NMDA Channels Together With L-Type Calcium Currents and Calcium-Activated Nonspecific Cationic Currents Are Sufficient to Generate Windup in WDR Neurons

2010 ◽  
Vol 104 (2) ◽  
pp. 1155-1166 ◽  
Author(s):  
P. Aguiar ◽  
M. Sousa ◽  
D. Lima
Keyword(s):  
Membrane Potential ◽  
Dorsal Horn ◽  
Action Potentials ◽  
Dynamic Range ◽  
Calcium Influx ◽  
Calcium Currents ◽  
Factors Affecting ◽  
Dorsal Horn Neurons ◽  
C Fibers ◽  
Wdr Neurons

Windup is characterized as a frequency-dependent increase in the number of evoked action potentials in dorsal horn neurons in response to electrical stimulation of afferent C-fibers. This phenomenon was first described in the mid-60s, but the core mechanisms behind it still remain elusive. Several factors affecting its dynamics have been identified, but the distinction between modulating mechanisms from generating mechanisms is not always clear. Several mechanisms contribute to the excitation of dorsal horn neurons exhibiting windup, and one of our main aims was to help making this distinction. The approach presented here relies on mathematical and computational analysis to study the mechanism(s) underlying windup. From experimentally obtained windup profiles, we extract the time scale of the facilitation mechanisms that may support the characteristics of windup. Guided by these values and using simulations of a biologically realistic compartmental model of a wide dynamic range (WDR) neuron, we are able to assess the contribution of each mechanism for the generation of action potentials windup. We show that the key mechanisms giving rise to windup is the temporal summation of N-methyl-d-aspartate (NMDA) long-lasting postsynaptic responses taking place on top of a membrane potential cumulative depolarization. Calcium-activated nonspecific cationic currents driven by calcium influx from L-type calcium channels and synaptic currents support this cumulative depolarization and plateau formation in WDR neuron membrane potential. The effects of different nonhomogeneous stimulation protocols are explored, and their important role in clarifying many aspects of the windup generation is shown. The models are used to produce several predictions that can be tested experimentally.

Responses of rat medullary dorsal horn neurons following intranasal noxious chemical stimulation: effects of stimulus intensity, duration, and interstimulus interval

1993 ◽  
Vol 70 (6) ◽  
pp. 2260-2275 ◽  
Author(s):  
P. Peppel ◽  
F. Anton
Keyword(s):  
Dorsal Horn ◽  
Stimulus Intensity ◽  
Mechanical Stimulation ◽  
Interstimulus Interval ◽  
Dynamic Range ◽  
Chemical Stimulation ◽  
Dorsal Horn Neurons ◽  
C Fibers ◽  
Medullary Dorsal Horn ◽  
Wdr Neurons

1. Most quantitative examinations of nociception are performed with thermal or mechanical stimuli. Because nociceptive processing mechanisms may depend on the modality of the stimuli, comparable studies on chemonociception are necessary. 2. We examined the activity of chemonociceptive medullary dorsal horn neurons in halothane-anesthetized rats. For controlled noxious chemical stimulation, defined CO2 pulses were applied to the nasal mucosa. The effects of stimulus intensity, duration, and interstimulus interval (ISI) were tested by performing three different CO2 stimulation protocols (see below). 3. The recorded neurons were characterized by intranasal and facial stimuli of different modalities. The cells received input from intranasal A delta- and/or C-fibers. All tested neurons also responded to other intranasally applied irritants, e.g., mustard oil. Furthermore, the units were sensitive to intranasal high-threshold mechanical stimulation and to facial mechanical stimulation. According to the properties of their facial mechanoreceptive fields, the units were classified as wide dynamic range (WDR) or nociceptive specific (NS) neurons. The majority of the cells also responded to facially applied noxious heat stimuli, so that most of the recorded neurons were found to be multimodal. Some of the neurons, in addition, had convergent input from primary afferents innervating the maxillary tooth pulps or the cornea and periorbital structures. 4. In the first stimulation protocol we presented four different CO2 concentrations (25, 50, 75, and 100%; stimulus duration 2 s). In total, each concentration was applied 10 times (2 trains of 5 stimuli). Stimulus response functions (SRFs) were computed with average responses to identical stimuli. All but 2 of the 23 tested neurons displayed enhanced responses after stimulation with increasing intensities. In general, WDR cells (n = 15) discharged more vigorously to the same CO2 concentration than NS cells (n = 8). WDR neurons discriminated more reliably between stimulus intensities in the low to moderate range (25–50% CO2) than NS cells. Both categories of neurons, however, discriminated equally well in the moderate- to high-intensity range (50–75% CO2). The discriminatory capacity of WDR and NS neurons was reduced in the highest concentration range (75–100% CO2). The proportion of NS neurons significantly discriminating between these intensities tended to be higher compared with WDR neurons when stimuli were applied with long ISIs (120 s). 5. To examine the effects of the duration of the ISI, identical test sequences were performed with ISIs of 30 and 120 s. (ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla

2017 ◽  
Vol 118 (5) ◽  
pp. 2727-2744 ◽  
Author(s):  
Sergey G. Khasabov ◽  
Patrick Malecha ◽  
Joseph Noack ◽  
Janneta Tabakov ◽  
Glenn J. Giesler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptor Activation ◽  
Rostral Ventromedial Medulla ◽  
Dorsal Horn Neurons ◽  
Descending Modulation ◽  
Ventromedial Medulla ◽  
Neurokinin 1 ◽  
Wdr Neurons

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain. NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

Incision-induced Changes in Receptive Field Properties of Rat Dorsal Horn Neurons 

1999 ◽  
Vol 91 (3) ◽  
pp. 772-772 ◽  
Author(s):  
Peter K. Zahn ◽  
Timothy J. Brennan
Keyword(s):  
Receptive Field ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Background Activity ◽  
Mechanical Stimulus ◽  
High Threshold ◽  
Pain Mechanisms ◽  
Dorsal Horn Neurons ◽  
Plantar Aspect ◽  
Wdr Neurons

Background To learn more about pain mechanisms produced by surgery, responses of wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons were studied before and after an incision. For this study, an incision was made in a mechanically insensitive area of the receptive field (RF) of the dorsal horn neuron in the plantar aspect of the foot and changes in mechanical response properties were studied. Methods Action potentials from single dorsal horn neurons were recorded in halothane anesthetized rats and these neurons were characterized as WDR or HT. Changes in background activity and responses to a variety of mechanical stimuli adjacent to the incision, distant to the injury, and in areas throughout the hindquarters were recorded. Results Fifty neurons were recorded (29 WDR, 21 HT cells); only nine of these had a sustained increase in background activity after incision. Marked decreases in threshold to von Frey filaments applied adjacent to the wound occurred in 9 of 28 WDR neurons but in none of 21 HT cells. Von Frey filament thresholds distant to the incision were largely not changed. A blunt mechanical stimulus activated 18 of 22 WDR neurons when applied directly on the incision. HT cells were largely not excited by this mechanical stimulus after incision. The RF to pinch was enlarged in 31 neurons to include areas outside the injury. Pinch RFs of both WDR and HT cells expanded. Conclusion These results suggest that incisions in mechanically insensitive areas of the RF of dorsal horn neurons produced little change in background activity; expansion of pinch RFs outside the injury was common. Changing a mechanically insensitive area of the RF of WDR neurons to a mechanically sensitive area by an incision could contribute to pain behaviors that indicate primary mechanical hyperalgesia in behavioral studies.

Alterations in Ascending Dorsal Horn Neurons by a Surgical Incision in the Rat Foot

2000 ◽  
Vol 93 (5) ◽  
pp. 1294-1302 ◽  
Author(s):  
Erik P. Vandermeulen ◽  
Timothy J. Brennan
Keyword(s):  
Dorsal Horn ◽  
Dynamic Range ◽  
Background Activity ◽  
Mechanical Stimuli ◽  
Behavioral Experiments ◽  
Surgical Incision ◽  
Dorsal Horn Neurons ◽  
Low Threshold ◽  
Plantar Incision ◽  
Wdr Neurons

Background Little is known about the mechanisms of pain caused by a surgical incision. The authors have developed a rat model of postoperative pain characterized by decreased withdrawal thresholds to punctate mechanical stimuli after plantar incision. The present studies examined the response characteristics of dorsal horn neurons receiving input from the plantar aspect of the foot before and after a plantar incision placed adjacent to the low threshold area of the receptive field (RF). Methods Individual dorsal horn neurons from the lumbar enlargement were antidromically identified and characterized as low threshold, wide dynamic range (WDR), and high threshold (HT) based on their responses to brush and pinch. Thresholds (in millinewtons), the pinch RF, and stimulus-response functions (SRFs) to von Frey filaments characterized the neurons. SRFs were analyzed using area under the curve. Changes in background activity, punctate mechanical thresholds, SRFs, and RF were recorded after an incision was made adjacent to the most sensitive area of the RF. Results In all cells, an incision increased background activity; this remained elevated in 3 of 9 HT and 16 of 28 WDR neurons 1 h later. The SRFs were enhanced in 10 of 27 WDR neurons and in 2 of 8 HT cells after incision. Only the WDR neurons were responsive to filaments that produced withdrawal responses after incision in behavioral experiments. Increases in the RFs outside of the injured area occurred after incision in 15 of 29 WDR and 2 of 9 HT cells. Conclusion A plantar incision caused dorsal horn cell activation and central sensitization. Because the threshold of HT neurons did not decrease to the range of the withdrawal responses in behavioral experiments, particular WDR dorsal horn neurons likely contribute to the reduced withdrawal threshold observed in behavioral experiments. Both WDR and HT neurons are capable of transmitting enhanced responses to strong punctate mechanical stimuli after incision.

scholarly journals Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

2018 ◽  
Vol 120 (4) ◽  
pp. 1893-1905 ◽  
Author(s):  
Steve McGaraughty ◽  
Katharine L. Chu ◽  
Jun Xu
Keyword(s):  
Dorsal Horn ◽  
High Intensity ◽  
Dynamic Range ◽  
Spontaneous Firing ◽  
Wide Dynamic Range ◽  
Experimental Conditions ◽  
Rat Models ◽  
Dorsal Horn Neurons ◽  
Pathological Pain ◽  
Wdr Neurons

This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data were collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared with naive animals (1.9 Hz) but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low-intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high-intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high-intensity stimulation did not change relative to control in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Nav1.7, Nav1.8, P2X7, P2X3, H3), other targets affected neither evoked nor spontaneous firing of WDR neurons (e.g., H4, TRPM8, KCNQ2/3), and some only modulated evoked (e.g, ASIC1a, Cav3.2) whereas others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites, although the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics. NEW & NOTEWORTHY Data from multiple individual experiments were combined to show firing properties of wide dynamic range and nociceptive specific spinal dorsal horn neurons across varied pathological pain models. This high-powered analysis describes the sensitization following different forms of injury. Effects of diverse pharmacology on these neurons is also summarized from published and unpublished data all recorded under the same conditions to facilitate comparison. This comprehensive overview describes the function and utility of these neurons.

scholarly journals Strong Manual Acupuncture Manipulation Could Better Inhibit Spike Frequency of the Dorsal Horn Neurons in Rats with Acute Visceral Nociception

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Shouhai Hong ◽  
Shasha Ding ◽  
Fei Wu ◽  
Qiang Xi ◽  
Qiang Li ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Dynamic Range ◽  
Spike Frequency ◽  
Gastric Distension ◽  
Dependent Manner ◽  
Manual Acupuncture ◽  
Dorsal Horn Neurons ◽  
Visceral Nociception ◽  
Spinal Cord Level ◽  
Wdr Neurons

Afferent impulses from visceral nociception can be regulated by acupuncture at spinal cord level; however, the effects of different manual acupuncture (MA) manipulations on the afferent impulses are still unknown. Here, we analyzed the spike frequency of excitatory gastric-related wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) following acute gastric distension (GD) in rats and compared their responses to MA manipulations with four different frequencies (0.5, 1, 2, and 3 Hz) at Zusanli (ST36). Results indicated that the spike frequency was increased by acute GD stimulation. Under acute GD circumstances, the spike frequency was further activated by weak MA stimulation (0.5 and 1 Hz), while being significantly inhibited by strong MA stimulation (2 and 3 Hz). After 10 minutes of the strong MA stimulation, same intensity of acute GD caused less spike frequency. Our previous researches had demonstrated that different MA manipulations could increase spike frequency in an intensity-dependent manner in normal rats; these findings suggest that acupuncture may have different modulatory effects depending on the state of the stomach. Since neuronal spike frequency was related to the level of nociception, the results suggest that strong MA manipulation may have better effect on acute visceral nociception.

Descending inhibitory influences from periaqueductal gray, nucleus raphe magnus, and adjacent reticular formation. II. Effects on medullary dorsal horn nociceptive and nonnociceptive neurons

1983 ◽  
Vol 49 (4) ◽  
pp. 948-960 ◽  
Author(s):  
J. O. Dostrovsky ◽  
Y. Shah ◽  
B. G. Gray
Keyword(s):  
Dorsal Horn ◽  
Dynamic Range ◽  
Periaqueductal Gray ◽  
Nucleus Raphe Magnus ◽  
Nucleus Reticularis ◽  
Medullary Dorsal Horn ◽  
Significant Difference ◽  
Raphe Magnus ◽  
Somatosensory Responses ◽  
Wdr Neurons

1. This study examined the inhibitory effects elicited by brain stem stimulation on the somatosensory responses of trigeminal medullary dorsal horn (subnucleus caudalis of the spinal trigeminal nucleus) neurons. Single-unit extracellular recordings were obtained in chloralose-anesthetized cats. Neurons were classified as wide dynamic range (WDR), nociceptive specific (NS), or low-threshold mechanoreceptive (LTM). Conditioning stimuli were delivered to the periaqueductal gray (PAG), nucleus cuneiformis (CU), nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis (NGC), and nucleus reticularis magnocellularis (NMC). 2. Over 97% of the neurons tested could be inhibited by stimulation in all regions except PAG. Stimulation in the PAG inhibited 91% of the neurons tested. There was no statistically significant difference in the incidence of inhibition of WDR and NS nociceptive (noci) neurons and the LTM nonnociceptive (nonnoci) neurons. 3. Mean stimulation intensities necessary to produce inhibition were determined for each neuron from each stimulation site. The current thresholds necessary to inhibit the responses of noci neurons were found to be significantly lower, on the average, than those of nonnoci neurons at stimulation sites in the PAG, CU, and NGC. 4. Inhibition of the responses of WDR neurons required a lower mean current than for NS neurons but was statistically significant only for PAG and NGC. Thresholds for inhibiting the responses of NS neurons were similar to those for inhibiting the responses of LTM neurons for all regions except CU, where LTM thresholds were markedly but not significantly higher. 5. Stimulation thresholds were found to be lowest in NMC, while in NGC, NRM, and CU they were all similar and slightly higher. Stimulation in the PAG required the highest currents to produce inhibition. 6. These results indicate that stimulation in NRM and PAG not only inhibits the responses of noci neurons but also those of nonnoci neurons. Furthermore, stimulation in reticular regions adjacent to NRM and PAG is frequently even more effective in inhibiting the responses of both noci and nonnoci neurons. In addition, WDR neurons are more effectively inhibited than NS or LTM neurons. These results are compared with those obtained using similar methods in cat lumbar dorsal horn.

Low- and high-voltage-activated calcium currents in rat spinal dorsal horn neurons

1990 ◽  
Vol 63 (2) ◽  
pp. 273-285 ◽  
Author(s):  
P. D. Ryu ◽  
M. Randic
Keyword(s):  
Dorsal Horn ◽  
High Voltage ◽  
Calcium Current ◽  
Spinal Dorsal Horn ◽  
Calcium Currents ◽  
High Threshold ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Low Threshold ◽  
Spinal Dorsal Horn Neurons

1. Calcium currents in immature rat spinal dorsal horn neurons in transverse slices were studied with the single-electrode voltage-clamp technique. Using experimental conditions that minimized voltage-dependent Na+ and K+ currents, we distinguished low- and high-voltage-activated calcium currents on the basis of their voltage dependence and sensitivity to the Ca2(+)-channel agonist and antagonist drugs. 2. The low-voltage-activated transient calcium current is evoked with weak depolarizing voltage commands. It begins to activate at potentials positive to -70 mV and increases in amplitude and rate of decay with depolarization, the peak values being reached between -40 and -30 mV. The current is fully activated at a holding potential of about -110 mV. Steady-state inactivation is complete at potentials in the range of -60 to -50 mV. 3. The transient component of the high-threshold calcium current appears at membrane potentials close to -40 mV and slowly decays within several hundreds of milliseconds. The amplitude of the current increases with more negative holding potentials (-100 to -40 mV). 4. The sustained component of the high-threshold calcium current seems to activate at potentials positive to -40 mV and exhibits little inactivation during 0.3- to 0.5-s depolarizing commands. This component is better isolated at more depolarized holding potentials (between -40 and -30 mV) that inactivate the transient components of the low- and high-threshold calcium currents. 5. A rundown of calcium currents was seen in dorsal horn cells. The time stability of the transient and sustained components of the high-threshold calcium current was lower than that of the low-threshold transient current. The latter current seemed to be insensitive up to 1 h. 6. (-)-Bay K 8644 (1-10 microM), a dihydropyridine agonist, enhanced the high-threshold calcium current, in particular the sustained component, but not the transient low-threshold calcium current. The dihydropyridine antagonist nifedipine (5-50 microM) selectively reduced the sustained component of the high-threshold calcium current while having little or no effect on the transient components of the low- and high-threshold calcium currents. 7. Cadmium ions (60-100 microM) and cobalt ions (2 mM) markedly reduced both components of the high-threshold calcium current, and Cd2+ only slightly decreased the low-threshold transient current. However, all three components are indiscriminately blocked by higher concentrations of Cd2+ and Co2+.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Electrophysiological Changes in Adult Rat Dorsal Horn Neurons After Neonatal Peripheral Inflammation

2003 ◽  
Vol 90 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Yuan Bo Peng ◽  
Qing Dong Ling ◽  
M. A. Ruda ◽  
Daniel R. Kenshalo
Keyword(s):  
Spinal Cord ◽  
Receptive Field ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
High Threshold ◽  
Peripheral Inflammation ◽  
Mechanical Stimuli ◽  
Neonatal Rats ◽  
Adult Rats ◽  
Dorsal Horn Neurons

Neonatal peripheral inflammation has been shown to produce profound anatomical changes in the dorsal horn of adult rats. In this study, we explored whether parallel physiological changes exist. Neonatal rats were injected with complete Freund's adjuvant (CFA) into the left hind paw. At 8–10 wk of age, single dorsal horn neurons were recorded in response to graded intensities of mechanical stimuli delivered to the receptive field. In addition, cord dorsum potentials, produced by electrical stimuli delivered to the left sciatic nerve at 2.5× threshold, were recorded bilaterally from L2 to S3. There were significant increases in background activity and responses to brush and pinch in neonatal rats that were treated with CFA, as compared with control rats. Further analysis showed similar significant changes when dorsal horn neurons were categorized into wide dynamic range (WDR), high-threshold (HT), and low-threshold (LT) groups. The receptive field was significantly larger in neonatally treated rats as compared with control rats. Additionally, there was a significant increase in the response to a 49°C heat stimulus in neonatally treated rats as compared with control rats. There was also a trend for the amplitudes of N1, N2, and P waves of the cord dorsum potential to increase and latencies to decrease in neonatally treated rats, but no significant differences were detected between different levels of the spinal cord (L2 to S3). These data further support the notion that anatomical and physiological plasticity changes occurred in the spinal cord following early neonatal CFA treatment.

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