Is BDNF Sufficient for Information Transfer between Microglia and Dorsal Horn Neurons during the Onset of Central Sensitization?

Deep dorsal horn relay neurons (dDHNs) of the spinal cord are known to exhibit multiple firing patterns under the control of local metabotropic neuromodulation: tonic firing, plateau potential, and spontaneous oscillations. This work investigates the role of interactions between voltage-gated channels and the occurrence of different firing patterns and then correlates these two phenomena with their functional role in sensory information processing. We designed a conductance-based model using the NEURON software package, which successfully reproduced the classical features of plateau in dDHNs, including a wind-up of the neuronal response after repetitive stimulation. This modeling approach allowed us to systematically test the impact of conductance interactions on the firing patterns. We found that the expression of multiple firing patterns can be reproduced by changes in the balance between two currents (L-type calcium and potassium inward rectifier conductances). By investigating a possible generalization of the firing state switch, we found that the switch can also occur by varying the balance of any hyperpolarizing and depolarizing conductances. This result extends the control of the firing switch to neuromodulators or to network effects such as synaptic inhibition. We observed that the switch between the different firing patterns occurs as a continuous function in the model, revealing a particular intermediate state called the accelerating mode. To characterize the functional effect of a firing switch on information transfer, we used correlation analysis between a model of peripheral nociceptive afference and the dDHN model. The simulation results indicate that the accelerating mode was the optimal firing state for information transfer.

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Central Sensitization Induced in Trigeminal and Upper Cervical Dorsal Horn Neurons by Noxious Stimulation of Deep Cervical Paraspinal Tissues in Rats With Minimal Surgical Trauma

Journal of Manipulative and Physiological Therapeutics ◽

10.1016/j.jmpt.2009.08.012 ◽

2009 ◽

Vol 32 (7) ◽

pp. 506-514 ◽

Cited By ~ 19

Author(s):

Howard Vernon ◽

Kaiqi Sun ◽

Yunfeng Zhang ◽

Xian-Min Yu ◽

Barry J. Sessle

Keyword(s):

Dorsal Horn ◽

Central Sensitization ◽

Noxious Stimulation ◽

Surgical Trauma ◽

Dorsal Horn Neurons ◽

Upper Cervical ◽

Stimulation Of

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Peripheral and central hyperexcitability: Differential signs and symptoms in persistent pain

Behavioral and Brain Sciences ◽

10.1017/s0140525x97251484 ◽

1997 ◽

Vol 20 (3) ◽

pp. 404-419 ◽

Cited By ~ 129

Author(s):

Terence J. Coderre ◽

Joel Katz

Keyword(s):

Neuropathic Pain ◽

Postoperative Pain ◽

Experimental Evidence ◽

Dorsal Horn ◽

Central Sensitization ◽

Signs And Symptoms ◽

Persistent Pain ◽

Dorsal Horn Neurons ◽

Target Article

This target article examines the clinical and experimental evidence for a role of peripheral and central hyperexcitability in persistent pain in four key areas: cutaneous hyperalgesia, referred pain, neuropathic pain, and postoperative pain. Each suggests that persistent pain depends not only on central sensitization, but also on inputs from damaged peripheral tissue. It is instructive to think of central sensitization as comprised of both an initial central sensitization and an ongoing central sensitization driven by inputs from peripheral sources. Each of these factors, initial sensitization, ongoing central sensitization, and inputs from peripheral sources, contributes to the net activity in dorsal horn neurons and thus influences the expression of persistent pain or hyperalgesia. Since each factor, peripheral inputs and central sensitization (initial or ongoing), can contribute to both the initiation and maintenance of persistent pain, therapies should target both peripheral and central sources of pathology.

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Dorsal Horn α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking in Inflammatory Pain

Anesthesiology ◽

10.1097/aln.0b013e3181d3e1ed ◽

2010 ◽

Vol 112 (5) ◽

pp. 1259-1265 ◽

Cited By ~ 38

Author(s):

Yuan-Xiang Tao ◽

David S. Warner

Keyword(s):

Dorsal Horn ◽

Aspartic Acid ◽

Central Sensitization ◽

Inflammatory Pain ◽

Persistent Pain ◽

Receptor Trafficking ◽

Current Evidence ◽

Receptor Subunit ◽

Acid Receptor ◽

Dorsal Horn Neurons

Activation of synaptic N-methyl-D-aspartic acid receptor and its intracellular downstream signals in dorsal horn neurons of spinal cord contribute to central sensitization, a mechanism that underlies the development and maintenance of pain hypersensitivity in persistent pain. However, the molecular process of this event is not understood completely. Recently, new studies suggest that peripheral inflammatory insults drive changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit trafficking via N-methyl-D-aspartic acid receptor-triggered activation of protein kinases in dorsal horn and raise the possibility that such changes might contribute to central sensitization in persistent pain. This review presents current evidence regarding the changes that occur in the trafficking of dorsal horn alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits GluR1 and GluR2 under persistent inflammatory pain conditions and discusses the potential mechanisms by which such changes participate in the development and maintenance of inflammatory pain.

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Interferon-γ induces characteristics of central sensitization in spinal dorsal horn neurons in vitro

Pain ◽

10.1016/s0304-3959(03)00262-8 ◽

2003 ◽

Vol 106 (3) ◽

pp. 241-251 ◽

Cited By ~ 53

Author(s):

Kristina S Vikman ◽

Russell H Hill ◽

Eva Backström ◽

Brita Robertson ◽

Krister Kristensson

Keyword(s):

Dorsal Horn ◽

Central Sensitization ◽

Spinal Dorsal Horn ◽

Interferon Γ ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

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Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans

Scientific Reports ◽

10.1038/s41598-021-00313-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. Di Lionardo ◽

G. Di Stefano ◽

C. Leone ◽

G. Di Pietro ◽

E. Sgro ◽

...

Keyword(s):

Dorsal Horn ◽

Ulnar Nerve ◽

Central Sensitization ◽

Placebo Treatment ◽

Treatment Session ◽

Mechanical Hyperalgesia ◽

Double Blind ◽

Neurophysiological Study ◽

Dorsal Horn Neurons ◽

Capsaicin Application

AbstractThe N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

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Application of Nucleus Pulposus to L5 Dorsal Root Ganglion in Rats Enhances Nociceptive Dorsal Horn Neuronal Windup

Journal of Neurophysiology ◽

10.1152/jn.00762.2004 ◽

2005 ◽

Vol 94 (1) ◽

pp. 35-48 ◽

Cited By ~ 23

Author(s):

J. M. Cuellar ◽

P. X. Montesano ◽

J. F. Antognini ◽

E. Carstens

Keyword(s):

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Nucleus Pulposus ◽

Central Sensitization ◽

Dorsal Root ◽

Dynamic Range ◽

Spinal Neuron ◽

Peripheral Sensitization ◽

Dorsal Horn Neurons ◽

C Fiber

Herniation of the nucleus pulposus (NP) from lumbar intervertebral discs commonly results in radiculopathic pain possibly through a neuroinflammatory response. NP sensitizes dorsal horn neuronal responses, but it is unknown whether this reflects a central or peripheral sensitization. To study central sensitization, we tested if NP enhances windup—the progressive increase in the response of a nociceptive spinal neuron to repeated electrical C-fiber stimulation—a phenomenon that may partly account for temporal summation of pain. Single-unit recordings were made from wide dynamic range (WDR; n = 36) or nociceptive-specific (NS; n = 8) L5 dorsal horn neurons in 44 isoflurane-anesthetized rats. Subcutaneous electrodes delivered electrical stimuli (20 pulses, 3 times the C-fiber threshold, 0.5 ms) to the receptive field on the hindpaw. Autologous NP was harvested from a tail disc and placed onto the L5 dorsal root ganglion after recording of baseline responses ( n = 22). Controls had saline applied similarly ( n = 22). Electrical stimulus trains (0.1, 0.3, and 1 Hz; 5-min interstimulus interval) were repeated every 30 min for 3–6 h after each treatment. The total number of evoked spikes (summed across all 20 stimuli) to 0.1 Hz was enhanced 3 h after NP, mainly in the after-discharge (AD) period (latency > 400 ms). Total responses to 0.3 and 1.0 Hz were also enhanced at ≥60 min after NP in both the C-fiber (100- to 400-ms latency) and AD periods, whereas the absolute windup (C-fiber + AD − 20 times the initial response) increased at ≥90 min after treatment. In saline controls, windup was not enhanced at any time after treatment for any stimulus frequency, although there was a trend toward enhancement at 0.3 Hz. These results are consistent with NP-induced central sensitization. Mechanical responses were not significantly enhanced after saline or NP treatment. We speculate that inflammatory agents released from (or recruited by) NP affect the dorsal root ganglion (and/or are transported to cord) to enhance primary afferent excitation of nociceptive dorsal horn neurons.

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