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.

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.

Changes in Properties of Spinal Dorsal Horn Neurons and Their Sensitivity to Morphine after Spinal Cord Injury in the Rat

2005 ◽  
Vol 102 (1) ◽  
pp. 152-164 ◽  
Author(s):  
Jungang Wang ◽  
Mikito Kawamata ◽  
Akiyoshi Namiki
Keyword(s):  
Spinal Cord ◽  
Spontaneous Activity ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
High Threshold ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Cord Injury ◽  
Spinal Dorsal Horn Neurons ◽  
Wdr Neurons

Background To gain a better understanding of spinal cord injury (SCI)-induced central neuropathic pain, the authors investigated changes in properties of spinal dorsal horn neurons located rostrally and caudally to the lesion and their sensitivity to morphine in rats after SCI. Methods The right spinal cord of Sprague-Dawley rats was hemisected at the level of L2. At 10 to 14 days after the SCI, when mechanical hyperalgesia/allodynia had fully developed, spontaneous activity and evoked responses to mechanical stimuli of wide-dynamic-range (WDR) and high-threshold neurons rostral and caudal to the lesion were recorded. Effects of cumulative doses of systemic (0.1-3 mg/kg) and spinal (0.1-5 microg) administration of morphine on spontaneous activity and evoked responses to the stimuli of the neurons were evaluated. Results Spontaneous activity significantly increased in WDR neurons both rostral and caudal to the SCI site, but high-frequency background discharges with burst patterns were only observed in neurons rostral to the SCI site. Significant increases in responses to the mechanical stimuli were seen both in WDR and high-threshold neurons located both rostrally and caudally to the lesion. The responses to nonnoxious and noxious stimuli were significantly greater in caudal WDR neurons than in rostral WDR neurons. In contrast, the responses to pinch stimuli were significantly higher in rostral high-threshold neurons than those in caudal high-threshold neurons. Systemically administered morphine had a greater effect on responses to nonnoxious and noxious stimuli of rostral WDR neurons than those of caudal WDR neurons. Spinally administered morphine significantly suppressed responses of WDR neurons in SCI animals to nonnoxious stimuli compared with those in sham-operated control animals. Conclusions The findings suggest that changes in properties of spinal dorsal horn neurons after SCI are caused by different mechanisms, depending on the classification of the neurons and their segmental locations.

Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla

1995 ◽  
Vol 74 (4) ◽  
pp. 1742-1759 ◽  
Author(s):  
H. L. Fields ◽  
A. Malick ◽  
R. Burstein
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Gray Matter ◽  
Cervical Spinal Cord ◽  
Rostral Ventromedial Medulla ◽  
Minimum Threshold ◽  
Antidromic Activation ◽  
Spinal Cord Neurons ◽  
Ventromedial Medulla ◽  
On And Off Cells

1. The rostral ventromedial medulla (RVM) participates in the modulation of nociceptive transmission by spinal cord neurons. Previous anatomic studies have demonstrated that RVM neurons project to laminae I, II, and V of the dorsal horn; laminae VII and VIII of the intermediate and ventral horns; the intermediolateral column; and lamina X. The RVM contains at least three physiologically defined classes of neurons, two of which, the ON and the OFF cells, have been implicated in nociceptive modulation. Because these cells classes are intermingled in the RVM, it has not been possible to determine the spinal laminar projection targets of ON and OFF cells by anatomic methods. Therefore in the current study we employed antidromic microstimulation methods to determine the laminar projections of two of the three classes of RVM neurons, the ON and the OFF cells. 2. In lightly anesthetized (with methohexital sodium) rats, single-unit extracellular recordings were made from 48 RVM neurons that were physiologically characterized as ON (30) or OFF (18) cells. The recording locations of 45 of these neurons were recovered. Thirty-seven were found in the nucleus raphe magnus and eight were located near its dorsal and lateral borders. 3. Thirty-two physiologically identified RVM neurons (18 ON and 14 OFF cells) were antidromically activated from the cervical spinal cord using a monopolar stimulating electrode. The stimulating electrode was moved systematically in the white matter until antidromic activation could be produced with currents of < or = 20 microA (6.1 +/- 0.7 microA, mean +/- SE). The points from which minimum currents were required to antidromically activate the neurons were located mainly in the ipsilateral dorsolateral funiculus (DLF) (27 of 32). In a few cases, lowest antidromic threshold currents were found near the border between the DLF and ventrolateral funiculus (VLF) or, rarely, in the VLF itself. In these cases, the cell recordings were found to be near the dorsal boundary of the RVM. 4. While one electrode was used to stimulate the parent axon in the lateral funiculus, a second was used to explore the gray matter for the presence of collateral branches. The identification of a branch was initially determined by an increase in antidromic latency. At the same rostrocaudal plane of the spinal cord, stimulation of the DLF induced an antidromic spike that invaded the neuron earlier than the antidromic spike elicited by stimulation in the gray matter. Collateral branches were confirmed by establishing that the location of the minimum threshold point for antidromic activation of the neurons from the second electrode was in the gray matter, that the minimum current required to antidromically activate the neuron from that point was too low to activate the parent axon in the DLF, and that a collision occurred between the spikes induced by the two stimulating electrodes. 5. In 17 cases, physiologically identified RVM neurons (10 ON and 7 OFF cells) were antidromically activated from the gray matter of the cervical spinal cord using a current of 8.4 +/- 2.1 (SE) microA. Minimum threshold points for antidromic activation were found in laminae I-II (3 ON and 4 OFF cells), lamina V (5 ON and 6 OFF cells), and regions ventral to the lateral reticulated area (3 ON and 2 OFF cells) of the gray matter. As indicated by these numbers, some neurons were antidromically activated from more than one gray matter region. In general, all OFF cells and 9 of 10 ON cells were antidromically activated from low threshold points in either laminae I-II or lamina V. 6. In six cases, neurons were activated from separate points located in two or three different laminae of the gray matter. Three OFF cells were activated from laminae I-II and V, one OFF cell and one ON cell were activated from lamina V and from more ventral points, and one ON cell was activated from laminae I-II and from points ventral to lamina V.

scholarly journals Descending inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla

2021 ◽  
Author(s):  
Taylor Follansbee ◽  
Dan Domocos ◽  
Eileen Nguyen ◽  
Amanda Nguyen ◽  
Aristea Bountouvas ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Rostral Ventromedial Medulla ◽  
Projection Neurons ◽  
Descending Pathways ◽  
Descending Inhibition ◽  
Neurokinin 1 Receptor ◽  
Nociceptive Transmission ◽  
Descending Modulation ◽  
Ventromedial Medulla ◽  
Neurokinin 1

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if these descending pathways also modulate spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while facilitating mechanical nociception. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching behavior while enhancing mechanonociception. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the descending inhibition of spinal pruriceptive transmission.

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)

Spinothalamic and spinohypothalamic tract neurons in the sacral spinal cord of rats. II. Responses to cutaneous and visceral stimuli

1996 ◽  
Vol 75 (6) ◽  
pp. 2606-2628 ◽  
Author(s):  
J. T. Katter ◽  
R. J. Dado ◽  
E. Kostarczyk ◽  
G. J. Giesler
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptive Fields ◽  
High Threshold ◽  
Mechanical Stimuli ◽  
Power Functions ◽  
Nociceptive Neurons ◽  
Wdr Neurons ◽  
Sacral Spinal Cord

1. A goal of this study was to determine whether neurons in the sacral spinal cord that project to the diencephalon are involved in the processing and transmission of sensory information that arises in the perineum and pelvis. Therefore, 58 neurons in segments L6-S2 were activated antidromically with currents < or = 30 microA from points in the contralateral diencephalon in rats that were anesthetized with urethan. 2. Responses to mechanical stimuli applied to the cutaneous receptive fields of these neurons were used to classify them as low-threshold (LT), wide dynamic range (WDR) or high-threshold (HT) neurons. Twenty-two neurons (38%) responded preferentially to brushing (LT neurons). Eighteen neurons (31%) responded to brushing but responded with higher firing frequencies to noxious mechanical stimuli (WDR neurons). Eighteen neurons (31%) responded only to noxious intensities of mechanical stimulation (HT neurons). LT neurons were recorded predominantly in nucleus proprius of the dorsal horn. Nociceptive neurons (WDR and HT) were recorded throughout the dorsal horn. 3. Cutaneous receptive fields were mapped for 56 neurons. Forty-five (80%) had receptive fields that included at least two of the following regions ipsilaterally: the rump, perineum, or tail. Eleven neurons (20%) had receptive fields that were restricted to one of these areas or to the ipsilateral hind limb. Thirty-eight neurons (68%) had cutaneous receptive fields that also included regions of the contralateral tail or perineum. On the perineum, receptive fields usually encompassed perianal and perivaginal areas including the clitoral sheath. There were no statistically significant differences in the locations or sizes of receptive fields for LT neurons compared with nociceptive (WDR and HT) neurons. 4. Thirty-seven LT, WDR, and HT neurons were tested for their responsiveness to heat stimuli. Five (14%) responded to increasing intensities of heat with graded increases in their firing frequencies. Thirty-two LT, WDR, and HT neurons also were tested with cold stimuli. None responded with graded increases in their firing frequencies to increasingly colder stimuli. There were no statistically significant differences among the responses of LT, WDR, and HT neurons to either heat or cold stimuli. 5. Forty LT, WDR, and HT neurons were tested for their responsiveness to visceral stimuli by distending a balloon placed into the rectum and colon with a series of increasing pressures. Seventeen (43%) exhibited graded increases in their firing frequencies in response to increasing pressures of colorectal distention (CrD). None of the responsive neurons responded reproducibly to CrD at an intensity of 20 mmHg, and all responded at intensities of > or = 80 mmHg. More than 90% responded abruptly at stimulus onset, responded continuously throughout the stimulus period, and stopped responding immediately after termination of the stimulus. 6. Thirty-one neurons were tested for their responsiveness to distention of a balloon placed inside the vagina. Eleven (35%) exhibited graded increases in their firing frequencies in response to increasing pressures of vaginal distention (VaD). The thresholds and temporal profiles of the responses to VaD were similar to those for CrD. Twenty-nine neurons were tested with both CrD and VaD. Thirteen (45%) were excited by both stimuli, four (14%) responded to CrD but not VaD, and one (3%) was excited by VaD but not CrD. Neurons excited by CrD, VaD, or both were recorded throughout the dorsal horn. 7. As a population, WDR neurons, but not LT or HT neurons, encoded increasing pressures of CrD and VaD with graded increases in their firing frequencies. The responses of WDR neurons to CrD differed significantly from those of either LT or HT neurons. Regression analyses of the stimulus-response functions of responsive WDR neurons to CrD and VaD were described by power functions with exponents of 1.6 and 2.4, respectively.(ABSTRACT TRUNCATED)

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