Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors

Central sensitization represents a sustained hypersensitive state of dorsal horn nociceptive neurons that can be evoked by peripheral inflammation or injury to nerves and tissues. It reflects neuroplastic changes such as increases in neuronal spontaneous activity, receptive field size, and responses to suprathreshold stimuli and a decrease in activation threshold. We recently demonstrated that purinergic receptor mechanisms in trigeminal subnucleus caudalis (Vc; medullary dorsal horn) are also involved in the initiation and maintenance of central sensitization in brain stem nociceptive neurons of trigeminal subnucleus oralis. The aim of the present study was to investigate whether endogenous ATP is involved in the development of central sensitization in Vc itself. The experiments were carried out on urethan/α-chloralose anesthetized and immobilized rats. Single neurons were recorded and identified as nociceptive-specific (NS) in the deep laminae of Vc. During continuous saline superfusion (0.6 ml/h it) over the caudal medulla, Vc neuronal central sensitization was readily induced by mustard oil application to the tooth pulp. However, this mustard-oil-induced central sensitization could be completely blocked by continuous intrathecal superfusion of the wide-spectrum P2X receptor antagonist pyridoxal-phosphate-6-azophenyl-2, 4-disulphonic acid tetra-sodium (33–100 μM) and by apyrase (an ectonucleotidase enzyme, 30 units/ml). Superfusion of the selective P2X1, P2X3 and P2X2/3 receptor antagonist 2′,3′- O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate (6–638 μM) partially blocked the Vc central sensitization. The two P2X receptor antagonists did not significantly affect the baseline nociceptive properties of the Vc neurons. These findings implicate endogenous ATP as an important mediator contributing to the development of central sensitization in nociceptive neurons of the deep laminae of the dorsal horn.

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Activation of peripheral P2X receptors is sufficient to induce central sensitization in rat medullary dorsal horn nociceptive neurons

Neuroscience Letters ◽

10.1016/j.neulet.2012.08.007 ◽

2012 ◽

Vol 526 (2) ◽

pp. 160-163 ◽

Cited By ~ 10

Author(s):

Pavel S. Cherkas ◽

Jonathan O. Dostrovsky ◽

Barry J. Sessle

Keyword(s):

Dorsal Horn ◽

Central Sensitization ◽

P2x Receptors ◽

Nociceptive Neurons ◽

Medullary Dorsal Horn

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Endomorphin-1 and Endomorphin-2 Modulate Responses of Trigeminal Neurons Evoked by N-Methyl-d-Aspartic Acid and Somatosensory Stimuli

Journal of Neurophysiology ◽

10.1152/jn.2000.83.6.3570 ◽

2000 ◽

Vol 83 (6) ◽

pp. 3570-3574 ◽

Cited By ~ 6

Author(s):

Xiao-Min Wang ◽

Kai-Ming Zhang ◽

Layron O. Long ◽

Carmina A. Flores ◽

Sukhbir S. Mokha

Keyword(s):

Dorsal Horn ◽

Opioid Receptor ◽

Inhibitory Effect ◽

Noxious Stimulus ◽

Evoked Responses ◽

Natural Stimulus ◽

Nociceptive Neurons ◽

Medullary Dorsal Horn ◽

Trigeminal Neurons ◽

Μ Opioid Receptor

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.

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

Journal of Neurophysiology ◽

10.1152/jn.1998.80.4.2210 ◽

1998 ◽

Vol 80 (4) ◽

pp. 2210-2214 ◽

Cited By ~ 16

Author(s):

Kai-Ming Zhang ◽

Xiao-Min Wang ◽

Angela M. Peterson ◽

Wen-Yan Chen ◽

Sukhbir S. Mokha

Keyword(s):

Dorsal Horn ◽

Dynamic Range ◽

Inhibitory Effect ◽

Male Rats ◽

Evoked Responses ◽

Superficial Dorsal Horn ◽

Nociceptive Neurons ◽

Adrenoceptor Antagonist ◽

Medullary Dorsal Horn ◽

Wdr Neurons

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.

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Responses of monkey medullary dorsal horn neurons during the detection of noxious heat stimuli

Journal of Neurophysiology ◽

10.1152/jn.1989.62.2.437 ◽

1989 ◽

Vol 62 (2) ◽

pp. 437-449 ◽

Cited By ~ 61

Author(s):

W. Maixner ◽

R. Dubner ◽

D. R. Kenshalo ◽

M. C. Bushnell ◽

J. L. Oliveras

Keyword(s):

Dorsal Horn ◽

Stimulus Intensity ◽

Dynamic Range ◽

Thermal Stimulus ◽

Mechanical Stimuli ◽

Behavioral Task ◽

Noxious Heat ◽

Nociceptive Neurons ◽

Medullary Dorsal Horn ◽

Wdr Neurons

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.

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The correlation of monkey medullary dorsal horn neuronal activity and the perceived intensity of noxious heat stimuli

Journal of Neurophysiology ◽

10.1152/jn.1989.62.2.450 ◽

1989 ◽

Vol 62 (2) ◽

pp. 450-457 ◽

Cited By ~ 85

Author(s):

R. Dubner ◽

D. R. Kenshalo ◽

W. Maixner ◽

M. C. Bushnell ◽

J. L. Oliveras

Keyword(s):

Dorsal Horn ◽

Neuronal Activity ◽

Peak Discharge ◽

Mechanical Stimuli ◽

Noxious Heat ◽

Nociceptive Neurons ◽

Perceived Intensity ◽

Medullary Dorsal Horn ◽

The Relationship ◽

Detection Speed

1. We examined the relationship between the activity of medullary dorsal horn nociceptive neurons and the monkeys' ability to detect noxious heat stimuli. In two different detection tasks, the temperature of a contact thermode positioned on the monkey's face increased from 38 degrees C to temperatures between 44 and 48 degrees C (T1). After a variable time period, the thermode temperature increased an additional 0.2-1.5 degrees C (T2), and the monkeys' detection speed from the onset of T2 was determined. We previously have established that detection speed is a measure of the perceived intensity of noxious thermal stimuli. Nociceptive neurons were classified as wide-dynamic-range (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) and nociceptive-specific (NS, responsive only to noxious stimuli). WDR neurons were subclassified as WDR1 and WDR2 based on the higher slope values of the stimulus-response functions of WDR1 neurons. The monkeys were trained to detect small increases in noxious heat, and their detection speeds were correlated with the responses of WDR1, WDR2, and NS neurons. 2. Detection speeds to T2 temperatures of 1.0 degrees C from preceding T1 temperatures of 45 and 46 degrees C were faster during a preceding ascending series of stimuli than during a descending series. Similarly, the peak discharge frequencies of WDR1 neurons in response to the same stimuli were greater during the ascending series of T2 temperatures. In contrast, the responses of WDR2 and NS neurons showed no significant differences during the ascending and descending series of stimuli. 3. Detection speeds following 0.4, 0.6, and 0.8 degrees C T2 stimuli were higher when the preceding T1 temperature was 46 degrees C as compared with detection speeds to the identical stimuli when the preceding T1 temperature was 45 degrees C. WDR1 neurons also exhibited a significant increase in peak discharge frequency to these same T2 stimuli when the preceding T1 temperature was 46 degrees C. In contrast, the neuronal activity of WDR2 and NS neurons did not differ on 45 and 46 degrees C T1 trials. 4. The relationship between detection speed and neuronal peak discharge frequency was examined in response to different pairs of T1 and T2 stimuli when T1 was either 45 or 46 degrees C. There was a significant correlation between detection speed and neuronal discharge for WDR1 and WDR2 neurons. No correlation was observed for NS neurons. 5. The magnitude of neuronal activity on correctly detected and nondetected trials was compared when T1 was 46 degrees C and T2 was 0.2 degree C.(ABSTRACT TRUNCATED AT 400 WORDS)

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