scholarly journals 108 Neuropathic Pain and Ectopic Spontaneous Action Potential Activity of Human Primary Sensory Neurons

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 222-222
Author(s):  
Robert Y North ◽  
Laurence D Rhines ◽  
Claudio E Tatsui ◽  
Ganesh Rao ◽  
Patrick M Dougherty
Keyword(s):  
Neuropathic Pain ◽  
Patch Clamp ◽  
Spontaneous Activity ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Membrane Properties ◽  
Primary Sensory Neurons ◽  
Whole Cell Patch Clamp ◽  
Intrinsic Membrane Properties

Abstract INTRODUCTION Hyperexcitability of primary sensory neurons and its most extreme form, spontaneous activity, are key cellular-level drivers of neuropathic pain. Though extensively studied in animal models of neuropathic pain and established as a phenomenon occurring in human primary sensory neurons, this altered electrophysiology has not been rigorously studied for human primary sensory neurons nor has its relationship to clinical symptoms of neuropathic pain been established. METHODS The study was approved by the M.D. Anderson IRB. Written informed consent for participation was obtained from each tissue donor. Human dorsal root ganglia and medical histories were obtained from patients undergoing oncological spine surgery that necessitated sacrifice of spinal nerve roots as part of standard of care. Clinical data regarding presence of radicular/neuropathic pain was obtained through retrospective review of medical records or collected at time of study enrollment. Neurons were dissociated from surrounding tissue, briefly maintained in cell-culture (24-72 hours), and examined with whole-cell patch clamp techniques. RESULTS >Electrophysiological recordings were obtained from a total of 110 neurons, dissociated from 23 dorsal root ganglia, donated by 13 patients. Spontaneous activity was noted in 15% (12/79) of neurons from ganglia with pain in a corresponding dermatome vs 0% (0/31) of neurons from pain free ganglia (P < 0.05) Compared to neurons without spontaneous activity, human sensory neurons with spontaneous activity had significantly altered intrinsic membrane properties; depolarized resting membrane potential, hyperexcitability, and altered action potential kinetics (all P < 0.05). CONCLUSION Utilizing whole-cell patch clamp of dissociated human primary sensory neurons from patients both with and without neuropathic pain this study presents two important new findings: 1) first demonstration of a statistically significant association between in vitro spontaneous activity of dissociated human primary sensory neurons and neuropathic pain 2) the first characterization of the altered intrinsic membrane properties associated with spontaneous activity in human primary sensory neurons.

scholarly journals Dorsal Root Ganglia Homeobox downregulation in primary sensory neurons contributes to neuropathic pain in rats

2020 ◽  
Vol 16 ◽  
pp. 174480692090446
Author(s):  
Takaya Ito ◽  
Atsushi Sakai ◽  
Motoyo Maruyama ◽  
Yoshitaka Miyagawa ◽  
Takashi Okada ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Primary Sensory Neurons

scholarly journals Enhanced T-type calcium channel 3.2 activity in sensory neurons contributes to neuropathic-like pain of monosodium iodoacetate-induced knee osteoarthritis

2020 ◽  
Vol 16 ◽  
pp. 174480692096380
Author(s):  
Seung Min Shin ◽  
Yongsong Cai ◽  
Brandon Itson-Zoske ◽  
Chensheng Qiu ◽  
Xu Hao ◽  
...  
Keyword(s):  
Sensory Neuron ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spinal Dorsal Horn ◽  
Primary Sensory Neurons ◽  
Primary Sensory Neuron ◽  
Spinal Dorsal ◽  
Osteoarthritis Pain ◽  
Monosodium Iodoacetate

The monosodium iodoacetate knee osteoarthritis model has been widely used for the evaluation of osteoarthritis pain, but the pathogenesis of associated chronic pain is not fully understood. The T-type calcium channel 3.2 (CaV3.2) is abundantly expressed in the primary sensory neurons, in which it regulates neuronal excitability at both the somata and peripheral terminals and facilitates spontaneous neurotransmitter release at the spinal terminals. In this study, we investigated the involvement of primary sensory neuron-CaV3.2 activation in monosodium iodoacetate osteoarthritis pain. Knee joint osteoarthritis pain was induced by intra-articular injection of monosodium iodoacetate (2 mg) in rats, and sensory behavior was evaluated for 35 days. At that time, knee joint structural histology, primary sensory neuron injury, and inflammatory gliosis in lumbar dorsal root ganglia, and spinal dorsal horn were examined. Primary sensory neuron-T-type calcium channel current by patch-clamp recording and CaV3.2 expression by immunohistochemistry and immunoblots were determined. In a subset of animals, pain relief by CaV3.2 inhibition after delivery of CaV3.2 inhibitor TTA-P2 into sciatic nerve was investigated. Knee injection of monosodium iodoacetate resulted in osteoarthritis histopathology, weight-bearing asymmetry, sensory hypersensitivity of the ipsilateral hindpaw, and inflammatory gliosis in the ipsilateral dorsal root ganglia, sciatic nerve, and spinal dorsal horn. Neuronal injury marker ATF-3 was extensively upregulated in primary sensory neurons, suggesting that neuronal damage was beyond merely knee-innervating primary sensory neurons. T-type current in dissociated primary sensory neurons from lumbar dorsal root ganglia of monosodium iodoacetate rats was significantly increased, and CaV3.2 protein levels in the dorsal root ganglia and spinal dorsal horn ipsilateral to monosodium iodoacetate by immunoblots were significantly increased, compared to controls. Perineural application of TTA-P2 into the ipsilateral sciatic nerve alleviated mechanical hypersensitivity and weight-bearing asymmetry in monosodium iodoacetate osteoarthritis rats. Overall, our findings demonstrate an elevated CaV3.2 expression and enhanced function of primary sensory neuron-T channels in the monosodium iodoacetate osteoarthritis pain. Further study is needed to delineate the importance of dysfunctional primary sensory neuron-CaV3.2 in osteoarthritis pain.

scholarly journals Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity

2021 ◽  
Vol 2 ◽  
Author(s):  
Zachary K. Ford ◽  
Ashlie N. Reker ◽  
Sisi Chen ◽  
Feni Kadakia ◽  
Alexander Bunk ◽  
...  
Keyword(s):  
Sensory Neuron ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Cannabinoid Receptors ◽  
Calcium Influx ◽  
Membrane Properties ◽  
Neuron Activity ◽  
Membrane Excitability ◽  
Bidirectional Modulation

Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system. Anatomical characterization of in situ gene expression and immunoreactivity showed that 61 and 53% of human sensory neurons express the CB1 gene and receptor, respectively. Calcium influx evoked by the algogen capsaicin was measured by Fura-2AM in dissociated human sensory neurons pre-exposed to the inflammatory mediator prostaglandin E2 (PGE2) alone or together with CB13 (1 μM), a cannabinoid agonist with limited blood–brain barrier permeability. Both a higher proportion of neurons and a greater magnitude of response to capsaicin were observed after exposure to CB13, indicating cannabinoid-mediated sensitization. In contrast, membrane properties measured by patch-clamp electrophysiology demonstrated that CB13 suppressed excitability and reduced action potential discharge in PGE2-pre-incubated sensory neurons, suggesting the suppression of sensitization. This bidirectional modulation of sensory neuron activity suggests that cannabinoids may suppress overall membrane excitability while simultaneously enhancing responsivity to TRPV1-mediated stimuli. We conclude that peripherally restricted cannabinoids may have both pro- and anti-nociceptive effects in human sensory neurons.

scholarly journals S100 protein-immunoreactive primary sensory neurons in the trigeminal and dorsal root ganglia of the rat

1997 ◽  
Vol 748 (1-2) ◽  
pp. 253-257 ◽  
Author(s):  
Hiroyuki Ichikawa ◽  
David M Jacobowitz ◽  
Tomosada Sugimoto
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
S100 Protein ◽  
Primary Sensory Neurons

scholarly journals AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats

2020 ◽  
Vol 16 ◽  
pp. 174480691990081 ◽  
Author(s):  
Lingli Liang ◽  
Jun Zhang ◽  
Lixia Tian ◽  
Shuo Wang ◽  
Linping Xu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Primary Sensory Neurons

scholarly journals Axotomy Depletes Intracellular Calcium Stores in Primary Sensory Neurons

2009 ◽  
Vol 111 (2) ◽  
pp. 381-392 ◽  
Author(s):  
Marcel Rigaud ◽  
Geza Gemes ◽  
Paul D. Weyker ◽  
James M. Cruikshank ◽  
Takashi Kawano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Primary Sensory Neurons ◽  
Fura 2 ◽  
Intracellular Ca ◽  
Ganglion Neurons

Background The cellular mechanisms of neuropathic pain are inadequately understood. Previous investigations have revealed disrupted Ca signaling in primary sensory neurons after injury. The authors examined the effect of injury on intracellular Ca stores of the endoplasmic reticulum, which critically regulate the Ca signal and neuronal function. Methods Intracellular Ca levels were measured with Fura-2 or mag-Fura-2 microfluorometry in axotomized fifth lumbar (L5) dorsal root ganglion neurons and adjacent L4 neurons isolated from hyperalgesic rats after L5 spinal nerve ligation, compared to neurons from control animals. Results Endoplasmic reticulum Ca stores released by the ryanodine-receptor agonist caffeine decreased by 46% in axotomized small neurons. This effect persisted in Ca-free bath solution, which removes the contribution of store-operated membrane Ca channels, and after blockade of the mitochondrial, sarco-endoplasmic Ca-ATPase and the plasma membrane Ca ATPase pathways. Ca released by the sarco-endoplasmic Ca-ATPase blocker thapsigargin and by the Ca-ionophore ionomycin was also diminished by 25% and 41%, respectively. In contrast to control neurons, Ca stores in axotomized neurons were not expanded by neuronal activation by K depolarization, and the proportionate rate of refilling by sarco-endoplasmic Ca-ATPase was normal. Luminal Ca concentration was also reduced by 38% in axotomized neurons in permeabilized neurons. The adjacent neurons of the L4 dorsal root ganglia showed modest and inconsistent changes after L5 spinal nerve ligation. Conclusions Painful nerve injury leads to diminished releasable endoplasmic reticulum Ca stores and a reduced luminal Ca concentration. Depletion of Ca stores may contribute to the pathogenesis of neuropathic pain.

Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia

1999 ◽  
Vol 277 (6) ◽  
pp. G1180-G1188 ◽  
Author(s):  
Xin Su ◽  
Ruth E. Wachtel ◽  
G. F. Gebhart
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Maximal Response ◽  
Sodium Currents ◽  
Inward Current ◽  
Voltage Gated ◽  
Whole Cell Patch Clamp ◽  
Cation Conductance ◽  
Bath Application

DiI-labeled colon sensory neurons were acutely dissociated from S1 rat dorsal root ganglia (DRG) and studied using perforated whole cell patch-clamp techniques. Forty-six percent (54/116) of labeled sensory neurons responded to capsaicin (10− 8– 10− 5M) with an increase in inward current, which was a nonspecific cation conductance. Responses to capsaicin applied by puffer ejection were dependent on dose, with a half-maximal response at 4.9 × 10− 7 M; bath application was characterized by marked desensitization. Voltage-gated Na+currents in 23 of 30 DRG cells exhibited both TTX-sensitive and TTX-resistant components. In these cells, capsaicin induced an inward current in 11 of 17 cells tested. Of the cells containing only a TTX-sensitive component, none of six cells tested was sensitive to capsaicin. In all cells that responded to capsaicin with an increase in inward current, capsaicin abolished voltage-gated Na+currents ( n = 21). Capsazepine (10− 6 M) significantly attenuated both the increase in inward current and the reduction in Na+currents. Na+ currents were not significantly altered by adenosine, bradykinin, histamine, PGE2, or serotonin at 10− 6 M and 10− 5 M. These findings may have important implications for understanding both the irritant and analgesic properties of capsaicin.

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