Peripheral and Central Pain Pathways and Pathophysiology

Mapping Intimacies ◽

10.1093/med/9780197512166.003.0004 ◽

2021 ◽

pp. 29-33

Author(s):

Jery D. Inbarasu ◽

Eduardo E. Benarroch

Keyword(s):

Dorsal Root ◽

Tissue Injury ◽

Nociceptive Neurons ◽

Central Processing ◽

Dorsal Horn Neurons ◽

Emotional Suffering ◽

Pain Pathways ◽

Bodily Sensation ◽

Complex Integration ◽

Local Modulation

Pain is an unpleasant sensory experience that may be associated with actual or potential tissue damage. Perception of pain includes 3 aspects: sensory-discriminative (intensity and location), cognitive (bodily sensation), and affective-emotional (suffering). Pain is a complex integration of anatomical pathways, including dorsal root ganglion nociceptive neurons, dorsal horn neurons, spinothalamic and spinobulbar pathways, the thalamus, the cortex, and local modulation. Peripheral and central sensitization may occur after tissue injury. This chapter reviews the peripheral and central processing of pain and concludes with a discussion of pain pathophysiology.

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Modulating Effect of Peptide Semax on the Level of Synaptic Activity and Short-Term Plasticity in Glutamatergic Synapses of Co-Cultured Dorsal Root Ganglion and Dorsal Horn Neurons of Rats

International Journal of Physiology and Pathophysiology ◽

10.1615/intjphyspathophys.v7.i3.90 ◽

2016 ◽

Vol 7 (3) ◽

pp. 263-272

Author(s):

Mariia S. Shypshyna ◽

Mycola S. Veselovsky ◽

Nikolai F. Myasoedov ◽

Stanislav I. Shram ◽

Svetlana A. Fedulova

Keyword(s):

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Dorsal Root ◽

Synaptic Activity ◽

Glutamatergic Synapses ◽

Short Term ◽

Short Term Plasticity ◽

Dorsal Horn Neurons

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M2-Receptor Subtype Does Not Mediate Muscarine-Induced Increases in [Ca2+]i in Nociceptive Neurons of Rat Dorsal Root Ganglia

Journal of Neurophysiology ◽

10.1152/jn.2000.84.4.1934 ◽

2000 ◽

Vol 84 (4) ◽

pp. 1934-1941 ◽

Cited By ~ 21

Author(s):

Rainer Haberberger ◽

Reas Scholz ◽

Wolfgang Kummer ◽

Michaela Kress

Keyword(s):

Receptor Antagonist ◽

Muscarinic Receptor ◽

Sensory Neurons ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Muscarinic Receptor Subtypes ◽

Rt Pcr ◽

Nociceptive Neurons

Multiple muscarinic receptor subtypes are present on sensory neurons that may be involved in the modulation of nociception. In this study we focused on the presence of the muscarinic receptor subtypes, M2 and M3 (M2R, M3R), in adult rat lumbar dorsal root ganglia (DRG) at the functional ([Ca2+]i measurement), transcriptional (RT-PCR), and translational level (immunohistochemistry). After 1 day in culture exposure of dissociated medium-sized neurons (20–35 μm diam) to muscarine was followed by rises in [Ca2+]i in 76% of the neurons. The [Ca2+]i increase was absent after removal of extracellular calcium and did not desensitize after repetitive application of the agonist. This rise in [Ca2+]i may be explained by the expression of M3R, which can induce release of calcium from internal stores via inositoltrisphospate. Indeed the effect was antagonized by the muscarinic receptor antagonist atropine as well as by the M3R antagonist, 4-diphenylacetoxy-N-(2 chloroethyl)-piperidine hydrochloride (4-DAMP). The pharmacological identification of M3R was corroborated by RT-PCR of total RNA and single-cell RT-PCR, which revealed the presence of mRNA for M3R in lumbar DRG and in single sensory neurons. In addition, RT-PCR also revealed the expression of M2R, which did not seem to contribute to the calcium changes since it was not prevented by the M2 receptor antagonist, gallamine. Immunohistochemistry demonstrated the presence of M2R and M3R in medium-sized lumbar DRG neurons that also coexpressed binding sites for the lectin I-B4, a marker for mainly cutaneous nociceptors. The occurrence of muscarinic receptors in putative nociceptive I-B4-positive neurons suggests the involvement of these acetylcholine receptors in the modulation of processing of nociceptive stimuli.

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Microsurgical DREZ lesions for the control of cancer-related pain

Neurosurgical Focus: Video ◽

10.3171/2020.7.focvid2033 ◽

2020 ◽

Vol 3 (2) ◽

pp. V14 ◽

Cited By ~ 1

Author(s):

Edoardo Mazzucchi ◽

Andrei Brinzeu ◽

Patrick Mertens ◽

Marc Sindou

Keyword(s):

General Condition ◽

Dorsal Root ◽

Lateral Part ◽

Entry Zone ◽

Dorsal Root Entry Zone ◽

Patients With Cancer ◽

Root Entry Zone ◽

Refractory Pain ◽

Pain Pathways ◽

Good General Condition

Pain in patients with cancer is a major problem, and sometimes it is necessary to surgically interrupt pain pathways to effectively control refractory pain. Surgical lesion of the dorsal root entry zone (DREZ) was first performed in 1972 for the treatment of pain related to a Pancoast-Tobias tumor. The rationale of DREZotomy is to preferentially interrupt the nociceptive inputs in the lateral part of the DREZ and the ventrolateral (excitatory) part of the dorsal horn. Microsurgical DREZotomy is one technique for DREZ lesioning that is suited for tailored control of pain in patients in good general condition who are experiencing pain in a well-defined territory.The video can be found here: https://youtu.be/JtLQDP7gYSQ

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Proton block of proton-activated TRPV1 current

The Journal of General Physiology ◽

10.1085/jgp.201511386 ◽

2015 ◽

Vol 146 (2) ◽

pp. 147-159 ◽

Cited By ~ 18

Author(s):

Bo Hyun Lee ◽

Jie Zheng

Keyword(s):

Tissue Injury ◽

Ion Selectivity ◽

Extracellular Ph ◽

The Body ◽

Ion Permeation ◽

Nociceptive Neurons ◽

Trpv1 Channels ◽

Highly Sensitive ◽

Body Core ◽

Polymodal Nociceptor

The TRPV1 cation channel is a polymodal nociceptor that is activated by heat and ligands such as capsaicin and is highly sensitive to changes in extracellular pH. In the body core, where temperature is usually stable and capsaicin is normally absent, H+ released in response to ischemia, tissue injury, or inflammation is the best-known endogenous TRPV1 agonist, activating the channel to mediate pain and vasodilation. Paradoxically, removal of H+ elicits a transient increase in TRPV1 current that is much larger than the initial H+-activated current. We found that this prominent OFF response is caused by rapid recovery from H+ inhibition of the excitatory current carried by H+-activated TRPV1 channels. H+ inhibited current by interfering with ion permeation. The degree of inhibition is voltage and permeant ion dependent, and it can be affected but not eliminated by mutations to acidic residues within or near the ion selectivity filter. The opposing H+-mediated gating and permeation effects produce complex current responses under different cellular conditions that are expected to greatly affect the response of nociceptive neurons and other TRPV1-expressing cells.

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Five Sources of a Dorsal Root Potential: Their Interactions and Origins in the Superficial Dorsal Horn

Journal of Neurophysiology ◽

10.1152/jn.1997.78.2.860 ◽

1997 ◽

Vol 78 (2) ◽

pp. 860-871 ◽

Cited By ~ 28

Author(s):

Patrick D. Wall ◽

Malcolm Lidierth

Keyword(s):

Motor Cortex ◽

Dorsal Horn ◽

Dorsal Root ◽

Repetitive Stimulation ◽

Superficial Dorsal Horn ◽

Dorsal Horn Neurons ◽

Dorsal Roots ◽

Myelinated Fibers ◽

Root Potential ◽

Stimulation Of

Wall, Patrick D. and Malcolm Lidierth. Five sources of a dorsal root potential: their interactions and origins in the superficial dorsal horn. J. Neurophysiol. 78: 860–871, 1997. The dorsal root potential (DRP) was measured on the lumbar dorsal roots of urethan anesthetized rats and evoked by stimulation of five separate inputs. In some experiments, the dorsal cord potential was recorded simultaneously. Stimulation of the L3 dorsal root produced a DRP on the L2 dorsal root containing the six components observed in the cat including the prolonged negative wave (DRP V of Lloyd 1952 ). A single shock to the myelinated fibers in the sural nerve produced a DRP on the L6 dorsal root after the arrival in the cord of the afferent volley. The shape of this DRP was similar to that produced by dorsal root stimulation. Repetitive stimulation of the myelinated fibers in the gastrocnemius nerve also produced a prolonged negative DRP on the L6 dorsal root. When a single stimulus (<5 μA; 200 μs) was applied through a microelectrode to the superficial Lissauer Tract (LT) at the border of the L2 and L3 spinal segments, a characteristic prolonged negative DRP (LT-DRP) began on the L2 dorsal root after some 15 ms. Stimulation of the LT evoked DRPs bilaterally. Recordings on nearby dorsal roots showed this DRP to be unaccompanied by stimulation of afferent fibers in those roots. The LT-DRP was unaffected by neonatal capsaicin treatment that destroyed most unmyelinated fibers. Measurements of myelinated fiber terminal excitability to microstimulation showed that the LT-DRP was accompanied by primary afferent depolarization. Repetitive stimulation through a microelectrode in sensorimotor cortex provoked a prolonged and delayed negative DRP (recorded L2–L4). Stimulation in the cortical arm area and recording on cervical dorsal roots showed that the DRP was evoked more from motor areas than sensory areas of cortex. Interactions were observed between the LT-DRP and that evoked from the sural or gastrocnemius nerves or motor cortex. The LT-DRP was inhibited by preceding stimulation of the other three sources but LT stimulation did not inhibit DRPs evoked from sural or gastrocnemius nerves on the L6 dorsal root or from motor cortex on the L3 root. However, LT stimulation did inhibit the DRP evoked by a subsequent Lissaeur tract stimulus. Recordings were made from superficial dorsal horn neurons. Covergence of input from LT sural, and gastrocnemius nerves and cortex was observed. Spike-triggered averaging was used to examine the relationship between the ongoing discharge of superficial dorsal horn neurons and the spontaneous DRP. The discharge of 81% of LT responsive cells was correlated with the DRP.

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P2X Receptor–Mediated Ionic Currents in Dorsal Root Ganglion Neurons

Journal of Neurophysiology ◽

10.1152/jn.1999.82.3.1590 ◽

1999 ◽

Vol 82 (3) ◽

pp. 1590-1598 ◽

Cited By ~ 118

Author(s):

Edward C. Burgard ◽

Wende Niforatos ◽

Tim van Biesen ◽

Kevin J. Lynch ◽

Edward Touma ◽

...

Keyword(s):

Dorsal Root ◽

Slow Component ◽

Ionic Currents ◽

P2x Receptors ◽

Fast Component ◽

Dorsal Root Ganglion Neurons ◽

P2x Receptor ◽

Receptor Subtype ◽

Nociceptive Neurons ◽

Ganglion Neurons

Nociceptive neurons in the dorsal root ganglia (DRG) are activated by extracellular ATP, implicating P2X receptors as potential mediators of painful stimuli. However, the P2X receptor subtype(s) underlying this activity remain in question. Using electrophysiological techniques, the effects of P2X receptor agonists and antagonists were examined on acutely dissociated adult rat lumbar DRG neurons. Putative P2X-expressing nociceptors were identified by labeling neurons with the lectin IB4. These neurons could be grouped into three categories based on response kinetics to extracellularly applied ATP. Some DRG responses (slow DRG) were relatively slowly activating, nondesensitizing, and activated by the ATP analogue α,β-meATP. These responses resembled those recorded from 1321N1 cells expressing recombinant heteromultimeric rat P2X2/3 receptors. Other responses (fast DRG) were rapidly activating and desensitized almost completely during agonist application. These responses had properties similar to those recorded from 1321N1 cells expressing recombinant rat P2X3 receptors. A third group (mixed DRG) activated and desensitized rapidly (P2X3-like), but also had a slow, nondesensitizing component that functionally prolonged the current. Like the fast component, the slow component was activated by both ATP and α,β-meATP and was blocked by the P2X antagonist TNP-ATP. But unlike the fast component, the slow component could follow high-frequency activation by agonist, and its amplitude was potentiated under acidic conditions. These characteristics most closely resemble those of rat P2X2/3 receptors. These data suggest that there are at least two populations of P2X receptors present on adult DRG nociceptive neurons, P2X3 and P2X2/3. These receptors are expressed either separately or together on individual neurons and may play a role in the processing of nociceptive information from the periphery to the spinal cord.

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Fixative Composition Alters Distributions of Immunoreactivity for Glutaminase and Two Markers of Nociceptive Neurons, Nav 1.8 and TRPV1, in the Rat Dorsal Root Ganglion

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.2009.954008 ◽

2009 ◽

Vol 58 (4) ◽

pp. 329-344 ◽

Cited By ~ 22

Author(s):

E. Matthew Hoffman ◽

Ruben Schechter ◽

Kenneth E. Miller

Keyword(s):

Dorsal Root Ganglion ◽

Dorsal Root ◽

Picric Acid ◽

Detection Sensitivity ◽

Formaldehyde Concentration ◽

Drg Neurons ◽

Nociceptive Neurons ◽

Drg Neuron ◽

Neuron Populations

Most, if not all, dorsal root ganglion (DRG) neurons use the neurotransmitter glutamate. There are, however, conflicting reports of the percentages of DRG neurons that express glutaminase (GLS), the enzyme that synthesizes glutamate, ranging from 30% to 100% of DRG neurons. Defining DRG neuron populations by the expression of proteins like GLS, which indicates function, is routinely accomplished with immunolabeling techniques. Proper characterization of DRG neuron populations relies on accurate detection of such antigens. It is known intuitively that fixation can alter immunoreactivity (IR). In this study, we compared the effects of five formaldehyde concentrations between 0.25% and 4.0% (w/v) and five picric acid concentrations between 0.0% and 0.8% (w/v) on the IR of GLS, the voltage-gated sodium channel 1.8 (Nav 1.8), and the capsaicin receptor TRPV1. We also compared the effects of five incubation time lengths from 2 to 192 hr, in primary anti-serum on IR. Lowering formaldehyde concentration elevated IR for all three antigens, while raising picric acid concentration increased Nav 1.8 and TRPV1 IR. Increasing IR improved detection sensitivity, which led to higher percentages of labeled DRG neurons. By selecting fixation conditions that optimized IR, we found that all DRG neurons express GLS, 69% of neurons express Nav 1.8, and 77% of neurons express TRPV1, indicating that some previous studies may have underestimated the percentages of DRG neurons expressing these proteins. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.

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