α2-Adrenoceptors Modulate NMDA-Evoked Responses of Neurons in Superficial and Deeper Dorsal Horn of the Medulla

1998 ◽  
Vol 80 (4) ◽  
pp. 2210-2214 ◽  
Author(s):  
Kai-Ming Zhang ◽  
Xiao-Min Wang ◽  
Angela M. Peterson ◽  
Wen-Yan Chen ◽  
Sukhbir S. Mokha

Kai-Ming Zhang, Xiao-Min Wang, Angela M. Peterson, Wen-Yan Chen, and Sukhbir S. Mokha. α2-Adrenoceptors modulate NMDA-evoked responses of neurons in the superficial and deeper dorsal horn of the medulla. J. Neurophysiol. 80: 2210–2214, 1998. Extracellular single unit recordings were made from neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in 21 male rats anesthetized with urethan. NMDA produced an antagonist-reversible excitation of 46 nociceptive as well as nonnociceptive neurons. Microiontophoretic application of a preferential α2-adrenoceptor (α2AR) agonist, (2-[2,6-dichloroaniline]-2-imidazoline) hydrochloride (clonidine), reduced the NMDA-evoked responses of 86% (6/7) of nociceptive-specific (NS) neurons, 82% (9/11) of wide dynamic range (WDR) neurons, and 67% (4/6) of low-threshold (LT) neurons in the superficial dorsal horn. In the deeper dorsal horn, clonidine inhibited the NMDA-evoked responses of 94% (16/17) of NS and WDR neurons and 60% (3/5) of LT neurons. Clonidine facilitated the NMDA-evoked responses in 14% (1/17) of NS, 9% (1/11) of WDR, and 33% (2/6) of LT neurons in the superficial dorsal horn. Idazoxan, an α2AR antagonist, reversed the inhibitory effect of clonidine in 90% (9/10) of neurons, whereas prazosin, an α1-adrenoceptor antagonist with affinity for α2BAR, and α2CAR, were ineffective. We suggest that activation of α2ARs produces a predominantly inhibitory modulation of the NMDA-evoked responses of nociceptive neurons in the medullary dorsal horn.

2000 ◽  
Vol 83 (6) ◽  
pp. 3570-3574 ◽  
Author(s):  
Xiao-Min Wang ◽  
Kai-Ming Zhang ◽  
Layron O. Long ◽  
Carmina A. Flores ◽  
Sukhbir S. Mokha

The present study investigated the modulation of N-methyl-d-aspartate (NMDA)-evoked and peripheral cutaneous stimulus-evoked responses of trigeminal neurons by endomorphins, endogenous ligands for the μ-opioid receptor. Effects of endomorphins, administered microiontophoretically, were tested on the responses of nociceptive neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized rats. Endomorphin-1 and endomorphin-2 predominantly reduced the NMDA-evoked responses, producing an inhibitory effect of 54.1 ± 2.96% (mean ± SE; n = 34, P < 0.001) in 92% (34/37) of neurons and 63.6 ± 3.61% ( n = 32, P< 0.001) in 91% (32/35) of neurons, respectively. The inhibitory effect of endomorphins was modality specific; noxious stimulus-evoked responses were reduced more than nonnoxious stimulus-evoked responses. Naloxone applied at iontophoretic current that blocked the inhibitory effect of [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, reduced the peak inhibitory effect of endomorphins on the NMDA- and natural stimulus-evoked responses. We suggest that endomorphins by acting at μ-opioid receptor selectively modulate noxious stimulus-evoked responses in the medullary dorsal horn.


1989 ◽  
Vol 62 (2) ◽  
pp. 437-449 ◽  
Author(s):  
W. Maixner ◽  
R. Dubner ◽  
D. R. Kenshalo ◽  
M. C. Bushnell ◽  
J. L. Oliveras

1. We examined the activity of thermally sensitive trigeminothalamic neurons and nonprojection neurons in the medullary dorsal horn (trigeminal nucleus caudalis) in three monkeys performing thermal and visual detection tasks. 2. An examination of neuronal stimulus-response functions, obtained during thermal-detection tasks in which noxious heat stimuli were applied to the face, indicated that wide-dynamic-range neurons (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) could be subclassified based on the slope values of linear regression lines. WDR1 neurons exhibited significantly greater sensitivity to noxious heat stimulation than WDR2 neurons or nociceptive-specific neurons (NS, responsive only to noxious stimuli). 3. In one behavioral task, the monkeys detected 1.0 degrees C increases in noxious heat from preceding noxious heat stimuli ranging from 44 to 48 degrees C. WDR1, WDR2, and NS neurons increased their discharge frequency as a function of the intensity of the first noxious heat temperature (T1) as well as the final temperature (T2). The responses of WDR1 neurons were greater than those produced by WDR2 or NS neurons across all the temperatures examined. The order of stimulus presentation affected the responses of WDR1 neurons to 1.0 degrees C increases in the noxious heat range but not those of WDR2 or NS neurons. 4. In a second behavioral task, the monkeys detected small increases in noxious heat (0.2-0.8 degrees C) from a first temperature of 46 degrees C. Although the responses of all three classes of neurons were monotonically related to stimulus intensity, WDR1 neurons exhibited greater sensitivity to small temperature increases than either WDR2 or NS neurons. 5. Subpopulations of all three classes of neurons exhibited responses that were independent of thermal stimulus parameters or sensory modality and that only occurred during the behavioral task. These task-related responses were time-locked to specific behavioral events associated with trial initiation and trial continuation. 6. These data provide evidence that a subpopulation of WDR neurons is the dorsal horn cell type most sensitive to small increases in noxious heat in the 45-49 degrees C temperature range and provides the most information about stimulus intensity. The findings support the view that nociceptive neurons have the capacity to precisely encode stimulus features in the noxious range and that WDR neurons are likely to participate in the monkeys' ability to perceive the intensity of such stimuli.


1983 ◽  
Vol 49 (4) ◽  
pp. 948-960 ◽  
Author(s):  
J. O. Dostrovsky ◽  
Y. Shah ◽  
B. G. Gray

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.


2001 ◽  
Vol 86 (6) ◽  
pp. 2868-2877 ◽  
Author(s):  
Koichi Iwata ◽  
Takao Imai ◽  
Yoshiyuki Tsuboi ◽  
Akimasa Tashiro ◽  
Akiko Ogawa ◽  
...  

The effects of inferior alveolar nerve (IAN) transection on escape behavior and MDH neuronal activity to noxious and nonnoxious stimulation of the face were precisely analyzed. Relative thresholds for escape from mechanical stimulation applied to the whisker pad area ipsilateral to the transection were significantly lower than that for the contralateral and sham-operated whisker pad until 28 days after the transection, then returned to the preoperative level at 40 days after transection. A total of 540 neurons were recorded from the medullary dorsal horn (MDH) of the nontreated naive rats [low-threshold mechanoreceptive (LTM), 27; wide dynamic range (WDR), 31; nociceptive specific (NS), 11] and sham-operated rats with skin incision (LTM, 34; WDR, 30; NS, 23) and from the ipsilateral (LTM, 82; WDR, 82; NS, 31) and contralateral MDH relative to the IAN transection (LTM, 77; WDR, 82; NS, 33). The electrophysiological properties of these neurons were precisely analyzed. Background activity of WDR neurons on the ipsilateral side relative to the transection was significantly increased at 2–14 days after the operation as compared with that of naive rats. Innocuous and noxious mechanical-evoked responses of LTM and WDR neurons were significantly enhanced at 2–14 days after IAN transection. The mean area of the receptive fields of WDR neurons was significantly larger on the ipsilateral MDH at 2–7 days after transection than that of naive rats. We could not observe any modulation of thermal responses of WDR and NS neurons following IAN transection. Also, no MDH neurons were significantly affected in the rats with sham operations. The present findings suggest that the increment of neuronal activity of WDR neurons in the MDH following IAN transection may play an important role in the development of the mechano-allodynia induced in the area adjacent to the area innervated by the injured nerve.


Cephalalgia ◽  
2008 ◽  
Vol 28 (6) ◽  
pp. 631-639 ◽  
Author(s):  
J Coste ◽  
DL Voisin ◽  
P Luccarini ◽  
R Dallel

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown. Here, we recorded from trigeminal WDR neurons using in vivo electrophysiological techniques in rats and assessed the wind-up phenomenon in response to stimuli of different intensities and frequencies. First, we found that the amplitude of C-evoked responses of WDR neurons to repetitive stimulation increased progressively to reach a peak, then consistently showed a stable or slightly decreasing plateau phase. Only the first phase of this time course fitted in with the wind-up description. Therefore, to assess wind-up, we measured a limited number of initial responses. Second, we showed that wind-up, i.e. the slope of the frequency-dependent increase in the response to C-fibre stimulation, was linearly correlated to the stimulus intensity. Intensities of brief C-fibre inputs were thus coded into frequencies of action potentials by second-order neurons through frequency-dependent potentiation of the evoked responses. Third, wind-up also occurred at stimulation intensities below the threshold for C-evoked responses in WDR neurons, suggesting that wind-up can amplify subthreshold C-fibre inputs to WDR neurons. This might account for the observation that sparse, subliminal, neuronal activity in nociceptors can become painful via central integration of neural responses. Altogether, the present results show that wind-up can provide trigeminal WDR neurons with the capability to encode the intensity of short-duration orofacial nociceptive stimuli and to detect subthreshold nociceptive input. Thus, not only may wind-up play a physiological role in trigeminal sensory processing, but its enhancement may also underlie the pathophysiology of chronic orofacial pain conditions.


2014 ◽  
Vol 19 (4) ◽  
pp. 205-211 ◽  
Author(s):  
Lei Ding ◽  
Jie Cai ◽  
Xiang-Yang Guo ◽  
Xiu-Li Meng ◽  
Guo-Gang Xing

BACKGROUND: Pregabalin (PGB) is a novel antiepileptic drug and is also used as a first-line medication for the treatment of neuropathic pain. However, the mechanisms of its analgesic effects remain largely unknown.OBJECTIVES: To elucidate the mechanisms underlying the antiallodynic action of PGB in rats with neuropathic pain.METHODS: In a rat model of neuropathic pain induced by spared nerve injury, mechanical allodynia, as a behavioural sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold with von Frey filaments. Activities of dorsal horn wide dynamic range (WDR) neurons were examined by extracellular electrophysiological recording in vivo.RESULTS: Spinal administration of PGB exerted a significant antiallodynic effect and a prominent inhibitory effect on the hypersensitivity of dorsal horn WDR neurons in rats with spared nerve injury.CONCLUSION: The antiallodynic action of PGB is likely dependent on the suppression of WDR neuron hyperexcitability in rats with neuropathic pain.


1993 ◽  
Vol 70 (6) ◽  
pp. 2260-2275 ◽  
Author(s):  
P. Peppel ◽  
F. Anton

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)


1996 ◽  
Vol 75 (6) ◽  
pp. 2606-2628 ◽  
Author(s):  
J. T. Katter ◽  
R. J. Dado ◽  
E. Kostarczyk ◽  
G. J. Giesler

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)


2015 ◽  
Vol 114 (4) ◽  
pp. 2528-2534 ◽  
Author(s):  
T. Akiyama ◽  
M. Nagamine ◽  
A. Davoodi ◽  
M. Iodi Carstens ◽  
F. Cevikbas ◽  
...  

Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml−1·min−1), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans.


1984 ◽  
Vol 52 (1) ◽  
pp. 39-53 ◽  
Author(s):  
J. W. Hu ◽  
B. J. Sessle

The activity of 160 single neurons excited by electrical stimulation of the canine tooth pulp was studied in the subnucleus caudalis (medullary dorsal horn) and the subnucleus oralis of the trigeminal (V) spinal tract nucleus in chloralose-anesthetized cats to test the effects of natural as well as electrical stimulation of the tooth pulp. The neurons were functionally classified on the basis of their cutaneous receptive-field properties as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), or nociceptive specific (NS). The orofacial receptive-field properties and responses evoked by electrical stimulation of the tooth pulp indicated that the oralis and caudalis neurons examined had characteristics typical of those previously documented for oralis LTM neurons and for caudalis LTM, WDR, and NS neurons. Each neuron was also tested with cold and warm stimulation of the canine tooth, and some neurons were also tested for responsiveness to thermal stimulation of the premolar tooth or to mechanical and chemical stimuli delivered to the dentine of the canine tooth. Although all the neurons could be excited by electrical stimulation of the pulp, we found that the only neurons that consistently responded to thermal pulp stimuli were those located in the V subnucleus caudalis. Moreover, only those caudalis neurons that had been functionally classified as nociceptive (4 WDR and 21 NS neurons) showed this responsiveness. Heating of the canine or premolar tooth excited 24 of these 25 nociceptive neurons; cooling activated only 3, and none of the small number of neurons tested with mechanical and chemical stimulation of the dentine was excited. The response of the nociceptive neurons to heating of the tooth contrasted with the responses of the same neurons to pinching and heating of their cutaneous receptive field.(ABSTRACT TRUNCATED AT 400 WORDS)


Sign in / Sign up

Export Citation Format

Share Document