P2X Receptors in Trigeminal Subnucleus Caudalis Modulate Central Sensitization in Trigeminal Subnucleus Oralis

This study investigated the role of trigeminal subnucleus caudalis (Vc) P2X receptors in the mediation of central sensitization induced in nociceptive neurons in subnucleus oralis (Vo) by mustard oil (MO) application to the tooth pulp in anesthetized rats. MO application produced a long-lasting central sensitization reflected in neuroplastic changes (i.e., increases in neuronal mechanoreceptive field size and responses to innocuous and noxious mechanical stimuli) in Vo nociceptive neurons. Twenty minutes after MO application, the intrathecal (i.t.) administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor antagonist, 2′-(or 3′-) O-trinitrophenyl-ATP (TNP-ATP), significantly and reversibly attenuated the MO-induced central sensitization for more than 15 min; saline administration had no effect. Administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor agonist, α,β-methylene ATP (α,β-meATP, i.t.) produced abrupt and significant neuroplastic changes in Vo nociceptive neurons, followed by neuronal desensitization as evidenced by the ineffectiveness of a second i.t. application of α,β-meATP and subsequent MO application to the pulp. Administration to the rostral Vc of the selective P2X1 receptor agonist β,γ-methylene ATP (β,γ-meATP, i.t.) produced no significant neuroplastic changes per se and did not affect the subsequent MO-induced neuroplastic changes in Vo nociceptive neurons. These results suggest that P2X3 and possibly also the P2X2/3 receptor subtypes in Vc may play a role in the initiation and maintenance of central sensitization in Vo nociceptive neurons induced by MO application to the pulp.

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Endogenous ATP Involvement in Mustard-Oil-Induced Central Sensitization in Trigeminal Subnucleus Caudalis (Medullary Dorsal Horn)

Journal of Neurophysiology ◽

10.1152/jn.00223.2005 ◽

2005 ◽

Vol 94 (3) ◽

pp. 1751-1760 ◽

Cited By ~ 38

Author(s):

C. Y. Chiang ◽

S. Zhang ◽

Y. F. Xie ◽

J. W. Hu ◽

J. O. Dostrovsky ◽

...

Keyword(s):

Receptor Antagonist ◽

Dorsal Horn ◽

Central Sensitization ◽

P2x Receptor ◽

Field Size ◽

Mustard Oil ◽

Tooth Pulp ◽

Nociceptive Neurons ◽

Medullary Dorsal Horn ◽

Trigeminal Subnucleus Caudalis

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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Central Sensitization of Nociceptive Neurons in Trigeminal Subnucleus Oralis Depends on Integrity of Subnucleus Caudalis

Journal of Neurophysiology ◽

10.1152/jn.00944.2001 ◽

2002 ◽

Vol 88 (1) ◽

pp. 256-264 ◽

Cited By ~ 40

Author(s):

Chen Yu Chiang ◽

Bo Hu ◽

James W. Hu ◽

Jonathan O. Dostrovsky ◽

Barry J. Sessle

Keyword(s):

Brain Stem ◽

Central Sensitization ◽

Mustard Oil ◽

Tooth Pulp ◽

Nociceptive Neurons ◽

Response Properties ◽

Functional Integrity ◽

Anesthetized Rats ◽

Noxious Stimuli

Our recent studies have shown that application to the tooth pulp of the inflammatory irritant mustard oil (MO) produces a prolonged (>40 min) “central sensitization” reflected in neuroplastic changes in the mechanoreceptive field (RF) and response properties of nociceptive brain stem neurons in subnuclei oralis (Vo) and caudalis (Vc) of the trigeminal spinal tract nucleus. In view of the previously demonstrated ascending modulatory influence of Vc on Vo, our aim was to determine whether the Vo neuroplastic changes induced by MO application to the tooth pulp depend on an ascending influence from Vc. In chloralose/urethan-anesthetized rats, MO application to the pulp produced significant increases in Vo nociceptive neuronal orofacial RF size and responses to mechanical noxious stimuli that lasted as long as 40–60 min. These changes were not affected by vehicle (saline) microinjected into Vc at 20 min after MO application, but 0.3 μl of a 5 mM CoCl2 solution microinjected into the ipsilateral Vc produced a reversible blockade of the MO-induced Vo neuroplastic changes. A similar volume and concentration of CoCl2 solution injected into subnucleus interpolaris of the trigeminal spinal tract nucleus did not affect the MO-induced neuroplastic changes in Vo. These findings indicate that inflammatory pulp-induced central sensitization in Vo is dependent on the functional integrity of Vc.

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Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp

Neuroscience ◽

10.1016/j.neuroscience.2006.06.063 ◽

2006 ◽

Vol 142 (3) ◽

pp. 833-842 ◽

Cited By ~ 32

Author(s):

S. Zhang ◽

C.Y. Chiang ◽

Y.F. Xie ◽

S.J. Park ◽

Y. Lu ◽

...

Keyword(s):

Central Sensitization ◽

Molar Tooth ◽

Mustard Oil ◽

Tooth Pulp ◽

Nociceptive Neurons ◽

Rat Molar

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Somatotopic distribution of trigeminal nociceptive neurons in ventrobasal complex of cat thalamus

Journal of Neurophysiology ◽

10.1152/jn.1985.53.6.1387 ◽

1985 ◽

Vol 53 (6) ◽

pp. 1387-1400 ◽

Cited By ~ 38

Author(s):

T. Yokota ◽

N. Koyama ◽

N. Matsumoto

Keyword(s):

Receptive Field ◽

Dynamic Range ◽

Tooth Pulp ◽

Mechanical Stimuli ◽

Canine Tooth ◽

Light Pressure ◽

Nociceptive Neurons ◽

Low Threshold ◽

Rostral Part ◽

Shell Region

Recordings were made from single thalamic units in the urethan-chloralose anesthetized cat. Altogether 2,905 trigeminal single units having a receptive field in the contralateral trigeminal integument were isolated from the somatosensory part of nucleus ventralis posteromedialis, or VPM proper. Each isolated unit was tested for responses to a series of mechanical stimuli. The stimuli included brushing the skin, touch, pressure, noxious pinch, and pinpricks. The majority of VPM proper units responded with the greatest discharge frequency to gentle mechanical stimulation: either hair movement or light pressure to the trigeminal integument, but 341 units were identified as trigeminal nociceptive units. They were partitioned into two functionally defined subclasses, nociceptive specific (NS) and wide dynamic range (WDR) units, but not intermingled with low-threshold mechanoreceptive (LTM) units. Both NS and WDR units were found at or near the margin of the VPM proper but not outside this nucleus. This marginal area was referred to as the shell region of the VPM proper. A total of 248 NS units was found within the shell region of the caudal third of the VPM proper. This part was called the NS zone. These units were somatotopically organized. In the rostral part of the NS zone, ophthalmic NS units having a receptive field in the contralateral ophthalmic division were located dorsolaterally, maxillary NS units occurred dorsomedially, and mandibular NS units were found ventromedially. In the caudal part of the NS zone, maxillary NS units were encountered in the dorsal shell region, whereas mandibular NS units were found in the ventromedial shell region. Ophthalmic NS units were not found in this part of the NS zone. Altogether 93 WDR units were encountered in the shell region of the VPM proper. They were confined to a narrow band approximately 300 micron wide just rostral to the NS zone. These units were somatotopically organized. Ophthalmic WDR units having a low-threshold center of the receptive field in the contralateral ophthalmic division were located dorsolaterally, maxillary WDR units were located dorsomedially, and mandibular WDR units were located ventromedially. The majority of maxillary as well as mandibular WDR units were activated by electrical stimulation of the contralateral maxillary and/or mandibular canine tooth pulp afferents. Both NS and WDR zones of the VPM proper extended into the shell region of the nucleus ventralis posterolateralis (VPL).(ABSTRACT TRUNCATED AT 400 WORDS)

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Neuroplasticity Induced by Tooth Pulp Stimulation in Trigeminal Subnucleus Oralis Involves NMDA Receptor Mechanisms

Journal of Neurophysiology ◽

10.1152/jn.2001.85.5.1836 ◽

2001 ◽

Vol 85 (5) ◽

pp. 1836-1846 ◽

Cited By ~ 40

Author(s):

Soo Joung Park ◽

Chen Yu Chiang ◽

James W. Hu ◽

Barry J. Sessle

Keyword(s):

Nmda Receptor ◽

Spontaneous Activity ◽

Emg Activity ◽

Tooth Pulp ◽

Mechanical Stimuli ◽

Nociceptive Neurons ◽

Mk 801 ◽

Response Properties ◽

Mechanical Threshold ◽

Maxillary Molar

We have recently demonstrated that application of the mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces significant increases in jaw muscle electromyographic (EMG) activity and neuroplastic changes in trigeminal (V) subnucleus caudalis. Since subnucleus oralis (Vo) as well as caudalis receives projections from molar pulp afferents and is also an integral brain stem relay of afferent input from orofacial structures, we tested whether MO application to the exposed pulp induces neuroplastic changes in oralis neurons and whether microinjection of MK-801, a noncompetitive NMDA antagonist, into the Vo influences the pulp/MO-induced neuroplastic changes in chloralose/urethan-anesthetized rats. Single neuronal activity was recorded in Vo, and neurons classified as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), nociceptive-specific (NS), deep (D), or skin/mucosa and deep (S + D). The spontaneous activity, mechanoreceptive field (RF) size, mechanical threshold, and response to suprathreshold mechanical stimuli applied to the neuronal RF were assessed prior to and throughout a 40- to 60-min period after MO application to the maxillary molar pulp. In animals pretreated with saline microinjection (0.3 μl) into the Vo, MO application to the pulp produced a significant increase in spontaneous activity, expansion of the pinch or deep RF, decrease in the mechanical threshold, and increase in response to suprathreshold mechanical stimuli of the nociceptive (WDR, NS, and S + D) neurons except for those nociceptive neurons having their RF only in the intraoral region. The pulpal application of MO did not produce any significant neuroplastic changes in LTM neurons. Furthermore, in animals pretreated with MK-801 microinjection (3 μg/0.3 μl) into the Vo, MO application to the pulp did not produce any significant changes in the RF and response properties of nociceptive neurons. In other animals pretreated with saline (0.3 μl) or MK-801 (3 μg/0.3 μl) microinjected into the Vo, mineral oil application to the pulp did not produce any significant changes in RF and response properties of nociceptive neurons. These findings indicate that the application of MO to the tooth pulp can induce significant neuroplastic changes in oralis nociceptive neurons and that central NMDA receptor mechanisms may be involved in these neuroplastic changes.

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Involvement of Peripheral Purinoceptors in Sympathetic Modulation of Capsaicin-Induced Sensitization of Primary Afferent Fibers

Journal of Neurophysiology ◽

10.1152/jn.00502.2006 ◽

2006 ◽

Vol 96 (5) ◽

pp. 2207-2216 ◽

Cited By ~ 15

Author(s):

Yong Ren ◽

Xiaoju Zou ◽

Li Fang ◽

Qing Lin

Keyword(s):

Receptor Agonist ◽

P2x Receptors ◽

Intradermal Injection ◽

Disulfonic Acid ◽

Mechanical Stimuli ◽

Primary Afferent ◽

C Fibers ◽

Afferent Fibers ◽

Sympathetic Modulation ◽

Primary Afferent Fibers

Purinoceptors are distributed in primary afferent terminals, where transmission of nociceptive information is modulated by these receptors. In the present study, we evaluated whether the activation or blockade of purinoceptors of subtypes P2X and P2Y in the periphery affected the sensitization of primary afferents induced by intradermal injection of capsaicin (CAP) and examined their role in sympathetic modulation of sensitization of primary nociceptive afferents. Afferent activity was recorded from single Aδ- and C-primary afferent fibers in the tibial nerve in anesthetized rats. Peripheral pretreatment with α,β-methylene adenosine 5′-triphosphate (α,β-meATP), a P2X-selective receptor agonist, could potentiate the CAP-induced enhancement of responses of Aδ- and C-primary afferent nociceptive fibers to mechanical stimuli in sympathetically intact rats. After sympathetic denervation, the enhanced responses of both Aδ- and C-fibers after CAP injection were dramatically reduced. However, this reduction could be restored when P2X receptors were activated by α,β-meATP. A blockade of P2X receptors by pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid could significantly reduce the CAP-induced sensitization of Aδ- and C-fibers. Pretreatment with uridine 5′-triphosphate, a P2Y-selective receptor agonist, did not significantly affect or restore the CAP-induced sensitization of Aδ- and C-fibers under sympathetically intact or sympathectomized conditions. Our study supports the view that ATP plays a role in modulation of primary afferent nociceptor sensitivity mainly by P2X receptors. Combined with our previous study, our data also provide further evidence that the sensitization of primary afferent nociceptors is subject to sympathetic modulation by activation of P2X as well as α1-adrenergic receptors.

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Differential Roles of mGluR1 and mGluR5 in Brief and Prolonged Nociceptive Processing in Central Amygdala Neurons

Journal of Neurophysiology ◽

10.1152/jn.00485.2003 ◽

2004 ◽

Vol 91 (1) ◽

pp. 13-24 ◽

Cited By ~ 75

Author(s):

Weidong Li ◽

Volker Neugebauer

Keyword(s):

Metabotropic Glutamate Receptor ◽

Central Nucleus ◽

Field Size ◽

Receptor Subtypes ◽

Mechanical Stimuli ◽

Group I ◽

Nociceptive Responses ◽

Nociceptive Processing ◽

Pain State ◽

Noxious Stimuli

The laterocapsular division of the central nucleus of the amygdala (CeA) is now defined as the “nociceptive amygdala” because of its high content of neurons that respond to painful stimuli. The majority of these neurons become sensitized in a model of arthritis pain. Here we address the role of G protein–coupled group I metabotropic glutamate receptor subtypes mGluR1 and mGluR5 in nociceptive processing under normal conditions and in pain-related sensitization. Extracellular single-unit recordings were made from 65 CeA neurons in anesthetized rats. Each neuron's responses to brief mechanical stimuli, background activity, receptive field size, and threshold were measured before and after induction of the kaolin/carrageenan mono-arthritis in one knee and before and during applications of agonists and antagonists into the CeA by microdialysis. All neurons received excitatory input from the knee(s) and responded most strongly to noxious stimuli. Before arthritis, a group I mGluR1 and mGluR5 agonist (DHPG, n = 10) potentiated the responses to innocuous and noxious stimuli. This effect was mimicked by an mGluR5 agonist (CHPG, n = 15). In the arthritis pain state (>6 h after induction), the facilitatory effects of DHPG ( n = 9), but not CHPG ( n = 7), increased. An mGluR1 antagonist (CPCCOEt) had no effect before arthritis ( n = 12) but inhibited the responses of sensitized neurons in the arthritis pain state ( n = 8). An mGluR5 antagonist (MPEP) inhibited brief nociceptive responses under normal conditions ( n = 19) and prolonged nociception in arthritis ( n = 8). These data suggest a change of mGluR1 function and activation in the amygdala in pain-related sensitization, whereas mGluR5 is involved in brief as well as prolonged nociception.

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NMDA Receptor Mechanisms Contribute to Neuroplasticity Induced in Caudalis Nociceptive Neurons by Tooth Pulp Stimulation

Journal of Neurophysiology ◽

10.1152/jn.1998.80.5.2621 ◽

1998 ◽

Vol 80 (5) ◽

pp. 2621-2631 ◽

Cited By ~ 97

Author(s):

Chen Yu Chiang ◽

Soo Joung Park ◽

Chun L. Kwan ◽

James W. Hu ◽

Barry J. Sessle

Keyword(s):

Nmda Receptor ◽

Spontaneous Activity ◽

Dynamic Range ◽

Molar Tooth ◽

Mustard Oil ◽

Emg Activity ◽

Tooth Pulp ◽

Nociceptive Neurons ◽

Small Fiber ◽

Maxillary Molar

Chiang, Chen Yu, Soo Joung Park, Chun L. Kwan, James W. Hu, and Barry J. Sessle. NMDA receptor mechanisms contribute to neuroplasticity induced in caudalis nociceptive neurons by tooth pulp stimulation. J. Neurophysiol. 80: 2621–2631, 1998. We recently demonstrated that application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces significant and prolonged increases in jaw muscle electromyographic (EMG) activity that are suggestive of central neuroplasticity. Because small-fiber afferents, including pulp afferents, access nociceptive neurons in trigeminal (V) subnucleus caudalis, this study examined whether pulpal application of MO induces neuroplastic changes in caudalis nociceptive neurons (wide dynamic range and nociceptive specific) and whether central N-methyl-d-aspartate (NMDA) receptor mechanisms are involved in these MO-induced neuroplastic changes. After pretreatment with vehicle (saline, 10 μl i.t.) to the surface of the medulla, the pulpal application of MO to the maxillary molar tooth pulp produced a significant increase in neuronal spontaneous activity, a significant expansion of the pinch and/or tactile mechanoreceptive field (RF), a significant decrease in mechanical threshold, and significant increases in neuronal responses to graded pinch stimuli. Compared with vehicle-treated rats, pretreatment with the NMDA receptor antagonist MK-801 (10 μg/10 μl i.t.) followed by MO application to the pulp in another group of rats significantly reduced or abolished these MO-induced neuroplastic changes in nociceptive neurons. In another group of rats pretreated with saline (intrathecally), mineral oil application to the pulp did not show any significant changes in spontaneous activity or RF properties over the 40-min observation period. The pulpal application of MO in other rats (pretreated with saline, intrathecally) did not produce any significant neuroplastic changes in caudalis low-threshold mechanoreceptive neurons. These results indicate that the MO-induced activation of molar pulpal afferents can produce profound NMDA receptor-related neuroplastic changes in caudalis nociceptive neurons. Such neuroplastic changes may contribute to the hyperalgesia and spread of pain that can be associated with pulpal inflammation.

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