interneurons. By contrast, bursts of postsynaptic potentials or action potentials were relatively well transmitted as the temporal summation of these recurring signals gave prolonged depolarizations comparable to prolonged current injection. While synaptic clustering, active channels and reduction of membrane resistance by ongoing synaptic activity will have additional profound effects in vivo, the present in vitro modelling suggests that passive signal transmission in neurons will depend on type of signal conveyed, on directionality and on membrane state. This will be particularly important for thalamic interneurons, whose presynaptic dendrites may either work independently or function in concert with each other and with the soma. Our findings suggest that bursts may be particularly well transmitted along dendrites, allowing firing format to alter the functional anatomy of the cell.


Journal ArticleDOI
TL;DR: A conductance-based model for synaptic transmission and postsynaptic integration reveals how post Synaptic responses and their variability depend on the number of synaptic inputs.