• Biomolecules & Therapeutics
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• 제26권3호
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• pp.255-267
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• 2018

Inflammation is one of the main causes of pathologic pain. Knowledge of the molecular links between inflammatory signals and pain-mediating neuronal signals is essential for understanding the mechanisms behind pain exacerbation. Some inflammatory mediators directly modulate the excitability of pain-mediating neurons by contacting the receptor molecules expressed in those neurons. For decades, many discoveries have accumulated regarding intraneuronal signals from receptor activation through electrical depolarization for bradykinin, a major inflammatory mediator that is able to both excite and sensitize pain-mediating nociceptor neurons. Here, we focus on the final effectors of depolarization, the neuronal ion channels, whose functionalities are specifically affected by bradykinin stimulation. Particular G-protein coupled signaling cascades specialized for each specific depolarizer ion channels are summarized. Some of these ion channels not only serve as downstream effectors but also play critical roles in relaying specific pain modalities such as thermal or mechanical pain. Accordingly, specific pain phenotypes altered by bradykinin stimulation are also discussed. Some members of the effector ion channels are both activated and sensitized by bradykinin-induced neuronal signaling, while others only sensitized or inhibited, which are also introduced. The present overview of the effect of bradykinin on nociceptor neuronal excitability at the molecular level may contribute to better understanding of an important aspect of inflammatory pain and help future design of further research on the components involved and pain modulating strategies.

• 대한치과의사협회지
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• 제49권6호
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• pp.321-326
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• 2011

Neuropathic pain is caused by functional abnonnalities of structural lesions in the peripheral or central nervous system, and occurs without peripheral nociceptor stimulation. Trigeminal neuropathy always pose differential location difficulties as multiple diseases are capablc of producing them: they can be the result of traumatism, tumors, or diseases of the connective tissue, infectious or demyelinating diseases, or may be of idiopathic origin. There are a number of mechanisms described as causing neuropathy. They can be described as ectopic nerve activity, neuroma, ephatic trasmission, change of sodium channel expression, sympathetic activity, central sensitization, and alteration in central inhibition systems. More than I mechanism may be active to create individual clinical presentations. In order to provide better pain control, the mechanism-based approach in treating neuropathic pain should be familiar to physicians.

• Journal of Korean Neurosurgical Society
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• 제59권6호
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• pp.559-563
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• 2016

Objective : Low back pain, caused intervertebral disc degeneration has been treated by thermal annuloplasty procedure, which is a non-surgical treatement. The theoretical backgrounds of the annuloplasty are thermal destruct of nociceptor and denaturization of collagen fiber to induce contraction, to shrink annulus and thus enhancing stability. This study is about temperature and its distribution during thermal annuloplasty using 1414 nm Nd : YAG laser. Methods : Thermal annuloplasty was performed on fresh human cadaveric lumbar spine with 20 intact intervertebral discs in a $37^{\circ}C$ circulating water bath using newly developed 1414 nm Nd : YAG laser. Five thermocouples were attached to different locations on the disc, and at the same time, temperature during annuloplasty was measured and analyzed. Results : Thermal probe's temperature was higher in locations closer to laser fiber tip and on lateral locations, rather than the in depth locations. In accordance with the laser fiber tip and the depth, temperatures above $45.0^{\circ}C$ was measured in 3.0 mm depth which trigger nociceptive ablation in 16 levels (80%), in accordance with the laser fiber end tip and laterality, every measurement had above $45.0^{\circ}C$, and also was measured temperature over $60.0^{\circ}C$, which can trigger collagen denaturation at 16 levels (80%). Conclusion : When thermal annuloplasty is needed in a selective lesion, annuloplasty using a 1414 nm Nd : YAG laser can be one of the treatment options.

• International Journal of Oral Biology
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• 제31권2호
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• pp.45-51
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• 2006

R-type($Ca_v2.3$) calcium channel contributes to pain sensation in peripheral sensory neurons. Six isoforms of $Ca_v2.3$ that result from combinations of presence or deletion of three inserts(insert I and insert in the II-III loop, and insert III in N-terminal regions) have been demonstrated to be present in different mammalian tissues. However, the molecular basis of $Ca_v2.3$ in trigeminal ganglion(TG) neurons is not known. In the present study, we determined which isoforms of $Ca_v2.3$ are expressed in rat TG neurons using the RT-PCR analysis. Whole tissue RT-PCR analyses revealed that only two isoforms, $Ca_v2.3a$ and $Ca_v2.3e$, were present in TG neurons. From single-cell RT-PCR, we found that $Ca_v2.3e$ rather than $Ca_v2.3a$ was the major isoform expressed in TG neurons, and $Ca_v2.3e$ was preferentially detected in small-sized neurons that express nociceptive marker, transient receptor potential vanilloid 1(TRPV1). Our results suggest that $Ca_v2.3e$ in trigeminal neurons may be a potential target for the pain treatment.

• The Korean Journal of Physiology and Pharmacology
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• 제4권1호
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• pp.15-24
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• 2000

Although nociceptive informations are thought to be processed via different neural mechanisms depending on the types of stimuli, sufficient data have not been accumulated yet. We performed a series of experiments to elucidate the possible neural mechanisms as to chemical stimuli such as formalin, capsaicin and ATP. Single unit activity of wide dynamic range (WDR) neurons and high threshold cells were recorded extracellularly from the lumbosacral enlargement of cat spinal cord before and after chemical stimulation to its receptive field (RF). Each chemical substance - formalin $(20{\mu}l,\;4%),$ capsaicin (33 mM) or Mg-ATP (5 mM)- was injected intradermally into the RFs and then the changes in the spontaneous activity, mechanical threshold and responses to the peripheral mechanical stimuli were observed. In many cases, intradermal injection of formalin (5/11) and capsaicin (8/11) resulted in increase of the spontaneous activity with a biphasic pattern, whereas ATP (8/8) only showed initial responses. Time courses of the biphasic pattern, especially the late response, differed between formalin and capsaicin experiments. One hour after injection of each chemical (formalin, capsaicin, or ATP), the responses of the dorsal horn neurons to mechanical stimuli increased at large and the RFs were expended, suggesting development of hypersensitization (formalin 6/10, capsaicin 8/11, and ATP 15/19, respectively). These results are suggested that formalin stimulates peripheral nociceptor, local inflammation and involvement of central sensitization, capsaicin induces central sensitization as well as affects the peripheral C-polymodal nociceptors and neurogenic inflammation, and ATP directly stimulates peripheral nociceptors.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.613-624
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• 1997

Dorsal root ganglion (DRG) is composed of neuronal cell bodies of primary afferents with diverse functions. Various types of ion channels present on DRG neurons may reflect those functions. In the present study, voltage-gated potassium currents in DRG neurons of neonatal rats were characterized by whole-cell voltage clamp method. Two types of delayed rectifier and three types of transient potassium currents were identified according to their electrophysiological properties. The delayed rectifier currents were named $I_{Ke}$ (early inactivating) and $I_{K1}$ (late inactivating). Steady state inactivation of $I_{Ke}$ began from -100 mV lasting until -20 mV. $I_{K1}$ could be distinguished from $I_{Ke}$ by its inactivation voltage range, from -70 mV to +10 mV. Three transient currents were named $I_{Af}$ (fast inactivation), $I_{Ai}$ (intermediate inactivation kinetics), and $I_{As}$ (slow inactivation). $I_{Af}$ showed fast inactivation with time constant of $10.6{\pm}2.0$ msec, $I_{Ai}$ of $36.9{\pm}13.9$ msec, and $I_{As}$ of $60.6{\pm}2.9$ msec at +30 mV, respectively. They also had distinct steady state inactivation range of each. Each cell expressed diverse combination of potassium currents. The cells most frequently observed were those which expressed both $I_{K1}$ and $I_{Af}$, and they had large diameters. The cells expressing $I_{Ke}$ and expressing $I_{Ke}$, $I_{Ai}$, and $I_{As}$ usually had small diameters. Judging from cell diameter, capsaicin sensitivity or action potential duration, candidates for nociceptor were the cells expressing $I_{Ke}$, expressing $I_{Ke}$ and $I_{Ai}$, and expressing $I_{Ke}$ and $I_{As}$. The types and distribution of potassium currents in neonatal rat DRG were similar to those of adult rat DRG (Gold et al, 1996b).

• Journal of Oral Medicine and Pain
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• 제38권2호
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• pp.215-219
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• 2013

하행성 억제계란 중뇌, 연수, 뇌교에 존재하는 해부학적 유해수용 조절성 기전을 일컫는 용어이다. 이들 부위를 전기적으로 자극을 하면 진통효과가 나타나며, 하행성 억제계의 실패시 지속적인 통증이 야기된다는 것을 알 수 있다. 또한 우울불안 같은 질환은 만성 신경병성 통증 상태로 쉽게 진행됨이 밝혀졌다. 이러한 요인들이 만성 신경병성 통증에 영향을 주는 경로는 아마도 하행성 억제계일 가능성이 있다. 흥미롭게도, 광범위하게 하행성 억제계가 작동하지 않을 경우 과민성 대장증상이 호발하는 것으로 보인다. 또한 이러한 환자들은 높은 불안, 우울 지수가 관찰되기도 한다. 다양한 연구에서, 하행성 억제계에 관여하는 ${\alpha}2$ 아드레날린성 약물, 아편유사약물들이 만성 통증에 사용될 수 있음을 동물에서 평가 중이다. 아직 신체내에서 얼마나 하행성 억제계가 일어나고 있는가에 대해서는 임상적으로 증명하기 힘든 감이 있지만, 여러 감각 신경기전의 수정에 중요한 구실을 하고 있는 것으로 믿어진다. 즉 중추신경계는 대상을 인식하기 위해 말초정보를 받아들이는 기능만 있는 것이 아니라 여러 방법으로 정보의 홍수를 조절하고 선택하는 기능을 동시에 갖추고 있는 것으로 생각된다.

• Molecules and Cells
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• 제20권3호
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• pp.315-324
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• 2005

Pain is an unpleasant sensation experienced when tissues are damaged. Thus, pain sensation in some way protects body from imminent threat or injury. Peripheral sensory nerves innervated to peripheral tissues initially respond to multiple forms of noxious or strong stimuli, such as heat, mechanical and chemical stimuli. In response to these stimuli, electrical signals for conducting the nociceptive neural signals through axons are generated. These action potentials are then conveyed to specific areas in the spinal cord and in the brain. Sensory afferent fibers are heterogeneous in many aspects. For example, sensory nerves are classified as $A{\alpha}$, $-{\beta}$, $-{\delta}$ and C-fibers according to their diameter and degree of myelination. It is widely accepted that small sensory fibers tend to respond to vigorous or noxious stimuli and related to nociception. Thus these fibers are specifically called nociceptors. Most of nociceptors respond to noxious mechanical stimuli and heat. In addition, these sensory fibers also respond to chemical stimuli [Davis et al. (1993)] such as capsaicin. Thus, nociceptors are considered polymodal. Recent advance in research on ion channels in sensory neurons reveals molecular mechanisms underlying how various types of stimuli can be transduced to neural signals transmitted to the brain for pain perception. In particular, electrophysiological studies on ion channels characterize biophysical properties of ion channels in sensory neurons. Furthermore, molecular biology leads to identification of genetic structures as well as molecular properties of ion channels in sensory neurons. These ion channels are expressed in axon terminals as well as in cell soma. When these channels are activated, inward currents or outward currents are generated, which will lead to depolarization or hyperpolarization of the membrane causing increased or decreased excitability of sensory neurons. In order to depolarize the membrane of nerve terminals, either inward currents should be generated or outward currents should be inhibited. So far, many cationic channels that are responsible for the excitation of sensory neurons are introduced recently. Activation of these channels in sensory neurons is evidently critical to the generation of nociceptive signals. The main channels responsible for inward membrane currents in nociceptors are voltage-activated sodium and calcium channels, while outward current is carried mainly by potassium ions. In addition, activation of non-selective cation channels is also responsible for the excitation of sensory neurons. Thus, excitability of neurons can be controlled by regulating expression or by modulating activity of these channels.