投稿

1. 本誌には金沢医科大学医学会正会員の総説，原著，症例報告および短報を掲載するが，正会員以外でも編集委員会の承認があれば掲載することができる。そのほか学会抄録，雑報，本学学位論文の審査要旨を掲載することがある。
2. 倫理規定：投稿論文は基礎研究，臨床研究のいずれにおいても生命倫理に十分な配慮がなされたものであること。また，個人情報の保護のために必要な処置を講じたものでなければならない。
1) ヒトを対象とする研究はヘルシンキ宣言の理念を踏まえ，「臨床研究法」「人を対象とする生命科学・医学系研究に関する倫理指針」および金沢医科大学等の人を対象とする医学系研究に関する規定を遵守し，金沢医科大学等の各倫理審査委員会の承認を得た上で実施した旨を明記すること。特に，「患者の権利，プライバシーの保護」に努め，論文作成に際して，下記の指針を遵守すること。
a. 患者個人の特定が可能となる氏名やイニシャル，住所，カルテ番号，
入院番号等は記載しない。
b. 患者の職業や紹介先施設名・診療科名などについても，患者個人が特定される可能性のある場合は記載しない。
c. 日付は，患者個人を特定できないと判断される場合でも，年月までの記載とする。
d. 顔写真を掲載する場合は，患者個人を特定できぬよう目隠しを付す。
e. 以上の配慮をしても患者個人が特定される場合は，論文内容を提示したうえで，患者本人 ( または遺族か代理人，小児では保護者 ) から発表に関する同意を得ること ( 同意書のコピーは投稿時に添付すること )。
2) 動物実験は「研究機関等における動物実験等の実施に関する基本指針( 文部科学省 )」もしくは「厚生労働省の所管する実施機関における動物実験等の実施に関する基本指針」の規定を遵守し，金沢医科大学等の動物実験委員会の承認を得た上で実施した旨を明記すること。遺伝子組換
え動物実験においては，金沢医科大学等の組換え DNA 実験安全委員会の承認を得た上で実施した旨を明記すること。
3) 遺伝性疾患やヒトゲノム・遺伝子解析を伴う症例の報告では，「人を対象とする生命科学・医学系研究に関する倫理指針」および金沢医科大学
等のヒトゲノム・遺伝子解析研究に関する規定を遵守し，金沢医科大学
等の倫理審査委員会の承認を得た上で実施した旨を明記すること。
4) 遺伝子治療臨床研究に関しては，「遺伝子治療等臨床研究に関する指針」の規定を遵守すること。
5) その他，国が告示した倫理指針に該当する研究は，各指針にそれぞれ合致している旨を明記すること。
3. 原稿様式：原稿は英文または和文とし，標題，要約，キーワード，ランニ
ングタイトル，本文，図，表，文献を基本とする ( 本文が和文の場合のみ，
英文抄録が必要 )。また原稿は，A4 版用紙に Microsoft Word で作成した文書ファイルまたは PDF とし，図表は Microsoft Word，Microsoft Excel，Microsoft PowerPoint 等で作成したファイルとする。図・写真は 300dpi 以上の解像度で作成された JPEG，TIFF および PNG 形式のファイルでも受け付ける。原稿は，文字サイズ 11 ポイント，英文は 1 ページ当たり 20 行で 300
語程度，和文は 40 字 ×20 行を目安に作成すること。また用紙の上下左右は十分にあけ，用紙の下余白にページ番号を付記すること。原稿の長さは原則として，本文，図，表を合わせて 30 枚 ( 和文 20,000 字，英文 8,000 語 ) 以
内とすること。本文が英文の場合は半角入力とし，和文の場合は横書き，
ひらがな，現代かなづかいとし，原則として当用漢字を使用する。和文中の外国語 ( 薬物一般名等 ) はすべて英語綴りの小文字とし，文頭・人名・固有名詞・動植物学名・ドイツ語名詞・商品名・製品名は大文字ではじめる。
4. 標題：原稿第 1 頁に標題，著者名，所属の順で記入し，掲載希望区分を左肩に記入する。連絡著者名の右肩にアスタリスク (＊) を付し，連絡先として，連絡著者の所属機関・氏名・住所および E-mail アドレス等を記載する。
5. 要約：本文が英文の場合は 300 語以内，和文の場合は 600 字以内の要約をつける。論文の概要が具体的にわかるように，目的・対象と方法・結果・
結論，または背景・症例・所見・結論などに分けて記載する。
6. キーワード：5 個以内のキーワードをつけること。
7. ランニングタイトル：本文が英文の場合は英文 ( 半角 80 字以内 )，和文の場合は和文 ( 全角 40 字以内 ) のランニングタイトルを記入すること。
8. 本文：実験研究は，緒言 ( はじめに )，実験方法，結果 ( 成績 )，考察 ( 考按 )に区分する。臨床報告は，緒言 ( はじめに )，症例，考察 ( 考按 ) に区分する。
金沢医科大学等の倫理審査委員会の承認を得た研究である場合は，本文中にその旨を明記すること。倫理規定を逸脱していると編集委員会が判断したものについては，査読の結果にかかわらず不採択とすることがある。和文の場合，外国の人名，地名，物質名などは原則として外国語そのままを用いる。ただし，慣用の和名がある場合はカタカナで書く。適当な日本語訳のない用語は原綴を用いる。動植物，微生物などの学名はイタリック体で記載する。薬品名は原則として日本語の一般名を用いる。特殊な，あるいは特定分野のみで用いられている単位，符号，略語ならびに表現には必ず簡単な説明を加える。数字は原則としてアラビア数字を使用するが，「十数回」，「百分率」などの場合は例外とする。度量衡の記載は原則としてメートル法による。本文中に見出し符号を付す場合は，1，1)，(1)，i) の順に付すこと。ただし，緒言，実験方法等の論文構成の各項目には付けないこととする。しばしば繰り返される語は略語を用いてもよいが，初出の際は規程

完全な用語を用い，以下に略語を使用することを明記する。統計処理を行った際には統計学的検定法を明記する。
9. 利益相反 (conflict of interest) の開示：投稿論文の内容に関する利益相反の有無を筆頭著者，共著者全員について論文の末尾に明記すること。またすべての著者は本誌所定の利益相反自己申告書を別途添付すること。
10. 文献：本文中の文献引用は，引用順に一連番号を本文と同行に (1)，(1-3)，(1，3-5) などと記し，肩付とはしない。文献欄の記載は，下記の要領により番号順に配列する。
1) 雑誌の場合は著者名 ( 筆頭著者から 3 名までとし，3 名をこす場合は「ほか」または「et al」と記載する )，標題，掲載誌名 ( 略名 )，発行年 ( 西暦 )，巻数，頁数 ( 開始頁 - 終了頁 ) の順に記載する。
・ Johnstone BM, Taylor KJ, Boyle AJ: Mechanics of the Guinea pig cochlea.
J Acoust Soc Am 1970; 47: 504-8.
・ Ferguson B, Matyszak MK, Esiri MM et al: Axonal damage in acutemultiple sclerosis. Brain 1997; 120: 393-9.
・ 柴田整一 , 三村信英 , 木村二郎ほか : 進行しない所謂“慢性腎炎”．日腎誌 1962; 4: 31-7.
2) 単行本の場合は著者名 , 標題 , 編集者名 , 書名 , 版数 , 発行所所在地 , 発行
所 , 発行年 , 頁数 ( 開始頁 - 終了頁 ) の順とする。
・ Mostofi FK: Benign hyperplasia of the prostate gland. In Campbell MF,
Harrison JH (Eds), Urology (3rd ed), Philadelphia, WB Saunders, 1970;
1065-129.
・ 丸野義和 : 体液平衡異常と腎臓 , 東京 , 南江堂 , 1970; 75-7.
・ 河野祐治 , 吉良潤一 : HIV-1 と免疫変化概説 . 杉田秀夫 , 田平武 ( 編 ),HIV-1 感染による神経障害の診療マニュアル , 東京 , 新興医学出版社 ,1997; 118-37.
3) インターネット上の資料や情報を引用する場合，URL とアクセスした年月日を記載する。
・ 厚生労働省：がん対策推進基本計画 , http://www.mhlw.go.jp/bunya/
kenkou/dl/gan_keikaku02.pdf (2016 年 7 月 1 日にアクセス ) ．
4) 著者名が人名でないときは次のようにする。
・ 日本病理学会編 : 日本病理剖検輯報 , 14 輯 , 東京 , 日本病理剖検輯報刊行
会 , 1972.
5) 引用雑誌の略名は，MEDLINE または Index Medicus および医学中央雑誌収載誌目録によること。
6) オンラインジャーナル (Epub のみ ) および早期公開 (Epub on ahead) の場合，電子出版 (Epub) 年月日や DOI があれば掲載する。
7) 原則として，特殊な報告書，投稿中原稿，私信などで一般的に入手不可
能な資料は文献としての引用を差し控えること。
11. 図：出来上がり寸法は横幅 8 ㎝にするか，17 ㎝にするかを指定のこと。
12. 表：原則として本文が英文の場合は英文，和文の場合は和文 ( ただし，和文で表現し難い語句および字句は例外とする ) にて作成する。
13. 図の説明：原則として本文が英文の場合は英文，和文の場合は和文にて別紙に一括する。
14. 英文抄録：本文が和文の場合は，英文の標題，氏名，所属，要約 ( 総説・原著の場合は 400 語以内，症例報告・短報の場合は 200 語以内 )，キーワード，連絡先を記載する。
15. 原稿の採否および掲載の順序は編集委員会で決定する。
16. 原稿の校正は初校・再校とも著者校正とし，校正時の大幅な変更は許されない。また校正期日は厳守のこと。
17. 投稿論文内容は他誌に発表されていないものに限る。また投稿論文の二重投稿や同時投稿は認めない。ただし，本誌掲載和文論文の他誌への英文化再掲載 (secondary publication) 等については編集委員会が特に認めた場合はこの限りではない。
18. 掲載費のうち，総説では組上がり 10 頁まで，原著では 8 頁まで，症例報告・短報では 5 頁までを無料とする。超過分および別冊はすべて著者の負担とするが，依頼原稿の超過分は無料とする。なお，原稿にカラー写真等のある場合，版代は著者の負担とする。
19. 原稿提出：紙原稿 1 部，原稿の電子データ，投稿申込書，チェックリスト，
誓約書，利益相反自己申告書を下記あてに提出する。論文が受理されたときは，最終版の電子データ ( 図表，写真含む ) を提出すること。
20. 本誌に掲載された著作物の著作権は，本医学会に帰属する。
＜連絡先＞ 〒 920-0293 石川県河北郡内灘町大学 1 − 1
金沢医科大学内 金沢医科大学雑誌編集委員会
TEL．076-286-2211 ( 内線 7242)
E-mail: hrc-jimu@kanazawa-med.ac.jp
この規定は 1979 年 1 月一部改正した。 この規定は 1985 年 5 月一部改正した。
この規定は 1986 年 11 月一部改正した。 この規定は 1988 年 2 月一部改正した。
この規定は 1989 年 9 月一部改正した。 この規定は 1995 年 2 月一部改正した。
この規定は 1997 年 2 月一部改正した。 この規定は 2000 年 3 月一部改正した。
この規定は 2003 年 3 月一部改正した。 この規定は 2013 年 4 月一部改正した。
この規定は 2020 年 2 月一部改正した。 この規程は 2022 年 3 月一部改正した。
以上

Submission Guidelines
1. This Journal publishes reviews, original articles, case reports, and shortreports by regular members of the Medical Society of Kanazawa Medical
University. It may also publish works by non-regular members if the Editorial
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10.References: References in the main text should be numbered as (1), (1-3),(1, 3-5) in the order of appearance. Superscripts should not be used forcitations in the main text. The References section should be organized in thefollowing numerical order:
1) For journals, include the following information: author names (up to threeauthors beginning with the first author; in case of more than threeauthors, et al. should be used), title, journal name (abbreviated), year of
publication, volume number, and page number (start-end pages).
・ Johnstone BM, Taylor KJ, Boyle AJ: Mechanics of the Guinea pig cochlea.
J Acoust Soc Am 1970; 47: 504-8.
・ Ferguson B, Matyszak MK, Esiri MM et al: Axonal damage in acutemultiple sclerosis. Brain 1997; 120: 393-9.
2) For books, include the following information: author, title, editor, booktitle, editorial version, publisher’s address and name, year of publication,and page numbers (start-end pages).
・ Mostofi FK: Benign hyperplasia of the prostate gland. In Campbell MF,
Harrison JH (Eds), Urology (3rd ed), Philadelphia, WB Saunders, 1970;
1065-129.
3) Provide the URL and date of access when citing materials or informationfrom the Internet.
・ The Ministr y of Health, Labour and Welfare: Basic Plan to Promote
Cancer Control Programs, http://www.mhlw.go.jp/bunya/kenkou/dl/
gan_keikaku02.pdf (accessed on July 1, 2016).
4) Use the same abbreviations for names of cited journals as MEDLINE or
Index Medicus.
5) If available, the electronic publication (Epub) date and DOI should belisted for online journals (Epub format only) and early publications (Epubahead of print).
6) In principle, special repor ts, manuscripts under submission, private
letters, and other materials that are not commonly available should not becited as references.
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16.Submission: To the address below, send one paper copy of the manuscript,
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Send submissions to: Editorial Board, Journal of Kanazawa Medical University
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E-mail: hrc-jimu@kanazawa-med.ac.jp
These guidelines were partially revised in March, 2022.

金沢医科大学雑誌
第 47 巻 第 1 号

2022 年 6 月

目

次

総

説
Pain Regulation by Peripheral Glutamate and its Abnormalities ……………………………………………… 1
Takayoshi Masuoka
Review of Biliary Drainage in the Management for Preoperativeand Unresectable Malignant Distal Biliary Obstructions ………………………………………………… 7
Tsuyoshi Mukai, Hiroaki Kuno, Rika Kobayashi, Junji Kamai,
Sadafumi Azukisawa, Ken Kawaura, Hidekazu Kitakata, Tasuku Hayashi,
Hikaru Takano, Naoko Sakurai, Ranji Hayashi, Toshimi Otsuka, Tohru Ito
Research History and Current Concept of the Autonomic Nervous System ……………………………… 13
Masato Asahina

金沢医科大学総合医学研究所 2021 年度 研究セミナー 抄録 ……………………………………………… 20※ 新型コロナウイルス感染拡大防止のため，2021 年度精神神経科学教室懇話会は開催中止となった。

編

集

金沢医科大学医学会

編集委員

西野 善一（委員長），清川 悦子（副委員長），岩脇 隆夫，高村 博之，林
康彦，古市 賢吾，正木 康史，水野 史朗，山田 壮亮，
米倉 秀人

J Kanazawa Med Univ 47：1 −6, 2022

Pain Regulation by Peripheral Glutamate and its Abnormalities
Takayoshi Masuoka*
Department of Pharmacology, Kanazawa Medical University

Abstract: The activities of primary sensory nerves that branch off from the dorsal root and trigeminal
ganglia are important for understanding the reception and transmission of a wide variety of painful andnonpainful sensations, such as touch, and temperature. Glutamate is well-established as a principal
neurotransmitter in the central nervous system; however, it also works as a peripheral mediator to regulate
neuronal and non-neuronal cells. Many studies have revealed that peripheral glutamate is one of theendogenous pro-nociceptive mediators that decreases the threshold for nociceptive stimuli throughchanging sensitivities of nociceptors and membrane excitabilities in sensory afferents. Here we reviewed
the knowledge about the functions of peripheral glutamate in pain regulation and its abnormalities underpathophysiological conditions.
Key Words: glutamate, primary sensory neurons, pain, inflammation

Introduction
The primary sensory afferents stemming from dorsal
root ganglia (DRG) and trigeminal ganglia (TG) haveessential roles in the reception and transmission of awide range of sensations. The stimulation of nociceptive
sensory afferents by exogenous and endogenous
irritants leads to uncomfortable sensations like pain
and itch, which act as essential protective mechanisms
to prevent tissue damage in organisms. Many of the
pro-inflammatory and inflammatory mediators, i.e.
4-hydroxynonenal, prostaglandins and interleukins,
activate nociceptors or alter their sensitivity andmembrane excitability resulting in the generation ofpain and hyperalgesia (1-3). Glutamate, which is wellestablished as a principal central neurotransmitter,propagates and modulates the pain signals in the spinal
cord and the brain stem where central endings ofprimary sensory neurons are located (4). However,recent studies have revealed that glutamate released
from neuronal and non-neuronal cells in periphery acts
as an endogenous pro-nociceptive mediator (5, 6).
1)Kohzaburo Fujikawa-Yamamoto
Division of Cell
Medicine, ResearchInstituteof Medical
Science,* Departmentof Pharmacology,
Kanazawa
Medical
University,
Kanazawa
Medical
University,
Uchinada,
Ishikawa
920-0293,
1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan
Japan
Tel: +81-76-286-2211 (ex 3721), Fax: +81-76-286-8191
Corresponding
author:Kohzaburo Fujikawa-Yamamoto
E-mail: masuoka@kanazawa-med.ac.jp
Accepted:
Accepted:November
December30,
13,2006
2021

Glutamate exhibits various effects on targeted cells
through acting on ionotropic and metabotropic receptors.
Ionotropic glutamate receptors (iGluRs) consist of Nmethyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy5-methyl-isoxazol-4-yl) propanoic acid (AMPA), andkinate (KA) receptors that pass sodium, potassium andcalcium ions resulting in membrane excitation (7).
Metabotropic glutamate receptors (mGluRs) have eight
subtypes (mGluR1-8) that are classified into threegroups – group I (mGluR1/5), group II (mGluR2/3)
and group III (mGluR4/6/7/8) – based on theirpharmacological action and coupling effectors (8).
Group I receptors coupled with Gq/11 protein activate
phospholipase C and increase in intracellular Ca2+
concentration, whereas group II and III receptors
coupled with Gi/o protein suppress adenylate cyclase
and simultaneously activate G protein-activated inwardly
rectifying potassium channels (8). Many iGluRs andmGluRs are expressed in primary sensory neurons, but
the expression pattern of each receptor subtype isdifferent depending on the neuronal type. For instance,
DRG neurons with small-sized soma that mainly
branch C and Aδ fibers to convey noxious information
express AMPA receptor GluA1-3 subunits, a kinate
receptor GluK1 subunit, and an NMDA receptor NR1
subunit, while large-sized DRG neurons that branch Aβ
fibers to communicate non-noxious somatosensory
information express AMPA receptor GluA2/3 subunits1		and an NMDA receptor NR1 subunit (9). In mGluRs,
the mGluR8 mostly express independent of soma size,
whereas mGluR2/3 are dominantly expressed in smallsized DRG neurons (10). Therefore, the effect of
glutamate in each type of sensory neuron is expected
to be different and to have various physiological roles
in sensory input. In this review, we discuss the functionsof peripheral glutamate in pain regulation and its
abnormalities under pathophysiological conditions.
1. Source of peripheral glutamate
Glutamate receptors and transporters widely expressin peripheral non-neuronal tissues such as that of thekidney, lung, liver, heart, stomach, bone and immune
system. They also regulate physiological andpathophysiological conditions in many organs (11).
One of the major sources of peripheral glutamate might
be inflammatory cells, such as neutrophils, monocytes/
macrophages and activated dendritic cells, through theglutamate/cystine antiporter SLC7A11 (system xC–transporter) (12-14). The extracellular concentration of
glutamate particularly increases in inflamed tissue – areaction which has been confirmed by a microdialysis
study of the inflammation induced by formalin in rat

Masuokaskin (15). In addition to inflammatory cells,
keratinocytes/melanocytes and nociceptive sensory
afferents (C and Aδ fibers) are also reported to be able
to produce and release glutamate in the skin (16, 17).
The glutamate from keratinocytes works as a homeostic
signal of a cutaneous barrier and epidermal hyperplasia
induced by the barrier disruption (18). The nociceptive
primary sensory neurons are glutamatergic andpeptidergic neurons whose activation transmits thepain message to the spinal dorsal horn neurons withglutamate, substance P, and calcitonin gene-related
peptide (CGRP) (17, 19). The nerve excitation ofprimary sensory neurons by nociceptive stimuli could
simultaneously release these transmitters by exocytosis
in peripheral tissues and organs from the afferents
including branched fibers (17). This peripheral
glutamate acts in autocrine and paracrine manners,
and may be involved in the activation and sensitizationof neighboring sensory nerves as well as neurogenic
inflammation around nerves receiving noxious
stimuli (5, 6). Thus, the transmission of peripheral
glutamate is considered to reinforce the warning
signals following nociception (Figure 1).

Figure 1. Schematic diagram of the glutamatergic regulation in nociceptive sensory afferents in periphery.
Noxious stimuli excite nociceptive sensory afferents through activation of nociceptor. The information is conveyed to the central terminals of dorsal root
ganglion neurons in the spinal cord and transmitted to secondary neurons. The peripheral glutamate released from a variety of cells, such as
keratinocyte, sensory afferents, inflammatory cells and cancer cells, positively and negatively regulates nociceptors and membrane excitabilities throughionotropic and metabotropic glutamate receptors (GluRs).

2peripheral glutamate and pain

2. Regulations through ionotropic receptors
Pharmacological activation of NMDA, AMPA andKA receptors in the skin is reported to induce
mechanical allodynia and hyperalgesia (20), suggestingthat peripheral ionotropic receptors potentiate pain.
Peripheral NMDA receptors are found in sensory nervesin deep tissues and may play a role in the pain regulationof these areas. For instance, the injection of glutamate
into the masseter muscle excites craniofacial afferent
fibers through NMDA receptors and evokes pain in
both rat and human subjects (21). In addition, thesubcutaneous injection of bee venom induces
hyperexcitability of spinal wide-dynamic range neurons
and persistent nociception that is attenuated by pre- andpost-treatment of NMDA receptor antagonists in thesame subcutaneous tissue (22). The NMDA receptors
in a state of resting potential are generally blocked bymagnesium ion; relieving the blockage of magnesiumion by membrane depolarization is necessary to activate
the receptors (7). The administration of magnesium ion
via an intravenous, intrathecal, or epidural route wasreported to alleviate various pain disorders (diabetic
neuropathy postherpetic neuralgia, and chemotherapyinduced peripheral neuropathy) and decrease
perioperative anesthetic and analgesic requirements (23).
AMPA receptors (GluA1/2/3) and KA receptors(GluK1/2) are also expressed in nociceptive primarysensory neurons (9, 24). Intramuscular administrationof the exogenous irritant mustard oil into the massetermuscle elicits nocifensive behavior and the firing of
secondary neurons connected with central terminals
of masseter nerves in the subnucleus caudalis of thetrigeminal nerve in the brain stem. The nociceptive
responses are suppressed by the concurrent local
administration of a selective AMPA/KA receptor
antagonist (25). A lack of the calcium-permeable
AMPA receptor GluA1 subunit in peripheral painsensing neurons in mice lead to reduced mechanicalhypersensitivity and sensitization in models of chronic
inflammatory pain and arthritis; therefore, GluA1containing AMPA receptors control the excitatory
drive from the periphery into the spinal cord (26). The
underlying mechanism is not clear but is thought to bea negative regulation of transient receptor potential
vanilloid 1 (TRPV1; one of the typical nociceptors)
responses to noxious stimuli in inflamed tissues andof neurotransmission in the central terminals (26).
3. Regulations through metabotropic receptors
Group I mGluRs (mGluR1/5) are excitatory
metabotropic receptors coupled to Gq/11 protein which
activates phospholipase C signals. Immunohistochemical
studies demonstrate that mGluR1α or mGluR5 areexpressed on peripheral primary afferent fibers inrodents (27-29). The pharmacological activation ofmGluR5 results in intracellular Ca2+ elevation in DRG
neurons (30). The activation of mGluR1/5 was reported
to sensitize some nociceptors, such as TRPV1, transient
receptor potentials ankyrin 1 (TRPA1), and acid-sensing
ion channels (ASICs). For instance, the mGluR1/5
agonist potentiates ASIC currents in DRG neurons, andincreases the duration of flinching behaviour through
ASIC induced by acidic solution (31). The activationof mGluR5 transiently sensitizes TRPV1 channel
activity and contributes to heat hyperalgesia (32, 33),
which is likely to be mediated by the production of
prostaglandins (34). Masseteric injection of mGlu1/5
agonist evokes mechanical hyperalgesia caused by thephosphorylation of TRPV1 serine residues, including
S800 in masseter afferents (35). On the other hand,activation of mGluR5 persistently inhibits voltagegated calcium currents in TRPV1-positive DRG
neurons and attenuates responses against nociceptive
heat stimuli (hypoalgesia). Therefore, mGluR5 signals
primarily exhibit algesic effects but also partiallyregulate analgesia in nociceptive nerves (32). Longterm stimulation of mGluR1/5 also elicits heart
hyperalgesia through an increase in the neuronal
population expressing functional TRPV1 via PLC,
PKC, MEK and p38 MAPK signaling in TRPA1positive nociceptive DRG neurons (36). Under
persistent elevation of extracellular glutamate in the
periphery induced by severe nociception andinflammation, this effect would contribute to thedevelopment of chronic heat hyperalgesia.
The group II mGluRs, mGluR2/3, are expressed inapproximately 40% of L4 and L5 dorsal root ganglion
neurons and are located in 32% of unmyelinated axons(C fibers) and 28% of myelinated axons (A fibers) indigital nerves (37). The activation of mGluR2/3 resultsin the suppression of TRPV1 sensitivities in rats (38).
Similarly, activation of the group III mGluRs, mGluR8
localized in TRPV1-positive nociceptive DRG neurons
and digital nerves, attenuates TRPV1-mediated pain
behavior through inhibiting adenylate cyclase (39). This
produces an analgesic effect on inflamed knee joints
by reducing neuronal discharge rates at the saphenous
nerve when inﬂamed (40). The blockage of peripheral
group II or III mGluRs exacerbates capsaicin (a TRPV1
agonist)-induced nociceptive nerve firing and pain
behavior, which is improved by a group II/III mGluRs
agonist (41). Therefore, the excessive activation of
nociceptors might stimulate group II/III mGluRs by asurplus of released glutamate, then reduce additional
excitation of nociceptive nerves. These reports suggestthat the group II and III mGluRs agonists haveinhibitory effects on pain possibly mediated by the
suppression of TRPV1, and are thought to be candidates
for novel analgesic drugs.
3		

4. Relationship with inflammatory pain
Complete Freund’s adjuvant (CFA)-induced arthritis
in the hind paw of rats elicits the expression of
glutaminase which converts glutamine into glutamate
in DRG neurons, especially those with small-sized soma,presumably nociceptive neurons (42). This reaction
implicates elevated glutamate release in central andperipheral terminals (43). The NMDA, AMPA and KA
receptor-positive axons are 26.9, 19.5 and 18.5% in thedermal-epidermal junction of normal human subjects,
respectively (44); The amounts of mRNA and proteinin the NMDA receptor NR1 subunit, AMPA receptor
GluA2 subunit, and KA receptor GluK2 subunit are
significantly elevated in inflamed human skin (45). The
proportion of unmyelinated axons expressing NMDA,AMPA or KA receptors is also reported to increase incases of CFA-induced inflammation in the hind pawof mice (46). We found that functions of metabotropic
receptors mGluR1/5 significantly change in chronic
inflammation, although the amount of mGluR proteinsremains unchanged. The mGluR1/5 agonist-induced
pain behavior in mice subjected to CFA-induced
inflammation was markedly potentiated by nerve growth
factor (NGF)-tropomyosin receptor kinase A (TrkA)
signaling (47). The underlying mechanism is a TRPV1
phosphorylation through increased TRPV1 and its
scaffolding protein (A-kinase anchor protein 5;
AKAP5) expression. That leads to an increase in the
subpopulation of DRG neurons with activatedmGluR1/5 signaling attributed to a direct excitation of
TRPV1 by diacylglycerol, a metabolite of PLC coupledwith mGluR (47). Therefore, a chronic inflammation
facilitates glutamate-mediated pain regulation throughexcitatory ionotropic and metabotropic glutamate
receptors, suggesting therapeutic targets for chronic
inflammatory pain.
5. Relationship with neuropathic pain
In neuropathic pain induced by chronic constriction
injury (CCI) of the rat sciatic nerve, the DRG neurons
exhibit increased excitability, i.e. decreased membrane
threshold and rheobase in subpopulation with smallsized soma (48). CCI simultaneously amplifies theinward current response induced by the AMPA receptor,
KA receptor and mGluR1/5 agonists, and increases
the population of neurons responding to the NMDA
receptor, AMPA receptor and mGluR1/5 agonists (48).
Part of these changes in glutamatergic responses could
be caused by an elevation of GluA1 and mGluR1
protein and a decrease in GluA2 protein in CCI. In
addition to the changes in receptor response, there arealso changes that occur in glutamate synthesis and in
vesicular glutamate; the intensities of immunoreactivities
to glutaminese and vesicular glutamate transporter
vGluT2 are elevated in S1 DRG neurons after the4

Masuokasurgical incision of a rat tail (49). Peripherally restricted
NMDA receptor antagonists as well as centrally acting
ones are reported to ameliorate allodynia of two
neuropathic pain models induced by CCI of the sciatic
nerve and spinal nerve ligation (50). Therefore,
peripheral glutamate is suggested to be involved in theaugmentation of neuropathic pain.
6. Relationship with cancer pain
A variety of human cancers overexpress the system
xC– transporter which imports cystine for glutathione
biosynthesis and antioxidant defense and releases
glutamate (51). System xC– has been found to play a
crucial role in tumor growth, progression, andmetastasis in various types of cancer including
pancreatic tumors (52), glioblastomas (53), breast
cancer (54), esophageal tumors (55), and ovariancancer (56). Breast cancer cells which often metastasize
to bone express system x C– and release glutamate,which causes bone cancer pain through the activation
and/or sensitization of peripheral sensory nerves.
Pharmacological attenuation of tumor-produced
glutamate ameliorates the sensitization of peripheral
sensory neurons by sulphasalazine, a system x C –inhibitor (57, 58).
Regarding cancer pain, prescription opioids are
frequently used for alleviating cancer pain. Opioids
can induce unexpected effects, e.g. opioid tolerance
and opioid-induced hyperalgesia both of which would
be caused by peripheral glutamate. The repeatedadministration of morphine leading to an increased
hyperalgesic response to glutamate in small diameter
DRG neurons simultaneously elevates the expressionof GluN2B and excitatory amino acid transporter 3/
excitatory amino acid carrier 1 (59). Furthermore, thecoadministration of a selective NMDA receptor
GluN2B subtype antagonist suppresses the opioidinduced hyperalgesia (59). Opioid μ receptor is reported
to functionally couple with mGluR5. This receptor’sallosteric modulator, 2-methyl-6-(phenylethynyl)
pyridine (MPEP), alters opioid-induced intracellularsignaling and μ receptor phosphorylation andinternalization, resulting in the prevention of opioid
tolerance (60). These findings suggest that peripheral
glutamatergic neurotransmission might affect theefficacy of opioid therapy.
Conclusion
Released glutamate from periphery regulates nociceptive
sensory afferents through various types of glutamate
receptors and intracellular signaling pathways. Large
varieties of modulation mechanisms are involved in thegeneration and sensitization of pain signals to the body,and morbid pain like chronic inflammatory pain orneuropathic pain. Further studies of the glutamatergic

peripheral glutamate and pain

regulation in primary sensory afferents could facilitate
the clinical management of inflammatory, neuropathic
and cancer pain, and could also identify promisingtargets for the development of novel analgesics.
Acknowledgement
This work was supported in part by a Grant for
Collaborative Research from Kanazawa Medical
University (C2021-4), JSPS KAKENHI grants(Numbers 20K09814), and the Smoking Research
Foundation of Japan.
Conflict of Interest Statement
The author has no potential conflict of interest to
declare.
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J Kanazawa Med Univ 47：7 −12, 2022

Review of Biliary Drainage in the Management for Preoperative and Unresectable
Malignant Distal Biliary Obstructions
Tsuyoshi Mukai 1, 2) *, Hiroaki Kuno 1), Rika Kobayashi 1), Junji Kamai 1), Sadafumi Azukisawa 1),
Ken Kawaura 1), Hidekazu Kitakata 1), Tasuku Hayashi 2), Hikaru Takano 2), Naoko Sakurai 2),
Ranji Hayashi 2), Toshimi Otsuka 2), Tohru Ito 1, 2)
1)
2)

Department of Gastroenterological Endoscopy, Kanazawa Medical University
Department of Gastroenterology, Kanazawa Medical University

Abstract: Endoscopic biliary drainage is recommended as a procedure for malignant distal biliary
obstruction. A covered self-expandable metallic stent (SEMS) is preferable in patients undergoing
preoperative chemotherapy for pancreatic cancer and recommended as the first-choice of biliary stent for
unresectable malignant distal biliary obstruction, because of its long patency and possibility of removal in
reintervention. However, a covered SEMS does not sufficiently reduce recurrent biliary obstruction(RBO) and prevent adverse events, and can even lead to occlusion by sludge formation and migration.
Therefore, measures to prevent these disadvantages are urgently needed. It is important to understand thecharacteristics of various stents and to select the most appropriate stent for each case based on the likely
need for reintervention for RBO or adverse events other than stent occlusion, as well as stent occlusion.
Key Words: malignant distal biliary obstruction, endoscopic biliary drainage, endoscopic transpapillary biliary stenting (EBS),
preoperative biliary drainage, covered self-expandable metallic stent (covered SEMS)

Introduction
Endoscopic biliary drainage includes endoscopic
naso-biliary drainage (ENBD), which is an external
drainage, and endoscopic transpapillary biliary
stenting (EBS), which is an internal drainage. Nagai
et al. (1) reported ENBD in 1976, and Soehendra et al.
(2) reported EBS using a plastic stent in 1980, andthey are now widely used as treatment procedures for
obstructive jaundice and cholangitis associated withbiliary obstruction. In 1983, a self-expandable metallic
stent (SEMS), was developed in the hope of prolonging
stent patency. Though it was initially placed througha percutaneous route, it is now possible to placeendoscopically. However, the disadvantage of an
uncovered SEMS is that it has mesh structures, which*1)Kohzaburo
DepartmentFujikawa-Yamamotoof Gastroenterological Endoscopy, Kanazawa
Division University,of Cell Medicine,Research
Institute ofMedicalIshikawa
Science,
Medical1-1 Daigaku,
Uchinada,
Kahoku,KanazawaJapan
Medical University, Uchinada, Ishikawa 920-0293,
920-0293,
Japan
Tel: +81-76-218-8415, Fax: +81-76-218-8416
Corresponding
author:Kohzaburo Fujikawa-Yamamoto
E-mail: tsuyomukai@yahoo.co.jp
Accepted:
30, 2006
Accepted:November
March 3, 2022

may cause occlusion due to tumor ingrowth or tissue
hyperplasia. In addition, once the uncovered SEMS isplaced, it cannot be removed, which often makes
reintervention difficult. Later, a covered SEMS for
malignant distal biliary obstruction was developed tocompensate for the disadvantages of the uncovered
SEMS, and now various types of SEMSs are available
for EBS and endoscopic ultrasound (EUS)-guided
biliary drainage (EUS-BD). In principle, covered
SEMS placement in a hilar biliary obstruction iscontraindicated if the lateral branches of theintrahepatic bile duct are obstructed.
The Japanese guidelines (3, 4) recommend
endoscopic covered SEMS placement for biliary
drainage of unresectable malignant distal biliary
obstruction. Although it is speculated that EUS-BD
will become the gold standard in the near future (5), atpresent, as stated in the guideline for EUS-BD (6), it
should be limited for use by experts to cases in which
endoscopic biliary drainage is difficult to perform. In
this article, we will explain endoscopic biliary drainage
for malignant distal biliary obstruction, bothpreoperative and unresectable cases.
7		Preoperative biliary drainage
1. Necessity of preoperative biliary drainage
Preoperative biliary drainage is expected to improve
symptoms associated with obstructive jaundice caused
by malignant bile duct obstruction (symptoms: decreased
liver reserve, coagulation abnormalities, impaired
absorption of fat and fat-soluble vitamins, decreased
immunity and gastrointestinal defense factors, andabnormal intestinal microbiota due to increased gramnegative bacteria). It is also believed to relieve
subjective symptoms such as skin pruritus, improve
the quality of life (QOL), and improve the prognosis.
Surgical resection is the only treatment that can be
expected to cure malignant distal biliary obstruction
caused by pancreatic cancer, cholangiocarcinoma, andampullary cancer. The most common operation ispancreatoduodenectomy, and since it is a highlyinvasive surgery, preoperative systemic management
including biliary drainage is very important.
In Japan, the waiting period for treatment of
obstructive jaundice due to malignant biliary
obstruction tends to be longer than in Europe and theUnited States, and direct surgery is not common
because of the emphasis on histopathological diagnosis
by cytology and biopsy as well as preoperative biliary
drainage, and the difficulty in obtaining the consent ofanesthesiologists (4). On the other hand, systematic
reviews and meta-analyses have reported thatpreoperative biliary drainage is not necessary for routine
surgery in Europe and the United States (7). Meanwhile,a multicenter randomized trial by van der Gaag et al.
(8) compared early surgery (mean waiting period 1.2
weeks) and surgery after preoperative biliary drainage
with a plastic stent (mean waiting period 5.2 weeks)
for pancreatic head cancer cases. They reported asignificantly higher incidence of complications within
120 days in the preoperative biliary drainage group,and early surgery with preoperative biliary drainage
tended to be less favorable. In addition, there was no
significant difference in postoperative mortality
between patients who underwent preoperative biliary
drainage and those who did not. According to a previous
report, a higher postoperative complication rate wasseen in patients who underwent preoperative biliary
drainage (9), whereas another report showed a lower
incidence of serious postoperative complications inpatients who underwent preoperative biliary drainage
using EBS (10), while another study reported that
ENBD was preferable to EBS if the waiting period isless than one month (11). However, there is a lack ofsufficient evidence to support this conclusion.
2. Necessity of preoperative anti-cancer therapy
The usefulness of preoperative neoadjuvant
chemotherapy (NAC) and/or radiotherapy for8

Mukai/Kuno/et al.

surgically-intended treatment of pancreatic cancer has
been discussed for some time (12, 13). A meta-analysis
of preoperative anti-cancer therapy versus direct surgery
for resectable and borderline resectable pancreaticcancer reported the possibility of long-term survivalwith preoperative anti-cancer therapy (13). In addition,a randomized phase II/III trial (Prep-02/JSAP05)
comparing NAC with gemcitabine and S-1 versus direct
surgery for patients with pancreatic cancer in theplanning for surgery showed a significantly better
survival rate in the NAC group. Preoperative anticancer therapy is becoming a standard treatment forplanned resection of pancreatic cancer (14, 15).
Since the guideline for initiating anti-cancer
therapy is a total bilirubin level of 3.0 mg/dL or less,preoperative biliary drainage is necessary for patientswith obstructive jaundice. In addition, since preoperative
anti-cancer therapy prolongs the waiting period,
preoperative biliary drainage is desirable to avoid
discontinuation or postponement of anti-cancer therapy
and to reduce the incidence of recurrent biliary
obstruction (RBO) and adverse events such as stentocclusion.
On the other hand, although there is an ongoingphase III trial in resectable distal cholangiocarcinoma
and duodenal papillary carcinoma, there is noevidence for the efficacy of preoperative anti-cancer
therapy, and direct surgery is currently performed
after establishing preoperative biliary drainage (16).
3. Approach route
There are three approach routes for biliary drainage:
endoscopic biliary drainage, percutaneous transhepatic
biliary drainage (PTBD), and EUS-BD. In preoperative
PTBD cases, there is a possibility of serious
complications such as portal vein or hepatic arteryinjury, and fistula recurrence is significantly morecommon in patients with multiple external drainage
tube placement, long-term external drainage tube
placement and papillary cholangiocarcinoma (17) andthe risk of peritoneal dissemination has also beenreported in pancreatic cancer cases (18). In addition,
because the survival rate of the preoperative PTBD
group is reported to be significantly lower than that of
the endoscopic biliary drainage group, PTBD should not
be the first choice (17). Although EUS-BD has a low
risk of impact on the operative field and postoperative
pancreatitis, as in the case of PTBD, it should also not
be the first choice because of the possibility of fistula
dissemination, the lack of dedicated treatment
devices, and the high adverse event rate (6, 18).
However, post-ERCP pancreatitis (PEP) may cause
postponement or discontinuation of surgery. Therefore,
endoscopic biliary drainage, which allows for theprevention of adverse events such as PEP is desirable.

Stent Selection for Malignant Distal Biliary Obstructions

4. ENBD vs EBS
Sasahira et al. (19) retrospectively reviewed 419 casesof preoperative biliary drainage (166 cases of ENBD
and 253 cases of EBS with a plastic stent), including
194 cases (46%) of pancreatic cancer, 172 cases (41%)
of cholangiocarcinoma, 50 cases (12%) of ampullarycancer, and 3 cases (1%) of gallbladder cancer. The
authors reported that the preoperative obstruction rate
was significantly lower in ENBD, and the trend became
more pronounced within 14 days after placement (19).
In addition, the risk of developing cholangitis washigher with EBS using a pigtail type plastic stent, andthe diameter of the plastic stent and drainage volume
could not be confirmed, whereas ENBD allowed for
direct confirmation of the drained bile juice and theadvantage of repeated bile cytology. However, longterm maintenance of an external drainage with ENBD
may decrease immunocompetence and coagulability
due to decreased enterohepatic circulation of bile, andmay decrease the QOL of patients. Therefore, it isnecessary to shift to EBS in patients who receive
preoperative anti-cancer therapy.
5. Stent selection in EBS (plastic stent vs SEMS,
uncovered SEMS vs covered SEMS)
Because of the relatively high rate of plastic stents
requiring reintervention for stent occlusion during thewaiting period, the usefulness of covered SEMSs overplastic stents has been widely reported in recent years(18). In the guideline for the management of pancreaticcancer (4), a SEMS is recommended for preoperative
cases with obstructive jaundice due to pancreatic cancer
because of the low need for reintervention during thewaiting period.
In the comparison between uncovered SEMSs andcovered SEMSs, although there was no significant
difference in stent patency and adverse events, acovered SEMS was considered to be the first choice as
preoperative biliary drainage because of its advantage
of being removable in reintervention. As for the
reintervention of a covered SEMS occlusion, it has beenreported that the patency was significantly longer inthe group of patients who underwent covered SEMS
removal followed by covered SEMS replacement thanin the group of patients who underwent plastic stent
replacement, and cleaning of the covered SEMS lumen
without covered SEMS removal (20).
6. Prevention of adverse events associated withcovered SEMS placement
Adverse events after covered SEMS placement include
acute cholecystitis and acute pancreatitis. Risk factors
for the development of cholecystitis include tumor
invasion of the cystic duct or gallbladder artery,placement of a covered SEMS with high axial force,and placement of a covered SEMS with a length of lessthan 60 mm (21, 22). It has also been reported that the
injection of contrast medium into the gallbladder is arisk factor for the development of cholecystitis (22),and it is therefore necessary to perform ENBD before
covered SEMS placement to reduce gallbladderswelling and to minimize the need for injection ofcontrast medium into the gallbladder during covered
SEMS placement. In addition, to prevent thedevelopment of cholecystitis, it is important to detectand treat it early, especially during periodic
examinations of patients with risk factors. For theintervention of cholecystitis, percutaneous transhepatic
gallbladder aspiration is the first choice, since
percutaneous transhepatic or EUS-guided gallbladderdrainage is associated with a risk of dissemination.
There have been reports showing that there is no
significant difference between plastic stents and SEMSs
in PEP. On the other hand, the incidence of PEP isreported to be significantly higher in patients who
underwent pancreatography, pancreatic duct biopsy, or
intraductal ultrasonography, in patients who experienced
difficulty with biliary cannulation (more than 15
minutes), in patients who had treatment time of morethan 30 minutes, and in patients without pancreatic
stenting (23). Therefore, pancreatic stenting for the
purpose of PEP prevention may be considered except
for cases of pancreatic head cancer with obstruction of
the main pancreatic duct.
Biliary drainage in unresectable malignant distalbiliary obstruction
1. Treatment outcome of various stents
Davids et al. (24) were the first to report theusefulness of an uncovered SEMS over a plastic stentin a randomized control trial (RCT). Subsequent
RCTs comparing plastic stents and uncovered SEMSs
have reported lower occlusion rates with largerdiameter uncovered SEMSs than with plastic stents(25-28) and showed longer patency periods foruncovered SEMSs than for plastic stents (29-32).
Isayama et al. reported for the first time the resultsof an RCT comparing covered SEMSs and uncovered
SEMSs for unresectable pancreatic cancer, whichshowed that covered SEMSs had a longer patency thanuncovered SEMSs because it prevented tumor ingrowth(33). Since then, there have been similar reports (34-36)
of longer patency with covered SEMSs, as well asreports of no significant differences in survival, stentpatency, stent obstruction, or adverse event rates (32,37, 38). Some meta-analyses (39-42) showed thatcovered SEMSs had a lower rate of occlusions due totumor ingrowth than uncovered SEMSs, but more stentocclusions due to migration, tumor overgrowth andsludge formation, and no significant difference in9		patency. In addition, although there was no significant
difference in the incidence of pancreatitis andcholecystitis, the authors concluded that it was preferable
to choose a covered SEMS, which has the advantage ofbeing removable, and for good management including
reintervention.
2. Improvement and development of covered
SEMSs
The guidelines (3, 4) also recommend a covered SEMS
as the first choice of biliary stent for unresectable
malignant distal biliary obstruction. On the other hand,
the reduction of RBO and adverse events of covered
SEMSs is not sufficient, and the improvement anddevelopment of covered SEMSs have been desired fora long time. In particular, it is important to prevent
sludge occlusion and migration, which are disadvantagesof covered SEMSs, and the improvement anddevelopment of covered SEMSs with larger diameters,
covered SEMSs with an anti-reflux valve, and covered
SEMSs for placement in the malignant distal biliary
obstruction are underway (43).
a. Diameter of covered SEMS
In a meta-analysis by Saleem et al. (42), it was
unclear whether there was a difference in patency
between the 8-mm and 10-mm covered SEMSs.
However, Kawashima et al. (44) compared the 8-mm
and 10-mm covered SEMSs (WallFlex Biliary RX
Fully Covered Stent; Boston Scientific Corp, MA,
USA) and found no significant difference in mediantime to RBO (TRBO); 275 days for the 8-mm covered
SEMS and 293 days for the 10-mm covered SEMS (P= 0.971), indicating non-inferiority of the 8-mm
covered SEMS over the 10-mm covered SEMS.
The results of our pilot study on the 12-mmdiameter covered SEMS (Niti-STM SUPREMO-12 stent;
Taewoong Medical, Seoul, Korea) (UMIN000007061)
suggest that the sludge occlusion rate may be lower thanthat of the 10-mm-diameter covered SEMS, and theadverse event rate was also considered to be acceptable(45). Recently, Lee et al. (46) conducted a prospective
comparative study of 10-mm and 12-mm covered
SEMSs (modified-BONASTENT M-intraductal;
Sewoon Medical, Seoul, Korea). The authors reported
that migration was significantly lower in the 12-mmcovered SEMS 8.0% (4/50) (P = 0.036) compared with23.1% (12/52) in the 10-mm covered SEMS, andpatency was significantly longer in the 12-mm covered
SEMS (228 days (P = 0.048) compared with 157 daysin the 10-mm covered SEMS.
b. Covered SEMSs with an anti-reflux valve
Misra et al. (47) reported that barium reflux into thebile duct was observed in all cases in which the lower
10

Mukai/Kuno/et al.

end of the SEMS was placed in the duodenum (acrossthe papilla). Prevention of duodenobiliary reflux via a
SEMS is thought to lead to reduced sludge formation,and since the report by Hu et al. (48), various anti-reflux
SEMSs have been developed. Hamada et al. (49)reported that TRBO and RBO by sludge formation orfood impaction of the anti-reflux SEMS (Niti-STM longcovered ComVi stent; Taewoong Medical, Seoul, Korea)
and the conventional covered SEMS (Niti-STM ComVi
stent; Taewoong Medical, Seoul, Korea) were notsignificantly different, but migration rate of the antireflux SEMS was higher than the conventional covered
SEMS (31% vs 12%, P = 0.038). In other reports, thedevelopment of anti-reflux SEMSs has not yet beenachieved (49).
c. Covered SEMS placement above the papilla
Choi et al. (50) reported that a modified 12-mmdiameter intraductal covered SEMS (BONASTENT
M-Intraductal 12; Standard Sci-Tech, Seoul, Korea)
was placed in 51 patients without endoscopic
sphincterotomy (EST), with a mean patency of 297
days with no migration.
In addition, Inoue et al. (51) demonstrated in aprospective study that covered SEMS placement above
the papilla in the bile duct without EST can likely
prevent migration and duodenobiliary reflux and reduce
PEP because the lower end of the covered SEMS does
not obstruct the pancreatic duct orifice. As a result, inthe prospective multi-center observational study using
the long-stringed covered SEMS (Niti-S TM Kaffes
Biliary Stent; Taewoong Medical, Seoul, Korea), themedian TRBO was 339 days, the RBO rate was 33%(13/40), and there was no migration. This covered
SEMS is designed with a thread for positioning andcan be removed in reintervention, but the indication islimited to patients with a distance of 10 mm or morefrom the distal end of biliary obstruction to the papilla.
d. Covered SEMSs with anti-migration system
There were some reports of covered SEMSs with antimigration system such as anchoring-fins (52),anchoring-flaps (53) and bumpy-shape (54). Recently,
Minaga et al. (55) reported that a laser-cut type covered
SEMS (covered ZEO stent; Zeon Medical Inc.,
Kawasaki, Japan) with a bumpy shape had higher
resistance to migration than any other braided covered
SEMSs. The results of the pilot study by Isayama et al.
(56) showed that migration occurred in 12.9% (4/31) of
the patients. However, the results of this study suggestthat the covered SEMS placement in reintervention forpatients who migrated with other covered SEMS may
be effective in preventing migration.

Stent Selection for Malignant Distal Biliary Obstructions

Conclusion
In biliary drainage for malignant distal biliary
obstruction, preoperative anti-cancer therapy is now
recommended in preoperative cases, especially inpancreatic cancer cases, and it is desirable to select acovered SEMS to avoid RBO during the waiting period,
but further accumulation of evidence is expected in
the future. A covered SEMS is also recommended forunresectable malignant distal biliary obstruction
cases, because it is expected to provide longer TRBO.
However, further improvement and development ofcovered SEMSs are needed to overcome its
disadvantages of occlusion by sludge formation andmigration. Finally, all stents and approach routes areindicated for unresectable malignant distal biliary
obstruction, but the stent selection should be based on
the prognosis, the clinical stage, the presence of anticancer therapy, and the method of reintervention for
RBO and adverse events.
Conflicts of interest
Authors declare no conflicts of interest for this article.
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fully covered metal stent, 12 mm in diameter, for intraductal placement inpatients with malignant biliary strictures: a feasibility study. Endoscopy
2016; 48: 625-31.
51. Inoue T, Suzuki Y, Okumura F et al: Intraductal placement of a fully
covered metal stent with a long string for distal malignant biliar yobstruction without endoscopic sphincterotomy: Prospective multi-center
feasibility study. Dig Endosc 2020; 32: 949-56.
52. Kuo MD, Lopresti DC, Gover DD et al: Intentional retrieval of viabil stentgrafts from the biliary system. J Vasc Interv Radiol 2006; 17: 389-97.
53. Park DH, Lee SS, Lee TH et al: Anchoring flap versus flared end, fully
covered self-expandable metal stents to prevent migration in patients withbenign biliar y strictures: a multicenter, prospective, comparative pilot
study (with videos). Gastrointest Endosc 2011; 73: 64-70.
54. Moon SH, Kim MH, Park DH et al: Modified fully covered self-expandable
metal stents with antimigration features for benign pancreatic-duct
strictures in advanced chronic pancreatitis, with a focus on the safety
profile and reducing migration. Gastrointest Endosc 2010; 72: 86-91.
55. Minaga K, Kitano M, Imai H et al: Evaluation of anti-migration propertiesof biliar y covered self-expandable metal stents. World J Gastroenterol
2016; 22: 6917-24.
56. Isayama H, Kawakubo K, Nakai Y et al: A novel, fully covered laser-cut
nitinol stent with antimigration proper ties for nonresectable distal
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2013; 7: 725-30.

J Kanazawa Med Univ 47：13 −19, 2022

Research History and Current Concept of the Autonomic Nervous System
Masato Asahina*
Department of Neurology, Kanazawa Medical University

Abstract: The term jiritsu shinkei-kei (autonomic or vegetative nervous system) has become well known
in Japan due to the popularization of a concept particular to Japan of a disease called jiritsu-shinkei
shiccho-sho (vegetative disorder). Despite the widespread use of the disease name, its actual meaning isoften misunderstood. This paper describes the research history and development of concepts regarding theautonomic nervous system, and explains the current concept. This paper also presents the history andconcept of jiritsu-shinkei shiccho-sho, which is often referred to inaccurately.
Key Words: autonomic nervous system, research history, anatomy, physiology

Introduction
In Japan, the term jiritsu shinkei-kei (autonomic orvegetative nervous system) is widely recognized by
the general public. This may be because the distinct
Japanese concept of a disease called jiritsu-shinkei
shiccho-sho (vegetative disorder), proposed by Abe (1),has been adopted into common use by the general
population. Jiritsu-shinkei means “autonomic nerves”
in English, and shiccho-sho translates to “imbalance”
or “dysregulation.” However, the popularization of theterm jiritsu-shinkei shiccho-sho seems to have muddled
an accurate understanding of the autonomic nervous
system. Healthcare professionals usually use the term
to indicate a psychosomatic disease or medically
unexplained symptoms, whereas the general publiclargely believes that it refers to a disease of theautonomic nervous system. This paper reviews thehistory of research concerning the autonomic nervous
system and explains the development of the concepts
regarding it. It also discusses jiritsu-shinkei shiccho-sho.
1. History of the Research on the Autonomic
Nervous System (2-7)
The earliest description of the extant autonomic nerves
is by Galen (Galenius or Galenos, 130-200)(Figure 1),
the Roman-Greek physician. He served the Roman
1)Kohzaburo Fujikawa-Yamamoto
Division of Cell
Medicine, ResearchInstituteof Medical
Science,* Departmentof Neurology,
Kanazawa
Medical
University,
1-1
Kanazawa
Medical
University,
Uchinada,
Ishikawa
920-0293,
Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan
Japan
Tel: +81-76-286-2211, Fax: +81-76-286-3259
Corresponding
author:Kohzaburo Fujikawa-Yamamoto
E-mail: asahina@kanazawa-med.ac.jp
Accepted:
2006
Accepted:November
March 31,30,
2022

Figure 1. Galen (line engraving by G. P. Busch), a Greek physician.
The neuroanatomical graphic he drew in Roman times depicts the vagus
nerve and the cervical sympathetic ganglion.
*This image with expired copyright is from Wellcome Collection,
London (Wellcome Library no. 3348i).

13

		

emperor and wrote some 600 books. Included in his
works is a description of the “sixth cranial nerve” andthe cervical sympathetic ganglia. What Galen describedas the sixth cranial nerve comprises what are nowclassified as the ninth (glossopharyngeal nerve), tenth(vagus nerve, including parasympathetic nerves), andeleventh (accessory nerve) cranial nerves. He noted thatthe sixth cranial nerve is distributed in the internalorgans via the thoracic and abdominal cavities, and that
sympathetic nerves have communicating branches(white ramus communicans). Galen thought thatperipheral nerves, including the autonomic nerves,connected various parts of the body, and acted aschannels through which the mind flowed and different
parts of the body “sympathized.” He believed that thesympathetic trunk (ganglionic chain) arose from thesixth cranial nerve, but the French anatomist Charles
Etienne (1504-1564) revealed that the sympathetic trunk
is separated from the sixth cranial nerve. In 1727, theFrench anatomist and ophthalmologist François Pourfour
du Peti (1664-1741) recognized that the sympathetic
nerves do not originate from the cranial nerves.
Thomas Willis (1621-1675), a British physician andanatomist, named the sympathetic trunk the “intercostal
nerve” and the vagus nerve the “wandering nerve.” He
was able to depict the vagus nerve with accuracy (Figure2). He thought that the cerebrum controlled voluntary
movements, while the cerebellum controlled involuntary
movements, coordinating both the intercostal nerve andwandering nerve. Later on, Jacques-Bénigne Winslow(1669-1760), a Danish anatomist, replaced the term
“intercostal nerve” with “great sympathetic nerve.” Healso named the vagus nerve “middle sympathetic nerve,”
and the facial nerve “small sympathetic nerve.” Winslow
speculated that the sympathetic ganglion originatedfrom the spinal cord rather than the cranial nerves,
and regarded it as a “little brain” that functions
independently.
Marie François Xavier Bichat (1771-1802), a
French anatomist and physiologist, proposed that the
body’s vital systems could be divided into two
categories: la vie organique (organic life) and la vie
animale (animal life). The former is similar to thecurrent concept of the autonomic nervous system. He
considered la vie organique, meaning the life ofplants, to be related to the “passions” and independentof education or habit. On the other hand, la vie animale
was thought to account for externally directed activityof the body, to be formed through habit and education,and governed by the intellect. This understanding
closely corresponds to the current concept of the somatic
nervous system. Like Winslow, Bichat considered thesympathetic trunk to be the little brain. Currently, his
idea that “the nervous system that controls internalorgans is an independent system” is widely accepted.
14

AsahinaFigure 2. The vagus nerve, cervical sympathetic ganglia, splanchnic nervesand cardiac plexus in a figure from “Cerebri Anatome” (1664) written
by Thomas Wills.
*This book with expired copyright is from Wellcome Collection,
London.

German anatomist and psychiatrist Johann Christian
Reil (1759–1813) proposed the term “vegetative nervous
system” (1807), which is still sometimes used as analias for the autonomic nervous system.
Histomorphology was established in the 19th
century, with Christian Gottfried Ehrenberg (17951876) considered likely as the first to observe nerve cells
in the sympathetic ganglion with the use of a microscope(1833); a more detailed observation of such cells was
accomplished in 1836 by German physiologist Gabriel
Valentin (1810-1883). Figure 3 shows a histologicalsketch of human sympathetic ganglion cells drawn by
Fernando de Castro (1896–1967). Polish-German
neurologist Robert Remak (1815-1865) discovered thepresence of unmyelinated fibers of sympathetic nerves
extending from the cell bodies of the sympathetic
ganglia to the organs (1838). Regarding the entericnerve, Georg Meisner (1829-1905) discovered thesubmucosal plexus of the gastrointestinal tract (1857),
and Leopold Auerbach (1828-1897) discovered theintermuscular plexus (1864).

The concept and history of the autonomic nervous system

Figure 3. Histological sketch of human sympathetic ganglion cells by
Fernando de Castro (1916) from Fernando de Castro Archives (http://
www.neurodrawings.org/drawings-ii).

In physiological research, Claude Bernard (18131878), a French physiologist, found that excision of thesympathetic nerve resulted in blood vessels dilating(1851), and Brown-Séquard (1817-1894) found that
sympathetic nerve stimulation induced constriction ofblood vessels (1852). During this period, it became clearthat the vagus nerve was involved in gastrointestinal
function. German brothers Ernrst Heinrich Weber(1795-1878) and Eduard Weber (1806-1871) found that
stimulating the vagus nerve caused cardiac arrest (1845).
Claude Bernard noticed an association between heart
activity stimulated via the vagus and the brain, i.e., thebrain-heart axis.
The development of pharmacology in the late
19th century led to the discovery of hormones andneurotransmitters. English physician George Oliver(1841-1915) identified that the adrenal gland contained
a certain substance with a strong pharmacological effect(1893). This discovery prompted further research
focusing on the extraction and isolation of that specificcomponent. American pharmacologist John Jacob Abel
(1857-1938) was able to extract the active substance(1897) and named it “epinephrine.” However, theprocess of purifying the substance remained incomplete
and it was extracted as a form of benzoyl compounds.
In 1900, using an extraction from the adrenal glands ofcattle, Japanese chemists Jokichi Takamine and Keizo

Uenaka successfully isolated the active substance asa form of a pure crystal and named it “adrenaline”(Takamine’s father was a court physician of Kaga-han
feudal domain). In Europe, the active substancebecame known as “adrenaline” in recognition of
Takamine’s work, while in the United States, it wascalled “epinephrine” following the evaluation andacceptance of Abel’s work. At present, adrenaline iswell known as a hormone that is closely correlatedwith the autonomic nervous system.
One of the most important neurotransmitters for theautonomic nervous system is acetylcholine, which isreleased from sympathetic and parasympathetic
preganglionic nerves and sympathetic postganglionicnerves. Acetylcholine was first synthesized by Adolf
von Baeyer, a German chemist, in 1867. Despite being
synthesized, the pharmacological characteristics ofacetylcholine would not be understood until muchlater. In 1911, Reid Hunt (1870-1948), an American
pharmacologist, discovered that choline derivatives,
especially acetylcholine, have a blood pressure-lowering
effect. However, at the time of this discovery, Huntwas unaware that acetylcholine was a biologicalsubstance. Henry Hallett Dale (1875-1968), an English
pharmacologist and physiologist, succeeded in isolating
acetylcholine (1914), and noticed a similarity between
the pharmacological effects of acetylcholine andparasympathetic nerve function. He then categorized thepharmacological effects of acetylcholine into muscarinicand nicotinic actions (1914). Otto Loewi (1873-1961),
a German-born American physician and pharmacologist,
asserted that “Vagusstoff” released by stimulating thevagal nerve was acetylcholine (1926), and his claim waslater proved to be correct. Dale classified autonomic
nerves as being adrenergic and cholinergic, based on
pharmacological studies (1933).
In addition to acetylcholine, an importantneurotransmitter for the autonomic nervous system isnoradrenaline, which is released from sympathetic
postganglionic nerves. Thomas Elliott (1877-1961)
clarified that the form of adrenaline extracted by
Takamine and Kaminaka has a sympathomimetic effect(1901), and identified that adrenaline can act as what
is now known as a neurotransmitter (1904). In 1921,
Loewi produced evidence that stimulating sympathetic
nerves induces the secretion of adrenaline-like
substances. Walter Cannon (1871-1945), an American
physiologist, revealed that the substance secreted fromthe sympathetic nerve terminals is not adrenaline,
but rather a different substance which he named“sympathin” (1931). Finally, Ulf von Euler (19051983), a Swedish physiologist and pharmacologist,
identified that “sympathin” is noradrenaline in 1941.
This achievement earned Euler the Nobel Prize inPhysiology or Medicine in 1970.
15		

Figure 4. John Newport Langley．
He created the current concept of autonomic nervous system.
*This image with expired copyright is from Wellcome Collection,
London (Wellcome Library no. 13036 ).

Walter Holbrook Gaskell (1847-1914), a British
physiologist, and John Newport Langley (1852-1925)(Figure 4), a British physiologist, played major rolesin the development of modern autonomic neurology.
Gaskell speculated that he had identified autonomic
outflows into the thoracolumbar (sympathetic nervous
system) and the craniosacral (parasympathetic nervous
system) systems, and that the two antagonized eachother. He named the autonomic nervous system “theinvoluntary system,” whereas Langley called it the“autonomic nervous system,” the name by which it is
known today.
One of Langley’s notable achievements was
proposing the term “autonomic nervous system” andcategorizing it into three systems: the sympathetic,
parasympathetic, and enteric nervous systems. He
assiduously investigated the autonomic nervous
system using several pharmacological techniques, andrevealed that nicotine has the property of blocking
neurotransmission in autonomic ganglia. By blocking
ganglionic neurotransmission with nicotine, it became
possible to functionally distinguish the nerves ending
in the autonomic ganglion, known as presynaptic orpreganglionic nerves, from those located in theautonomic ganglion that directly innervate effector
organs, known as postsynaptic or postganglionic nerves.
16

AsahinaLangley proposed dividing the autonomic nerve into
preganglionic and postganglionic nerves. He also
speculated the presence of a “receptive substance”
between the sympathetic nerve endings and effectors(1905). In this sense, he is considered to have predicted
the existence of neurotransmitters and receptors.
Results from his body of research were summarized in
the book “The Autonomic Nervous System” (1921).
Regarding the role of the brain in the functioningof the autonomic nervous system, C. Dittmar showedthat a control center for blood pressure can be foundaround the caudal pons or the rostral medulla
oblongata (1873). Based on the results of electricalstimulation experiments, S. W. Ranson (1880-1942)
later proved that the vasomotor center is located in the
medulla oblongata (1916). J. P. Karplus (1866-1936)
and A. Kreidl (1864-1928) proposed that the
hypothalamus may mediate sympathetic nerves(1909), and later revealed that the hypothalamus is
involved in the regulation of blood pressure (1926). Int h e 1 9 2 0 s , Wa l t e r R u d o l f H e s s ( 1 8 8 1 - 1 9 7 3 )determined that the hypothalamus is a control centerof the autonomic nervous system (1936), and he wasawarded the Nobel Prize in Physiology or Medicine in1949 for this achievement.
Regarding Japanese researchers, in addition to
Takamine (mentioned above), Yasu Kuno (1882-1977),
a physiologist, made outstanding achievements in thefield of the autonomic nervous system. He conducted
multifaceted and extensive research on sweat, including
the embryology and morphology of sweat glands, aswell as the physiology of perspiration. He developed adevice that can quantify perspiration, and conducted astudy establishing the physiology of perspiration ofhumans. Results of his research were later compiled
into the book “Physiology of Human Perspiration” in1934 (8). He also clarified the difference between
thermal perspiration and mental perspiration. Ken Kure
(1883-1940) introduced Langley’s concept of theautonomic nervous system to Japan in 1934.
2. The Current Concept of the Autonomic Nervous
SystemIn a restrictive or classic sense of the term, theautonomic nervous system, also called the vegetative
nervous system, indicates the peripheral efferent nerves
that regulate internal organs such as the heart, lung,gastrointestinal tract, blood vessels, and glands.
However, in a broader sense, it also encompasses
several areas of the central nervous system and thevisceral sensory nervous system. Based on Langley’sclassification (Figure 5), the autonomic nervous system
is classified into three categories: the sympathetic,
parasympathetic, and enteric nervous systems. However,under the current concept of the autonomic nervous

The concept and history of the autonomic nervous systemsystem, the enteric nervous system is often includedin the parasympathetic nervous system (9). Organs are
generally controlled by both the sympathetic andparasympathetic nervous systems, which work
antagonistically in some organs, such as in the heart,which functions under dual control. However, sweat
glands, arrector pili muscles, adrenal medulla, and bloodvessels of the skin are considered to be mediated onlyby the sympathetic nerves, while gastrointestinal motility
is mediated only by the parasympathetic nerves. Bothsympathetic and parasympathetic nerves promotesecretion in the salivary glands. Sympathetic andparasympathetic activities are not always antagonistic,
and their roles are dependent on each organ.

Figure 5. Sympathetic and parasympathetic innervation of organs (upper) and conceptual diagram of the autonomic nervous system (lower).
*Original chart

17

		

Several interconnected areas of the brain are
involved in the control of the body’s visceral function(10), and this network is called the central autonomic
network (CAN). CAN consists of the anterior cingulate
cortex, insular cortex, amygdala, hypothalamus,
periaqueductal gray, brainstem reticular formation,etc. Sympathetic outflow from CAN descends throughthe spinal cord and reaches the thoracic intermediolateralcolumn, where preganglionic sympathetic neurons arelocated. The axon of preganglionic sympathetic neurons
reach postganglionic sympathetic neurons in thesympathetic ganglions, which directly innervate endorgans. Parasympathetic preganglionic neurons arelocated in the brainstem and sacral spinal cord, andparasympathetic postganglionic neurons are found inparasympathetic ganglions near end-organs.
The role of the autonomic nervous system is tocontrol internal organs, such as the heart, lungs,
alimentary tract, blood vessels, and glands. It works inclose cooperation with the endocrine system to maintainthe “internal environment (milieu intérieur),” and thismechanism is called homeostasis. Electrolytes, glucose,body temperature, oxygen, and pH in tissue fluid are
kept at certain levels inside the body. Furthermore, theautonomic nervous system responds to rapid external
and internal changes. Reflexive mediation by thereticular formation of the brainstem is important for
short-term biological activities such as the regulationof blood pressure during standing load or posturalchange, and the respiratory response to CO2 retention.
The autonomic nervous system and endocrine
system are also involved in regulating biologicalfluctuations when changes occur within a certain range
in the internal environment. For relatively long-term
biological changes, such as those associated withcircadian rhythm and the changing of seasons, thehypothalamus is considered to play an important role.
Short-period fluctuations such as respiratory fluctuationsin heartbeat involve the brainstem reticular formation.
Furthermore, the autonomic nervous system works toassist physical functions. For example, perspiration of
the palm acts as a way to prevent slipping when grasping
objects, and secretion from Bartholin’s glands aids inlubrication during sexual intercourse.
It is often thought that sole function of the autonomic
nervous system is maintaining homeostasis. However,as mentioned above, it also works in cooperation withthe endocrine system to help regulate physiologicalfluctuations in the internal environment, such as those
associated with diurnal rhythm. In addition, autonomicand endocrine activities can intentionally and predictablychange the internal environment. For example, cardiac
sympathetic outflow increases when intending to standup in preparation for postural change. Another example
is perspiration of the palm induced by deep breathing.
18

Asahina

In this case, sympathetic sudomotor activities are elicitedby intending to take a deep breath before actually
doing so. This mechanism is referred to as “central
command” (11).
Emotional and psychological stress strongly affectautonomic and endocrine activities, and this results in
an impact to the internal environment. Sterling and Eyer
proposed a concept of “allostasis,” which emphasizeschanges in the internal environment caused by mental
stress in 1988 (12, 13). Humans and animals recognize
external events and environmental changes with theirfive senses. When a stimulus is perceived as being
potentially dangerous, there is an increase in heartbeat,
respiratory rate, blood flow to the muscles, andperspiration of the palms and soles in preparation forescape. Such autonomic and endocrine reactions, inwhich the limbic system is involved, are related toemotional behavior, and are determined based on theindividual’s experience and learning as well as their
instincts. Furthermore, when a dangerous stimulus
reoccurs after initial or subsequent exposure, autonomic
activity is markedly less responsive to that same
stimulus. This phenomenon is called “habituation,” andit results from cognitive processes mainly in the limbic
system. These mechanisms cause poor reproducibility
in autonomic function tests. From a different point ofview, the instability of autonomic activities reflects
activities of the limbic system, and is useful for theevaluation of emotion.
3. Jiritsu-shinkei shiccho-sho (Vegetative Disorder)
The term jiritsu-shinkei shiccho-sho was proposed by
Tatsuo Abe in the early 1960s (1). He translated it as“vegetative disorder” in English, but in light of current
research this translation may be considered inadequate.
“Autonomic imbalance disorder” may be a more
appropriate English term for Abe’s concept of thedisease. His ideas concerning the disease were basedon his clinical experience with patients with beriberi
and those with differential diagnoses. He noticed that
there were certain patients who complained of beriberilike symptoms without having beriberi or any of theassociated disorders. He initially used the term kakkeyou shoukougun (beriberi-like syndrome) for thesepatients, and later renamed it futei-syuso shoukougun(unidentified clinical syndrome). This syndrome wasclassified into three categories based on results from tests
on autonomic function and psychogenic background.
Hontai-sei (essential) jiritsu-shinkei shiccho-sho, oneof the three categories of unidentified clinical syndrome,is defined as having an autonomic imbalance but no
psychogenic background; in patients who do not havean autonomic imbalance but do have psychogenic
background, the syndrome is classified as a neurosis;
in patients with both an autonomic imbalance andThe concept and history of the autonomic nervous system

Figure 6. Jiritsu-shinkei shiccho-sho as a subtype of unidentified clinical syndrome.
This figure is modified from the one in cited reference (1).

psychogenic background, it is classified as a
psychosomatic disease (Figure 6). For the classification
hontai-sei jiritsu-shinkei shiccho-sho, the prefix hontaisei was eventually dropped as jiritsu-shinkei shicchosho became more prevalent as the preferred term.
Abe used a methacholine infusion test to evaluate
autonomic imbalance, and he classified the findings as
sympathetic-dominant, parasympathetic-dominant, andnormal based on the specific pattern of changes in bloodpressure. He judged the former two types to reflect anautonomic imbalance. However, both the sympatheticdominant type and the parasympathetic-dominant typecan be seen in healthy subjects and cannot be consideredpathological. At present, jiritsu-shinkei shiccho-sho is
not thought to be caused by autonomic dysfunction, but
is regarded as form of somatic symptoms related to thefunctioning of the autonomic nervous system in mental
disorders. This disorder may have to be classified as
medically unexplained symptoms, functional somatic
syndrome, or somatic symptom disorder.
Although Abe’s idea that jiritsu-shinkei shiccho-sho
is caused by autonomic dysfunction is not true, it should
be appreciated that he noted the close relationshipbetween emotion and autonomic response (emotional
behavior). This relationship, such as seen between
sweating on the palm and emotion (14), is well knownat present. However, it is still debated whether theautonomic activity is triggered by emotion or whether
emotions are recognized by feedback due to changes
in autonomic activity. In my personal opinion, theexpression of emotions and autonomic response could
proceed at the same time.

Conclusion
Even physicians and researchers tend to understand thepathophysiology of autonomic diseases based on theclassical concept of the autonomic nervous system,

because of the greatness of Langley and Gaskell.
However, in the last 100 years, knowledge about theautonomic nervous system has been accumulated. I hope
this paper will help to understand autonomic disorders
from a new perspective.
Conflict of Interest
The author report no disclosures relevant to themanuscript.
References

1. Abe T: Psychosomatic view-point for the unidentified clinical syndrome.
Jpn J Psychosom Med 1979; 19: 5-13.
2. Ackerknecht EH: The histor y of the discover y of the vegatative(autonomic) nervous system. Med Hist 1974; 18: 1-8.
3. Fletcher WM: John Newport Langley. In Memoriam. J Physiol 1926; 61: i4-15.
4. French R: The origins of the sympathetic nervous system from Vesalius to
Riolan. Med Hist 1971; 15: 45-54.
5. Tansey EM: Historical perspectives on the autonomic nervous system: with aparticular emphasis on chemical neurotransmission. In Mathias CJ, Bannister
R (Eds), Autonomic failure: a textbook of clinical disorders of the autonomic
nervous system (4th ed), Oxford, Oxford University Press, 1999; xxiii-xxix.
6. Takahashi A: The autonomic nervous system. An overview and historicalperspectives. Neurological Medicine 2008; 68: 219-34. (in Japanese)
7. Webber RH: Some aspects of the historical development of the autonomic
nervous system. J Neural Transm 1978; 42: 3-8.
8. Kuno Y: The Physiology of Human Perspiration, London, J & A Churchill,
1934.
9. Jänig W: Autonomic ner vous system. In Schmidt RF, Thews G (Eds),
Human Physiology (2nd ed), Heidelberg, Springer Berlin, 1989; 333-70.
10. Cersosimo MG, Benarroch EE: Central control of autonomic function andinvolvement in neurodegenerative disorders. Handb Clin Neurol 2013;
117: 45-57.
11. Lim CL, Seto-Poon M, Clouston PD et al: Sudomotor nerve conduction
velocity and central processing time of the skin conductance response.
Clin Neurophysiol 2003; 114: 2172-80.
12. Sterling P, Eyer J: Allostasis: a new paradigm to explain arousal pathology.
In Fisher S, Reason J (Eds), Handbook of Life Stress, Cognition and
Health, New York, John Wiley & Sons, 1988; 629-49.
13. McEwen BS: Physiology and neurobiology of stress and adaptation:
central role of the brain. Physiol Rev 2007; 87: 873-904.
14. Asahina M, Poudel A, Hirano S: Sweating on the palm and sole:physiological and clinical relevance. Clin Auton Res 2015; 25: 153-9.

19

金医大誌（J Kanazawa Med Univ）46：20 − 23, 2022
研究発表
1. 臨床応用を目指した脂肪由来幹細胞シートの品質評価の金沢医科大学総合医学研究所

2021 年度 研究セミナー 抄録
日時：2022 年3 月25 日 ( 金)
会場：金沢医科大学

試み
生命科学研究領域 細胞機能研究分野

13：00 〜 18：15

医学教育棟5 階中村有香

当研究室では，脂肪由来幹細胞 (ADSC) を用いた研究に取り組む中で，より実臨床で利用が期待されるスフェロイド形成に

E51 講義室よる大量培養ならびに細胞シートについて検討してきた。
スフェロイドとは，細胞同士が凝集して球形の塊になった状態
で，2 次元単層培養と比べて細胞間の結合が高く，より生体内に退職記念講演近い状態での機能発現を維持できることが知られている。培養

肺サーファクタント研究の軌跡

方法としては，①非接着型培養プレートで振とう培養する方法，―臨床と研究の二刀流をめざして―
総合医学研究所 生命科学研究領域 遺伝子機能研究分野

教授

長内和弘
1982 年に山形大学医学部を卒業し，思うところあり呼吸器内科を専攻した。当時教室は臨床より研究を重視する空気に満ちていた。肺胞疾患，とくに間質性肺炎・肺線維症，肺胞Ⅱ型上皮細胞 ( Ⅱ型細胞) について焦点をあてて研究を開始した。この頃は呼吸器学の領域でも分子生物学が興隆してきた時期で，肺サーファクタント (LS) 研究で評判の高い米国デンバーのコロ
ラド大学医学校・NJC 研究所に3 年間留学する機会を得ることができた。脂質生化学者Voelker 教授の下でクローニングしていた新規Rab低分子量タンパク質 (Rab38) の研究に打ち込んだ。
帰国後1年間を経て本学に赴任した。臨床業務に忙殺されながらも，Rab38 が末梢気道上皮細胞およびⅡ型肺胞上皮細胞に特異的に発現していることを発見した。この頃はその日のうちに帰宅することはほとんどなく，ゲリラ実験と称して研究に打ち込んでいた。ほどなくして眼皮膚型白皮症の形質を有するChocolate
マウスの原因遺伝子がRab38 であるとのペーパーが出た。アメ
リカより同マウスを輸入し，Ⅱ型細胞内の層状封入体の巨大化，肺組織でのリン脂質やサーファクタントプロテイン-B の著増，気腫性変化などを観察した。この頃は実験するたびに新しい発見があり，毎日わくわくしながら研究をしていた。さらに眼皮膚型白皮症，出血異常，間質性肺炎を呈するヘルマンスキー・パドラック症候群のモデルラット (Ruby) の原因遺伝子がRab38 であるとのペーパーも出てきた。アデノベクターを用いてRab38
を細胞，個体レベルで遺伝子導入することによりII 型細胞からのリン脂質の分泌や巨大化した層状封入体が野生型に近づくことなどを観察した。
こうして偶然釣り上げられた1 個のRab38 遺伝子がLS に関与し，その破綻は肺病変につながるという一連の事実を解明した
研究ができた事をうれしく思っている。本講演では臨床と研究の両立をめざすためのメッセージを添えたいと思う。

②表面張力を活かして細胞同士を接着する方法，③培養チャン
バーを回転させながら培養する方法が代表的な方法である。この中で，③の回転式培養方法によるスフェロイド形成について取り組んだ。
さらに，細胞シートでは，シートの品質評価について検討した。細胞シートとは培養容器内でコンフルエントに培養した細胞をシート状に剥離・回収した状態の細胞である。また，温度応
答性培養容器を用いることで剥離の際に酵素処理の必要がなく，容器表面に塗工された温感ポリマーの温度変化による特性を利用して細胞を回収することが可能となるため，細胞へのダメー
ジが低減されることが知られている。そこで，当研究室では得られた細胞シートの品質をDNA マイクロアレイを用いて遺伝子レベルで検討した。さらにトリパンブルー染色による死細胞の確認や形態評価としてHE 染色および走査型電子顕微鏡 (SEM)
下での観察を行なった。SEM 観察において，細胞シートの表面だけでなく，接着面である細胞の裏面を観察することができた。
2. 動物個体レベルで生じる細胞ストレスとその応答機構の実態解明 (2021)
生命科学研究領域 細胞医学研究分野

赤井良子

本研究セミナーでは小胞体ストレス応答分子により制御される過食行動の分子メカニズムへ迫ろうとする研究を中心に紹介する。
哺乳動物の摂食行動は視床下部を中心とした神経ネットワー
クによって制御されている。視床下部は摂食制御ホルモン ( レ
プチンやグレリンなど) および栄養素を感知し，全身のエネル
ギーバランスを一定に保つ役割を果たしている。また中脳はドーパミン神経により脂分や糖分といった食事の嗜好性を制御している。さらに大脳皮質は食の探索行動と連携することが分かっている。しかし一方で拒食や過食は心的ストレスや鬱病と関連すると考えられているが，そのような摂食行動異常の神経機構や分子機構は未だ不明な部分が多い。
これまで私たちは哺乳動物の小胞体ストレスについて研究を行ってきた。そのためにマウス個体レベルで小胞体ストレスを解析する実験の機会は少なくない。ツニカマイシンとよばれる薬剤は，培養細胞や酵母菌ではもちろん，マウスに小胞体スト20

レスを加える際にも頻繁に使われる。また意外なことにツニカの一経路である。N-degron を特異的に認識・結合するユビキチ

マイシンはマウスに過食行動も引き起こす。このことから私たンリガーゼ群をN-recognin と呼んでいる。UBR box N-recognin

ちは小胞体ストレス応答分子が摂食行動の制御に関与するかも4 (UBR4) は，N-recognin の一つで分子量574,000 の巨大タンパしれないと考えた。

ク質で，多細胞生物において進化的に保存されているが，そのそこで摂食中枢特異的に小胞体ストレス応答分子であるIRE1，

生理学的機能と分子機構は不明な点が多い。

ATF6，およびPERK を欠損させたマウスを用いて過食誘導実験を

UBR4 遺伝子ノックアウトマウスではYolk Sac における血管行い，摂食量と飲水量を測定した。興味深いことにPERK を欠損

新生異常を伴い胎生致死を示す。そこでUBR4flox マウスと，肝させたマウスでは摂食量の増え方が他に比べて小さかった。ま臓，腎臓，腸上皮特異的Cre マウスにより，コンディショナル

た視床下部の摂食中枢に由来する細胞株を用いた実験からは

UBR4KO マウスを作製した。その中で腸上皮特異的な表現型を

GADD34 が摂食制御ホルモンのシグナル経路と影響するデータ見出したので紹介する。

も得られた。これらの結果はPERK 経路が少なくとも部分的に摂タモキシフェン誘導による腸上皮特異的UBR4 欠損マウス

食中枢で過食行動を制御する機能を持つ可能性を示唆している。

(UBR4 (−) 群) と野生型 (UBR4 (＋) 群) との違いは見いだされなかった。一方，アゾキシメタン (AOM)/ デキストラン硫酸ナト

3. DNA 損傷誘導性の細胞死における核内セラミドの役割

リウム (DSS) 投与により，大腸炎関連大腸がんモデルを作製し生命科学研究領域 ゲノム損傷応答研究分野

たところ，UBR4 (−) 群では大腸炎の程度が悪化する傾向がみら谷口真

スフィンゴ脂質の1 つであるセラミドは，細胞脂質二重層の構成脂質であるだけでなく，皮膚角層でのセラミドのラメラ構造れた。大腸炎が発がん促進に関わっていることから，UBR4 が大
腸炎関連大腸がんを制御している可能性が示唆された。

は皮膚バリア機能を担っている。他方，細胞におけるセラミド

AOM/DSS 投与後，長期飼育することによって大腸がんを発生

は生理活性脂質としての機能も有しており，細胞死，炎症，細胞させたところ，AOM 投与後35 週間では，UBR4 (−) 群で67％の分化，オートファジーなどを誘導する (Taniguchi and Okazaki, J

マウスで大腸がんがみられたが，UBR4 ( ＋) 群での大腸がん発生

Lipid Atheroscler, 9 (2020); 380-405)。その中でもセラミドが誘導

率は33％であった。AOM 投与後52 週間では，UBR4 (−) 群ではする細胞死は，抗がん剤によるがん細胞死誘導にも関連してお100％，UBR4 (＋) 群では33％の大腸がん発生率を示した。以上

り，セラミドアナログなどが抗がん剤として作用するとして臨の結果から，UBR4 は大腸炎と大腸がん発生において抑制的な役床試験などにも進んでいる ( 谷口 真，岡崎俊朗，セラミド研究の割を持っていることが示唆された。

新展開，(2019); 286-302; Taniguchi and Okazaki, Cell Signal, 87(2021); 110119)。セラミドの合成経路は，小胞体においてアミノ酸であるL- セリンと脂肪酸の1 つから産生されるパルミトイルCoA からde novo 合成される経路，セラミドから産生されるガン
グリオシドなどのスフィンゴ糖脂質から再合成されるサルベー

5.「生体暗証番号」解読のための共培養研究とエクソソーム
研究先端医療研究領域 アンチエイジング研究分野

島崎猛夫

我々の最近のテーマは，①抗癌剤と癌幹細胞の関係性②エジ経路，また，セラミドとホスファチジルコリンから合成される

クソソームを介した抗がん剤によるEMT ( 上皮間葉移行) 誘導

スフィンゴミエリン (SM) が加水分解を受けるSM/ セラミドサ機構の解明 の2 つを主なテーマとして解析を行ってきた。いずイクルの3 つの経路が知られており，各々のセラミド産生経路がれのテーマにおいても共培養手法と細胞外小胞を重要な解析手

細胞死誘導に関連することが報告されている。しかしながら，

法及びターゲットの一つとして研究を進めている。

抗がん剤の中には核内のDNA に直接ダメージを与え，細胞死を①癌幹細胞は，その概念において癌の発生段階から幹細胞が誘導する薬剤も存在しているが，核内でのセラミド産生に関わ存在する先天性説 (Major) と後天性に誘導されて幹細胞が出現る分子は不明である。

する説 (Minor) がある。我々の研究では，後天性癌幹細胞誘導

本発表では，DNA 二本鎖切断を誘導する抗がん剤として知ら説を強く示唆する結果が得られ，研究を進めたところ，抗がんれるネオカルジノスタチン(Neocarzinostatin, NCS) が起こす剤耐性・癌幹細胞・細胞初期化に共通するメカニズムを見出し，

DNA 障害誘導性のアポトーシスにおいて，ataxua telangiectasia

その応用技術に関して特許出願を行っている。このメカニズム

mutated (ATM) 経路が重要であるが，このATM の活性化に核内は，刺激するシグナルの組み合わせや濃度・順番が重要であるのSM/ セラミドサイクルを介したセラミド産生が関連していることから，本セミナーではこれらの現象が生物学的暗証番号とことを見出したので報告する。

もいえる仕組みであることを報告する。

4. ユビキチンリガーゼUBR4 の大腸がんにおける役割

胞のコミュニケーションに大きな役割を果たしていることが明

生命科学研究領域 蛋白質制御研究分野

らかになり，細胞間情報伝達において新しく登場したスターの②生物学においてエクソソームを含めた細胞外小胞が各種細田崎隆史

Arg/N-degron pathway は，N 末端アミノ酸残基をタンパク質ような扱いを受けている。我々は，水平方向の共培養容器を開分解シグナル (N-degron) とするユビキチンタンパク質分解系

発し，抗癌剤によるEMT 誘導には，抗癌剤の暴露を受けた細胞
21

		
だけでなく，暴露されていない細胞にも同様の変化をもたらす

塩基配列が解析可能となり，ヒトの全ゲノム ( 約30 億塩基対)

ことや，その機序としてエクソソームを含めた細胞外小胞が関ですらわずか一日でその塩基配列を決定することが可能となっ与していることを明らかにしてきた。共培養と細胞外小胞に着ている。

目した研究手法の紹介と我々の研究成果について報告する。

近年，臨床遺伝子診断の場においても，NGS は一般的に用いられるようになり，がん遺伝子パネル検査を筆頭に多数の検体，
多数の標的遺伝子を同時に解析することが当たり前になってきた。その結果，検出されるバリアントの数は飛躍的に増加したが，一方で病的意義不明なバリアントの検出も増えた。特に深部イントロンのバリアントは，病的意義が分からないものがほとんどであり，結局殆どの検査機関では，エクソン部分に絞った解析しかしていないのが現状である。その他，大きな構造異常や6. 心筋細胞に毒性終末糖化産物が生成・蓄積して引き起こされる細胞障害の機序は何か？

低頻度モザイク変異についても，現在のNGS には解析技術上の先端医療研究領域 糖化制御研究分野問題があり，その改良や新規技術の開発が必要とされている。
髙田尊信

そこで，我々は現在の遺伝子診断法では見逃されることの多い，

現代の食生活においては，ブドウ糖や果糖を過剰に摂取する①低頻度モザイク変異，②スプライシング異常を伴う深部イン傾向にあり，それらの代謝中間体であるglyceraldehyde (GA) がトロン変異，③大きな構造異常を検出するため，Long Amplicon

細胞内で過剰に生成される。これまで当研究室では，GA に由来

Sequencing (LAS) と名付けた新規遺伝子解析法を確立した。本する終末糖化産物 (advanced glycation end-products, AGEs) で法では標的遺伝子の全genome DNA領域 (イントロンやプロモー

あるGlycer-AGEs が，他の経路から生成するAGEs と異なり強い

ター領域などを含む)，ならびに全長mRNA (cDNA) をLong-range

細胞障害性を示すことから「毒性終末糖化産物 (toxic AGEs,

PCR で増幅し，NGS により解析することで，①〜③を含めたほTAGE)」と命名し研究を遂行している。これまでの研究により，ぼ全ての遺伝子変異を安価で簡便に検出することが可能である。

TAGE が動脈硬化を介して心血管疾患を促進すること，および本発表では，LAS を用いることで初めて検出可能となった遺血中TAGE レベルが心血管疾患の予防/ 早期診断/ 治療評価の有

伝子変異の実例をいくつか挙げ，本解析法の特徴とその成果を益なマーカーとなりうることを明らかにしてきた。一方で，報告する。

TAGE が直接的に心臓に与える影響は明らかではない。
そこで本研究 ( 科研費基盤研究C, 21K11607) では，ラット初代
培養心筋細胞におけるTAGE 生成と細胞障害との関連を解析し8. 血小板溶解物を用いた単球由来抗原提示細胞の分化系譜
先端医療研究領域 ヒト幹細胞制御研究分野

下平滋隆

た。心筋細胞にGA を添加すると，TAGE の生成・蓄積に伴う拍動

HPL ( 血小板溶解物) を用いたIFN (Interferon)- 樹状細胞 (HPL-

数の減少および細胞死，ならびにオートファジー関連蛋白質のIFN-DC) の調製法を開発した [PCT/JP2021/040505; Vaccines

機能低下が引き起こされた。現在，拍動数の減少に関わるTAGE(Basel). 9(1), 10, 2021]。既存のIFN-DC と比較すると特徴的な表

化蛋白質を同定するため，プロテオミクス解析に取り組んでい現型を示し，抗原の飲食・貪食能やCD8+T 細胞への抗原提示能力

る。また，生理的濃度の高ブドウ糖および高果糖条件下においおよび抗原特異的細胞傷害性T 細胞の誘導能が高く，がん免疫療てもTAGE の生成・蓄積と拍動数の減少が起こることを明らかに法や感染症制御への臨床応用が期待される。

した。さらに，ヒト正常心臓線維芽細胞へのGA 添加実験におい

現在，ネオアンチゲンあるいはWT1 を標的としたがんワクチても，TAGE 蓄積に伴う細胞死が引き起こされた。本研究より，ンの再生医療等の臨床研究 (jRCTc040200005, jRCTc040210109)

心筋および心臓線維芽細胞内でのTAGE 蓄積が，①心筋細胞の拍及び再生医療センターでの受託製造事業において抗原提示細胞

動異常を引き起こし，②心臓線維芽細胞による心臓保護機構のとして提供している。

低下が相まって，心機能が低下する可能性が示唆される。

予備検証の結果では，HPL-IFN-DC はCD14+/CD68+ 細胞形質その他，竹内と逆井の研究課題も採択され，肝実質細胞，膵βが確認され，マクロファージ近縁の分化細胞の可能性が示唆さ

細胞，筋芽細胞および骨芽細胞などを対象にした研究も進めてれた。HPL による単球及びIFN-DC の遺伝子発現に与える影響いる。

と，HPL-IFN-DC の遺伝子発現がヒトのどの免疫細胞系譜に近「基盤研究A，21H04865 ( 竹内正義)」，「基盤研究C，21K11583 ( 逆似しているかを明らかにするために，次世代シークエンシング/

井 ( 坂井) 亜紀子)」

RNA-Seq により，細胞内に含まれるmRNA 分子を網羅的かつ定7. 次世代シーケンサーを用いた新規ゲノム変異解析法 (Long

量的に解析した。その解析結果から文献報告に基づきGene Set

Amplicon Sequencing (LAS) 法) の確立
先端医療研究領域 ゲノム疾患研究分野

硎Enrichment Analysis (GSEA) により評価した。
澄仁

次世代シーケンサー (NGS) の登場により，一度に膨大な数の
22

HPL-単球は，既報告のサブセット (Science 356(6335): eaah4573,
2017) のいずれにも属さず， Pro-inflammatory Monocyte の形質を示した。単球の接着起点は，炎症関連遺伝子や炎症反応の一対象者につき3 年に1 回の頻度での受診とし，2018-2020 年を第1つであるTNF-NFκB シグナル経路の活性化を誘導させ，HPL はクールとして被ばく線量20mSv 以上の3673 名で調査を開始し更にその反応を増強させた。一方，HPL 存在下ではIFN-DC の成た。全国76 の眼科クリニックの協力のもと，眼科医による散瞳

熟度を促進させないが，HPL-IFN-DC はIFN-DC と比較すると臓での検査を中心に進めた。対象者の多い県にある4 施設に対し器在住マクロファージに類似した遺伝子を発現していた。まては，白内障カメラを設置し徹照画像の撮影も行った。2018 年

た，M1/M2 に増加する遺伝子群を多く発現し，ヒト動脈硬化プ

開始時に送付した白内障検診の意向調査は2021 年3 月までにラーク層に豊富に検出されるマクロファージと類似性がある一1011 通の返信があり，うち受診希望者は701 名であった。第1

方で，CXCL4 で分化したM4 マクロファージの遺伝子発現に近似

クールの3 年間で497 名の検診が終了した。全497 名の白内障診していることが確認された。

断結果は，左右眼ともに微小混濁であるVacuoles (VC) も全くな

Pro-inflammatory monocyte は，CXCL4 などのHPL 由来の因子

い透明水晶体眼は26.4% であった。VC を含む水晶体混濁が認めによりM1/M2/M4 の潜在機能を有する未熟マクロファージが誘られたのは73.0% となったが，そのほとんどは矯正視力が1.0 以

導され，OK-432 による成熟化により，M4 マクロファージあるい

上の視力良好眼であった。後嚢下白内障の有所見率は7.7% では既存のマクロファージに当て嵌まらない (Pro-M4・M5) マクロあった。放射線白内障の初期変化とされる後嚢下中心のVC 有

ファージに収斂する可能性が示唆された。

病率は，30 代8.3 (2.3-20.0 (95%CI))%，40 代12.7 (6.3-19.2)%，50 代
14.1 (8.8-19.5)%，60 代22.8 (16.4-29.1)%，70 代35.3 (14.2-61.7)% と

9.「放射線業務従事者の健康影響に関する疫学研究」白内障調査報告

加齢に伴い増加が見られた。事故後7 年〜 9 年目の時点では，放射線被ばくにより視力低下をきたすような白内障を発症した症

プロジェクト研究センター 環境原性視覚病態研究部
初坂奈津子

例はいなかったが，低線量被ばくの水晶体への影響については
被ばく後20 年以上の追跡調査が必要とされている。微小混濁で本研究は東電福島第一原子力発電所の緊急作業従事者の放射あるVC は消失することもあるが，後嚢下中心にあるものは放射線被ばくによる健康への影響を長期に渡り検証することを目的

線白内障である後嚢下白内障に進行することもあり，今後どのとしている。当教室では全国規模で白内障調査を行い，放射線ような過程で進行するか引き続き調査の継続が必要である。

被ばくと水晶体混濁との関係について検討している。検診は各23