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Zhu T, Li H, Chen Y, Jia X, Ma X, Liu X, Feng Y, Ke J. ALPK1 Expressed in IB4-Positive Neurons of Mice Trigeminal Ganglions Promotes MIA-Induced TMJ pain. Mol Neurobiol 2023; 60:6264-6274. [PMID: 37442857 DOI: 10.1007/s12035-023-03462-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 06/22/2023] [Indexed: 07/15/2023]
Abstract
Pain is one of the main reasons for patients with temporomandibular joint (TMJ) disorders seeking medical care. However, there is no effective treatment yet as its mechanism remains unclear. Herein, we found that the injection of monoiodoacetate (MIA) into mice TMJs can induce typical joint pain as early as 3 days, accompanied by an increased percentage of calcitonin gene-related peptide positive (CGRP+) neurons and isolectin B4 positive (IB4+) in the trigeminal ganglions (TGs). Our previous study has discovered that alpha-kinase 1 (ALPK1) may be involved in joint pain. Here, we detected the expression of ALPK1 in neurons of TGs in wild-type (WT) mice, and it was upregulated after intra-TMJ injection of MIA. Meanwhile, the increased percentage of neurons in TGs expressing ALPK1 and CGRP or ALPK1 and IB4 was also demonstrated by the immunofluorescent double staining. Furthermore, after the MIA injection, ALPK1-/- mice exhibited attenuated pain behavior, as well as a remarkably decreased percentage of IB4+ neurons and an unchanged percentage of CGRP+ neurons, as compared with WT mice. In vitro assay showed that the value of calcium intensity was weakened in Dil+ neurons from ALPK1-/- mice of TMJ pain induced by the MIA injection, in relation to those from WT mice, while it was significantly enhanced with the incubation of recombinant human ALPK1 (rhA). Taken together, these results suggest that ALPK1 promotes mice TMJ pain induced by MIA through upregulation of the sensitization of IB4+ neurons in TGs. This study will provide a new potential therapeutic target for the treatment of TMJ pain.
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Affiliation(s)
- Taomin Zhu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Huimin Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Yuxiang Chen
- GuangDong Women and Children Hospital, Guangdong, 511400, China
| | - Xueke Jia
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Xiaohan Ma
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Xin Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Yaping Feng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Jin Ke
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China.
- Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
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Johnson NL, Patten T, Ma M, De Biasi M, Wesson DW. Chemosensory Contributions of E-Cigarette Additives on Nicotine Use. Front Neurosci 2022; 16:893587. [PMID: 35928010 PMCID: PMC9344001 DOI: 10.3389/fnins.2022.893587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
While rates of smoking combustible cigarettes in the United States have trended down in recent years, use of electronic cigarettes (e-cigarettes) has dramatically increased, especially among adolescents. The vast majority of e-cigarette users consume "flavored" products that contain a variety of chemosensory-rich additives, and recent literature suggests that these additives have led to the current "teen vaping epidemic." This review, covering research from both human and rodent models, provides a comprehensive overview of the sensory implications of e-cigarette additives and what is currently known about their impact on nicotine use. In doing so, we specifically address the oronasal sensory contributions of e-cigarette additives. Finally, we summarize the existing gaps in the field and highlight future directions needed to better understand the powerful influence of these additives on nicotine use.
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Affiliation(s)
- Natalie L. Johnson
- Department of Pharmacology and Therapeutics, Center for Smell and Taste, Center for Addiction Research and Education, University of Florida, Gainesville, FL, United States
| | - Theresa Patten
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Minghong Ma
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Mariella De Biasi
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Daniel W. Wesson
- Department of Pharmacology and Therapeutics, Center for Smell and Taste, Center for Addiction Research and Education, University of Florida, Gainesville, FL, United States
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Yang JM, Yang XY, Wan JH. Multiple roles for cholinergic signaling in pancreatic diseases. World J Gastroenterol 2022; 28:2910-2919. [PMID: 35978870 PMCID: PMC9280742 DOI: 10.3748/wjg.v28.i25.2910] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/18/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities, including sensory, motor, and visceral activities, through cholinergic signaling. Cholinergic signaling plays an important role in pancreatic exocrine secretion. A large number of studies have found that cholinergic signaling overstimulates pancreatic acinar cells through muscarinic receptors, participates in the onset of pancreatic diseases such as acute pancreatitis and chronic pancreatitis, and can also inhibit the progression of pancreatic cancer. However, cholinergic signaling plays a role in reducing pain and inflammation through nicotinic receptors, but enhances the proliferation and invasion of pancreatic tumor cells. This review focuses on the progression of cholinergic signaling and pancreatic diseases in recent years and reveals the role of cholinergic signaling in pancreatic diseases.
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Affiliation(s)
- Jun-Min Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Yu Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Hua Wan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Carstens E, Carstens MI. Sensory Effects of Nicotine and Tobacco. Nicotine Tob Res 2022; 24:306-315. [PMID: 33955474 PMCID: PMC8842437 DOI: 10.1093/ntr/ntab086] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 04/28/2021] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and unpleasant side effects such as nausea and dizziness. AIMS AND METHODS Here we review the sensory effects of nicotine and the underlying neurobiological processes. RESULTS AND CONCLUSIONS Nicotine elicits oral irritation and pain via the activation of neuronal nicotinic acetylcholine receptors (nAChRs) expressed by trigeminal nociceptors. These nociceptors excite neurons in the trigeminal subnucleus caudalis (Vc) and other brainstem regions in a manner that is significantly reduced by the nAChR antagonist mecamylamine. Vc neurons are excited by lingual application of nicotine and exhibit a progressive decline in firing to subsequent applications, consistent with desensitization of peripheral sensory neurons and progressively declining ratings of oral irritation in human psychophysical experiments. Nicotine also elicits a nAChR-mediated bitter taste via excitation of gustatory afferents. Nicotine solutions are avoided even when sweeteners are added. Studies employing oral self-administration have yielded mixed results: Some studies show avoidance of nicotine while others report increased nicotine intake over time, particularly in adolescents and females. Nicotine is consistently reported to increase human pain threshold and tolerance levels. In animal studies, nicotine is antinociceptive when delivered by inhalation of tobacco smoke or systemic infusion, intrathecally, and by intracranial microinjection in the pedunculopontine tegmentum, ventrolateral periaqueductal gray, and rostral ventromedial medulla. The antinociception is thought to be mediated by descending inhibition of spinal nociceptive transmission. Menthol cross-desensitizes nicotine-evoked oral irritation, reducing harshness that may account for its popularity as a flavor additive to tobacco products. IMPLICATIONS Nicotine activates brain systems underlying reward and antinociception, but at the same time elicits aversive sensory effects including oral irritation and pain, bitter taste, and other unpleasant side effects mediated largely by nicotinic acetylcholine receptors (nAChRs). This review discusses the competing aversive and antinociceptive effects of nicotine and exposure to tobacco smoke, and the underlying neurobiology. An improved understanding of the interacting effects of nicotine will hopefully inform novel approaches to mitigate nicotine and tobacco use.
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Affiliation(s)
- Earl Carstens
- Department of Neurobiology, Physiology and Behavior University of California, Davis, CA, USA
| | - M Iodi Carstens
- Department of Neurobiology, Physiology and Behavior University of California, Davis, CA, USA
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Körner J, Lampert A. Functional subgroups of rat and human sensory neurons: a systematic review of electrophysiological properties. Pflugers Arch 2022; 474:367-385. [PMID: 35031856 PMCID: PMC8924089 DOI: 10.1007/s00424-021-02656-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/23/2021] [Accepted: 12/14/2021] [Indexed: 11/15/2022]
Abstract
Sensory neurons are responsible for the generation and transmission of nociceptive signals from the periphery to the central nervous system. They encompass a broadly heterogeneous population of highly specialized neurons. The understanding of the molecular choreography of individual subpopulations is essential to understand physiological and pathological pain states. Recently, it became evident that species differences limit transferability of research findings between human and rodents in pain research. Thus, it is necessary to systematically compare and categorize the electrophysiological data gained from human and rodent dorsal root ganglia neurons (DRGs). In this systematic review, we condense the available electrophysiological data defining subidentities in human and rat DRGs. A systematic search on PUBMED yielded 30 studies on rat and 3 studies on human sensory neurons. Defined outcome parameters included current clamp, voltage clamp, cell morphology, pharmacological readouts, and immune reactivity parameters. We compare evidence gathered for outcome markers to define subgroups, offer electrophysiological parameters for the definition of neuronal subtypes, and give a framework for the transferability of electrophysiological findings between species. A semiquantitative analysis revealed that for rat DRGs, there is an overarching consensus between studies that C-fiber linked sensory neurons display a lower action potential threshold, higher input resistance, a larger action potential overshoot, and a longer afterhyperpolarization duration compared to other sensory neurons. They are also more likely to display an infliction point in the falling phase of the action potential. This systematic review points out the need of more electrophysiological studies on human sensory neurons.
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Affiliation(s)
- Jannis Körner
- Institute of Physiology, Uniklinik RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Clinic of Anesthesiology, Uniklinik RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Angelika Lampert
- Institute of Physiology, Uniklinik RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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Shreckengost J, Halder M, Mena-Avila E, Garcia-Ramirez DL, Quevedo J, Hochman S. Nicotinic receptor modulation of primary afferent excitability with selective regulation of Aδ-mediated spinal actions. J Neurophysiol 2020; 125:568-585. [PMID: 33326305 DOI: 10.1152/jn.00228.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABAA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%-37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABAA receptor blockers and retained after tetrodotoxin block of voltage-gated Na+ channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents.NEW & NOTEWORTHY Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: 1) selective control of Aδ afferent transmission and 2) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.
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Affiliation(s)
| | - Mallika Halder
- Department of Physiology, Emory University, Atlanta, Georgia
| | - Elvia Mena-Avila
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - David Leonardo Garcia-Ramirez
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Jorge Quevedo
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Shawn Hochman
- Department of Physiology, Emory University, Atlanta, Georgia
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Role of Potassium Ions Quantum Tunneling in the Pathophysiology of Phantom Limb Pain. Brain Sci 2020; 10:brainsci10040241. [PMID: 32325702 PMCID: PMC7226264 DOI: 10.3390/brainsci10040241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 12/19/2022] Open
Abstract
(1) Background: multiple theories were proposed to explain the phenomenon of phantom limb pain (PLP). Nevertheless, the phenomenon is still shrouded in mystery. The aim of this study is to explore the phenomenon from a new perspective, where quantum tunneling of ions, a promising field in medical practice, might play a major role. (2) Methods: investigators designed a quantum mathematical model based on the Schrödinger equation to examine the probability of potassium ions quantum tunneling through closed membrane potassium channels to the inside of phantom axons, leading to the generation of action potential. (3) Results: the model suggests that the probability of action potential induction at a certain region of the membrane of phantom neurons, when a neuron of the stump area is stimulated over 1 mm2 surface area of the membrane available for tunneling is 1.04 × 10−2. Furthermore, upon considering two probabilities of potassium channelopathies, one that decreased the energy of the barrier by 25% and another one by 50%, the tunneling probability became 1.22 × 10−8 and 3.86 × 10−4, respectively. (4) Conclusion: quantum models of potassium ions can provide a reliable theoretical hypothesis to unveil part of the ambiguity behind PLP.
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Chen Z, Yuan M, Ma Z, Wen J, Wang X, Zhao M, Liu J, Zhang X, Zhao S, Guo L. Significance of piezo‐type mechanosensitive ion channel component 2 in premature ejaculation: An animal study. Andrology 2020; 8:1347-1359. [PMID: 32100938 DOI: 10.1111/andr.12779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/09/2020] [Accepted: 02/22/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Zhenghao Chen
- Institution of Urology The Second Hospital of Shandong University Jinan China
| | - Mingzhen Yuan
- Shandong Provincial Hospital Affiliated to Shandong University Jinan China
| | - Zhen Ma
- School of Medicine Shandong University Jinan China
| | - Jiliang Wen
- School of Medicine Shandong University Jinan China
| | | | | | - Jiaxin Liu
- The First Affiliated Hospital of Zhejiang University Hangzhou China
| | - Xiulin Zhang
- Institution of Urology The Second Hospital of Shandong University Jinan China
| | - Shengtian Zhao
- Shandong Provincial Hospital Affiliated to Shandong University Jinan China
| | - Liqiang Guo
- Shandong Provincial Hospital Affiliated to Shandong University Jinan China
- School of Medicine Shandong University Jinan China
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Zhang X, Hartung JE, Friedman RL, Koerber HR, Belfer I, Gold MS. Nicotine Evoked Currents in Human Primary Sensory Neurons. THE JOURNAL OF PAIN 2019; 20:810-818. [PMID: 30659887 DOI: 10.1016/j.jpain.2019.01.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 12/18/2018] [Accepted: 01/03/2019] [Indexed: 11/28/2022]
Abstract
Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Because both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine evoked currents were detected in 40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10 µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent coexpression pattern was α3/β2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion that human sensory neurons may be an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.
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Affiliation(s)
| | - Jane E Hartung
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Robert L Friedman
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - H Richard Koerber
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | | | - Michael S Gold
- Department of Anesthesiology; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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10
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Wen J, Zu S, Chen Z, Daugherty SL, de Groat WC, Liu Y, Yuan M, Cheng G, Zhang X. Reduced bladder responses to capsaicin and GSK-1016790A in retired-breeder female rats with diminished volume sensitivity. Am J Physiol Renal Physiol 2018; 315:F1217-F1227. [PMID: 30019934 DOI: 10.1152/ajprenal.00198.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Literature documents an age-related reduction of bladder sensory function. Transient receptor potential vanilloid (TRPV)1 or TRPV4 channels have been implicated in bladder mechanotransduction. To investigate contributions of TRPV1 or TRPV4 to the age-related reduction of bladder sensory function, bladder responses to capsaicin (CAP; TRPV1 agonist) and GSK-1016790A (GSK; TRPV4 agonist) in retired breeder (RB; 12-15 mo) and young adult (2-3 mo) female rats were compared using multiple methods. Metabolic cage and continuous infusion cystometry [cystometrogram (CMG)] recordings revealed that RB rats exhibit larger bladder capacity and lower voiding frequency. RB rats also have a greater intravesical pressure threshold for micturition; however, the voiding contraction strength was equivalent to that in young rats. CAP (1 μM) or GSK (20 nM) administered intravesically evoked smaller changes in all CMG parameters in RB rats. In vitro, CAP (1 μM) or GSK (20 nM) evoked smaller enhancement of bladder strip contractions, while the muscarinic receptor agonist carbachol (at 100, 300, and 1,000 nM) elicited greater amplitude contractions in RB rats. Patch-clamp recording revealed smaller CAP (100 nM) induced inward currents in bladder primary sensory neurons, and Ca2+ imaging revealed smaller GSK (20 nM) evoked increases in intracellular Ca2+ concentration in urothelial cells in RB rats. These results suggest that RB rats have a decreased bladder sensory function commonly observed in elderly women, and could be used as an animal model to study the underling mechanisms. Reduced functional expression of TRPV1 in bladder afferents or reduced functional expression of urothelial TRPV4 may be associated with the diminished sensory function.
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Affiliation(s)
- Jiliang Wen
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Shulu Zu
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Zhenghao Chen
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Stephanie L Daugherty
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Yuqiang Liu
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Mingzhen Yuan
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Guanghui Cheng
- Department of Central Research Laboratory, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
| | - Xiulin Zhang
- Department of Urology, the Second Hospital of Shandong University, Jinan, Shandong, Peoples Republic of China
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Collins KL, Russell HG, Schumacher PJ, Robinson-Freeman KE, O'Conor EC, Gibney KD, Yambem O, Dykes RW, Waters RS, Tsao JW. A review of current theories and treatments for phantom limb pain. J Clin Invest 2018; 128:2168-2176. [PMID: 29856366 DOI: 10.1172/jci94003] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Following amputation, most amputees still report feeling the missing limb and often describe these feelings as excruciatingly painful. Phantom limb sensations (PLS) are useful while controlling a prosthesis; however, phantom limb pain (PLP) is a debilitating condition that drastically hinders quality of life. Although such experiences have been reported since the early 16th century, the etiology remains unknown. Debate continues regarding the roles of the central and peripheral nervous systems. Currently, the most posited mechanistic theories rely on neuronal network reorganization; however, greater consideration should be given to the role of the dorsal root ganglion within the peripheral nervous system. This Review provides an overview of the proposed mechanistic theories as well as an overview of various treatments for PLP.
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Affiliation(s)
| | - Hannah G Russell
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Patrick J Schumacher
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | | | - Ellen C O'Conor
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Kyla D Gibney
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Olivia Yambem
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Robert W Dykes
- School of Physical and Occupational Therapy, McGill University, Montreal, Quebec, Canada
| | | | - Jack W Tsao
- Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Neurology, Memphis Veterans Affairs Medical Center, Memphis, Tennessee, USA.,Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
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12
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Fornaro M, Sharthiya H, Tiwari V. Adult Mouse DRG Explant and Dissociated Cell Models to Investigate Neuroplasticity and Responses to Environmental Insults Including Viral Infection. J Vis Exp 2018. [PMID: 29578527 DOI: 10.3791/56757] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
This protocol describes an ex vivo model of mouse-derived dorsal root ganglia (DRG) explant and in vitro DRG-derived co-culture of dissociated sensory neurons and glial satellite cells. These are useful and versatile models to investigate a variety of biological responses associated with physiological and pathological conditions of the peripheral nervous system (PNS) ranging from neuron-glial interaction, neuroplasticity, neuroinflammation, and viral infection. The usage of DRG explant is scientifically advantageous compared to simplistic single cells models for multiple reasons. For instance, as an organotypic culture, the DRG explant allows ex vivo transfer of an entire neuronal network including the extracellular microenvironment that play a significant role in all the neuronal and glial functions. Further, DRG explants can also be maintained ex vivo for several days and the culture conditions can be perturbed as desired. In addition, the harvested DRG can be further dissociated into an in vitro co-culture of primary sensory neurons and satellite glial cells to investigate neuronal-glial interaction, neuritogenesis, axonal cone interaction with the extracellular microenvironment, and more general, any aspect associated with the neuronal metabolism. Therefore, the DRG-explant system offers a great deal of flexibility to study a wide array of events related to biological, physiological, and pathological conditions in a cost-effective manner.
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Affiliation(s)
- Michele Fornaro
- Department of Anatomy, Chicago College of Osteopathic Medicine (CCOM), Midwestern University;
| | - Harsh Sharthiya
- Department of Anatomy, Chicago College of Osteopathic Medicine (CCOM), Midwestern University
| | - Vaibhav Tiwari
- Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine (CCOM), Midwestern University
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13
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Cuny H, Yu R, Tae HS, Kompella SN, Adams DJ. α-Conotoxins active at α3-containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition. Br J Pharmacol 2017; 175:1855-1868. [PMID: 28477355 DOI: 10.1111/bph.13852] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 04/13/2017] [Accepted: 04/24/2017] [Indexed: 01/22/2023] Open
Abstract
Neuronal α3-containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non-neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the CNS remains not well understood, in part because there is a lack of subtype-selective antagonists. α-Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR-antagonist interactions. Given that human α3β4 subtype selective α-conotoxins are scarce and this is a major nAChR subtype in the PNS, the design of new peptides targeting this nAChR subtype is desirable. Recent studies using α-conotoxins RegIIA and AuIB, in combination with nAChR site-directed mutagenesis and computational modelling, have shed light onto specific nAChR residues, which determine the selectivity of the α-conotoxins for the human α3β2 and α3β4 subtypes. Publications describing the selectivity profile and binding sites of other α-conotoxins confirm that subtype-selective nAChR antagonists often work through common mechanisms by interacting with the same structural components and sites on the receptor. LINKED ARTICLES This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.
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Affiliation(s)
- Hartmut Cuny
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia.,Victor Chang Cardiac Research Institute, Developmental and Stem Cell Biology Division, Sydney, NSW, Australia
| | - Rilei Yu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Han-Shen Tae
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia
| | - Shiva N Kompella
- Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia
| | - David J Adams
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia
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14
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Luo D, Chen L, Yu B. Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis. Biochem Biophys Res Commun 2017; 488:204-210. [DOI: 10.1016/j.bbrc.2017.05.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 05/05/2017] [Indexed: 12/19/2022]
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15
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Du X, Hao H, Yang Y, Huang S, Wang C, Gigout S, Ramli R, Li X, Jaworska E, Edwards I, Deuchars J, Yanagawa Y, Qi J, Guan B, Jaffe DB, Zhang H, Gamper N. Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J Clin Invest 2017; 127:1741-1756. [PMID: 28375159 PMCID: PMC5409786 DOI: 10.1172/jci86812] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 02/02/2017] [Indexed: 01/05/2023] Open
Abstract
The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.
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Affiliation(s)
- Xiaona Du
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Han Hao
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Yuehui Yang
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Sha Huang
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Caixue Wang
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Sylvain Gigout
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Rosmaliza Ramli
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
- School of Dental Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Xinmeng Li
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Ewa Jaworska
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Ian Edwards
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Jim Deuchars
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Yuchio Yanagawa
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and Japan Science and Technology Agency, CREST, Maebashi, Japan
| | - Jinlong Qi
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Bingcai Guan
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - David B. Jaffe
- Department of Biology, UTSA Neurosciences Institute, University of Texas at San Antonio, San Antonio, Texas, USA
| | - Hailin Zhang
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
| | - Nikita Gamper
- Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; Shijiazhuang, China
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
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16
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Shelukhina I, Mikhailov N, Abushik P, Nurullin L, Nikolsky EE, Giniatullin R. Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain. Front Neurol 2017; 8:163. [PMID: 28496430 PMCID: PMC5406407 DOI: 10.3389/fneur.2017.00163] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/07/2017] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown. METHODS Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. RESULTS Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. CONCLUSION Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.
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Affiliation(s)
- Irina Shelukhina
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.,Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
| | - Nikita Mikhailov
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Polina Abushik
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Leniz Nurullin
- Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Kazan, Russian Federation.,Open Laboratory of Neuropharmacology, Kazan Federal University, Kazan, Russian Federation
| | - Evgeny E Nikolsky
- Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Kazan, Russian Federation.,Open Laboratory of Neuropharmacology, Kazan Federal University, Kazan, Russian Federation
| | - Rashid Giniatullin
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.,Laboratory of Neurobiology, Kazan Federal University, Kazan, Russian Federation
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17
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Zhou JR, Shirasaki T, Soeda F, Takahama K. The effects of suplatast tosilate on acutely dissociated sensory and paratracheal ganglia neurons. Am J Physiol Lung Cell Mol Physiol 2016; 311:L770-L778. [PMID: 27566004 DOI: 10.1152/ajplung.00451.2015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 08/23/2016] [Indexed: 11/22/2022] Open
Abstract
In this study, we investigated the effects of suplatast on acutely dissociated single neurons of sensory and paratracheal ganglia using a patch-clamp technique. Suplatast had little effect on various responses caused by capsaicin, acid, bradykinin, serotonin and adenosine 5'-triphosphate in rat sensory neurons. Suplatast, even at 10-3 M, also did not induce any current at various membrane potentials in rat and guinea pig paratracheal ganglia neurons. Further, acetylcholine- and bradykinin-induced depolarizations were not affected by suplatast. On the other hand, in rat paratracheal ganglia neurons, 10-5 M nicotine-induced current were inhibited by suplatast in a concentration-dependent manner with a 50% inhibitory concentration of 9.86x10-5 M. The effect was noncompetitive and voltage-dependent. Furthermore, the effect was use-independent and not affected by the pretreatment time of suplatast. The results suggested that suplatast may inhibit neurotransmission at the paratracheal ganglia via the inhibition of nicotinic current. Thus, suplatast may attenuate cough production through the improvement of pathological conditions of the lower airway via suppressed acetylcholine release from the postganglionic nerve terminal.
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18
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Gold MS, Badgaiyan RD, Blum K. A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry. Psychiatr Clin North Am 2015; 38:419-62. [PMID: 26300032 DOI: 10.1016/j.psc.2015.05.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors.
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Affiliation(s)
- Mark S Gold
- Departments of Psychiatry & Behavioral Sciences, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA 90033, USA; Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Rivermend Health Scientific Advisory Board, 2300 Windy Ridge Parkway South East, Suite 210S, Atlanta, GA 30339, USA; Drug Enforcement Administration (DEA) Educational Foundation, Washington, DC, USA.
| | - Rajendra D Badgaiyan
- Laboratory of Advanced Radiochemistry and Molecular and Functioning Imaging, Department of Psychiatry, College of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Kenneth Blum
- Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA; Department of Psychiatry, Center for Clinical & Translational Science, Community Mental Health Institute, University of Vermont College of Medicine, University of Vermont, Burlington, VT, USA; Division of Applied Clinical Research, Dominion Diagnostics, LLC, 211 Circuit Drive, North Kingstown, RI 02852, USA; Rivermend Health Scientific Advisory Board, Atlanta, GA, USA
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