동의생리병리학회지제 21 권 6 호 Korean J. Oriental Physiology & Pathology 21(6):1543 1548, 2007 전기침자극의기억조절효과 이상관 * 김민수 1 안련섭 2 김문수 3 성강경 원광대학교한의과대학한의학과, 1 : 전남대학교자연과학대학수학통계학부, 2 : 포천중문의과대학교대체의학대학원, 3: 전남대학교사회과학대학심리학과 Effects of Electroacupuncture on Memory Modulation Sang Kwan Lee*, Min Soo Kim 1, Ryun Sup Ahn 2, Moon Soo Kim 3, Kang Keyng Sung Department of Oriental Medicine, Wonkwang University, 1:Department of Statistics, Chonnam National University, 2:CHA Medical University, Graduate School of Complimentary and Alternative Medicine, 3:Department of Psychology, Chonnam National University Recent experiments investigating the analgesic or anti-stress effects of electro-acupuncture provide extensive evidence that opioid or stress hormone system is involved in those effects, respectively. It has been also suggested that opioid or stress hormones modulate long-term memory consolidation or retrieval in animals and human subjects. This article reviews the possibilitythat electroacupuncture can modulate memory consolidation or retrieval. The release of serum cortisol is enhanced or reduced by high-frequency or low-frequency electroacupuncture, respectively. Also the release of beta endorphin and enkephalin is enhanced by low-frequency electroacupuncture and the release of dynorphin is enhanced by high-frequency electroacupunture. The memory consolidation is enhanced by post-training injection of Glucocorticoids, Naloxone or Dynorphin. So this review suggests strongly that memory consolidation can be modulated by electroacupuncture. Key words : Electroacupuncture, Memory modulation, Memory consolidation, Stress hormone, Opioid hormone 서론 기억은 acquisition, consolidation, retrieval 등의다양한과정으로구성되어있고 1-3), 이러한단계에따라 stress hormone과 opioid hormone은각각다른효과를보인다. 특히, stress hormone 중에서 adrenal catecholamine은기억을증진시킨다는많은연구결과들이있지만 glucocorticoids의기억증진효과에대해서는상반된주장이있었다 4-6). 이에 Roozendaal 7) 은기억의각단계에따라 glucocorticoids 의상반된효과를동물실험을통해입증하였다. 또한, opioid hormone의종류에따라기억을증진시키거나억제한다는많은연구들이있다. Beta endorphin, Enkephalin, Dynorphin의주입은기억의응고화와인출을증가시키거나감소시키는특이적인효과를보인다 8,9). 전기침자극 (Electroacupuncture: EA) 의진통효과 (analgesic * 교신저자 : 이상관, 광주광역시남구주월동 543-8 원광대학교광주한방병원 E-mail : sklee@wonkwang.ac.kr, Tel : 062-670-6407 접수 : 2007/10/26 채택 : 2007/11/27 effect) 와항 stress 효과등이많은연구들을통해밝혀져오고있다. 진통효과는전기침자극의 frequency에따라다른효과를보이는데, low frequency에의해 Met-enkephalin, Beta endorphin, Endomorphin의분비가증가되고 10,11), high frequency에의해 Dynorphin A의분비가증가된다 12). 전기침자극의항 stress 효과관련연구들에따르면, 특히, low frequency 전기침자극은 immobilization stress task에노출된쥐의혈압, 심박수, 혈중 Norepinephrine, 혈중 Epinephrine 13) 의증가를억제하고, high frequency 의 stress task에의해혈중 Norepinephrine, Epinephrine, Dopamine, Corticosterone, ACTH 14) 가증가된다. 이상의 stress hormone에미치는전기침자극의영향은opioid antagonist인 Naloxone의주입에의해억제된다. 이상과같이 stresshormone이나 opioids hormone등은기억조절에중요한역할을하고있으며, 전기침자극은 stress 시스템또는 opioid 시스템을통해진통효과와항 stress 효과를보이고있다. 그러므로전기침자극역시기억조절에중요한역할을할수있을것으로사료되며이와관련된고찰이필요할것으로사료된다. - 1543 -
이상관 김민수 안련섭 김문수 성강경 재료및방법 1. 동물실험방법및재료 Benno Roozendaal의연구 3,7) 에서제시된재료와수술절차에따라생쥐 (Sprague-Dawley, Male, 300±10 g weight) 의양측 hippocampus에 vehicle과 Glucocorticoids agonist(ru 28362, 3 ng & 10 ng, respectively) 를농도를달리하여주입하였는데, 주입방법과실험절차는전형적인 inhibitory avoidance(ia) task 15) 를변형시킨 Liang의 modified IA task 16) 와동일한절차에따랐다. Hippocampus에 RU 28362의 post-context infusion은 memory consolidation 을증가시키지만, post-footshock infusion은 memory consolidation에특별한영향을주지않았다 (Fig. 2). Glucocorticoids를 retention test 직전 (pre-testing) 에뇌의특정영역에주입하면, IA task나 water-maze spatial task에서 retention 이손상된다. memory consolidation에미치는영향과상반되게 glucocorticoids의 memory retrieval 손상효과는일시적이고 hormone 수준이정상수준으로복귀되면사라지게된다 7,22). Day 1 Day 2 Day 3 Day 4 2. 고찰방법침의진통관련연구중에서 opioid system과관련된논문, 침의항 stress 효과에관련된논문, opioid hormone이나 stress hormone의기억과관련된논문총 36종을고찰하여침의기억조절효과의가능성을제시하였다. Contextual tranining Footshock training nfusion of glucocorticoids nfusion of glucocorticoids Retention test 결 과 Fig. 1. Experimental Design of Modified Inhibitory Avoidance Training by Liang 16). 1. stress hormone의기억조절효과기억은 acquisition, consolidation, retrieval 등의다양한과정으로구성되어있는데 1-3), 이러한단계에따라 stress hormone 은각각다른효과를보일수있다. Epinephrine의주입은 inhibitory avoidance(ia) task 15), multitrial avoidance task 16), one trial appetitive task 17), aversively motivated discrimination task 18) 등에서기억의파지 (retention) 를증가시킨다. Glucocorticoids를 training 직후 (post-training) 주입하면, 정서적으로각성된경험에대한기억의 consolidation을증가시키는데, 특정 dose까지 dose-dependent한특징을가지고있다 19). contextual-cue fear conditioning paradigm 20), water-maze spatial task 21) 등에서도이와비슷한양상을보인다. 또한, retention test 직전에 Glucocorticoids를주입하거나 stress task를부여하면 water-maze spatial task에서수행능력이손상되고, 이러한효과는 Metyrapone(Corticosterone synthesis inhibitor) 의전처치 (pre-treatment) 로사라진다 22). 저자는 Glucocorticoids가뇌의특정부위에서정보종류에따라다른효과를보이는지파악하기위해, Liang 16) 이제안한 modified inhibitory avoidance(modified IA) training를사용하여 Hippocampus에 Glucocorticoids receptor agonist(ru 28362) 를주입하였다. Modified IA training에서는첫째날 contextual training을시행한직후에해당약물을뇌의특정영역에주입하거나, 둘째날 footshock training을시행한직후에해당약물을뇌의특정영역에주입하여, 처리될정보종류에따라특정영역이어떻게관여되는지파악할수있게구성되어있다 (Fig. 1). 약물주입 24시간후 modified IA box에서 retention test 중에 lit compartment에서 dark compartment (footshock compartment) 로들어가는잠재시간 (latency time) 의측정을통해 memory consolidation 정도를확인하였다. Retention test 결과, Fig. 2. Enhanced retention of rats that received infusions of RU 28362 into hippocampus immediately after contextual training (left) but not footshock training (right). **: Significant difference (p<0.01) between RU 28362 and Vehicle group(in Press, Benno Roozendaal, Areg Barsegyan, Sangkwan Lee, Adrenal stress hormones, Amygdala activation, and memory for emotionally arousing experiences, Progress in Brain Research, 167: 79-97,2007). 종합해보면, stress hormone이나 stress task의처치는기억의 consolidation은증가시키고, retrieval 은손상시키는상반된조절효과를보이며, 특정부위에따른정보의존적인특성이있다 (Fig. 3). Fig. 3. Schematic diagram showing the effects of glucocorticoids(or stress hormone) on different processes of memory. 2. opioid system 의기억조절효과와 stress hormone 과의관련성 다양한 opioid hormone 의처치는기억의각단계에서각각 - 1544 -
전기침자극의기억조절효과 특징적인효과를보이고있다. Beta endorphin의 training 직후 (post-training) 주입은기억의 consolidation을손상시키고, Naloxone(μ opioid receptor antagonist) 의 training 직후 (post-training) 주입은기억의 consolidation을증가시킨다 8). 이러한효과는 stress hormone과밀접한관계가있다. 기억의 consolidation을손상시키는 Beta endorphine의주입은 Basolateral Amygdala(BLA) 에서 training으로유발된 Norepinephrine 수준을감소시키고, 기억의 consolidation을증가시키는 Naloxone의말초주입은 BLA에서 training으로유발된 Norepinephrine 분비를증가시킨다. 또한, Naloxone 혹은 ICI 174 864(delta opiate receptor antagonist) 의검사전주입 (pre-testing administration) 은기억의 retrieval을증가시킨다 23,24). Enkephalin을 inhibitory avoidance task 혹은 Y-maze discrimination task의 training 직후 (post-training) 에주입하면기억의 consolidation이손상되는데, Naloxone의주입은이러한효과를약화시킨다. 이상의효과들은부신 (adrenal grand) 을제거하면사라지게된다 9). Dynorphin의주입은낮은 footshock(0.2 ma) task에서는기억의 consolidation과 retrieval을모두증가시키지만, 높은 footshock(0.4 ma) task에서는별다른영향을주지않는다 25,26). OFQ/N을혐오적으로동기화되는 inhibitory avoidance training 직후 (post-training) 주입하면, 기억의 consolidation이손상되고, OFQ/N receptor antagonist를주입하여이러한효과가억제된다. 또한, OFQ/N의기억에미치는효과는기억조절과밀접하게관련되어있는 BLA의 noradrenergic system의활성이요구된다 27). Morphine의기억에미치는효과에대해, Saha 등은 Morphine의검사전주입 (pre-testing administration) 은기억의 retrieval을손상시킨다고하였고, Shiigi 등은반대로증가시킨다고하였다 28,29). 3. 전기침자극의진통효과및항 stress 효과침자극은자율신경계와 hormone시스템 (hypothalamus pituitary adrenocorticalsystem: HPA system) 의활성을조절하는것으로제안되어왔고 30,31), 최근에는전기침자극 (Electroacupuncture: EA) 의진통효과 (analgesic effect) 와항 stress 효과등에많은연구들이시행되어오고있다. 침자극의진통효과의기전은 opioid system과관련되어다양하게연구되고있다. 요약하면, low frequency(2 Hz) 의전기침자극에의해 Met-enkephalin의분비가증가되고, high frequency(100 Hz) 의전기침자극에의해 Dynorphin A의분비가증가된다. Beta endorphin과 Endomorphin도 low frequency(2 Hz) 의전기침자극에의해용이하게분비된다 10,11). 또한, low frequency(4 Hz) 전기침자극의진통효과는 Naloxone에의해억제될수있다 32). Han 등은동물실험과임상시험을통해 low frequency와 high frequency의조합은 4종류의 opioid peptide를동시에분비시키므로진통목적의치료에최적이라고제안하였다 33) (Fig. 4). Frequency of EA Low (2Hz) Intermediate (15Hz) High (100Hz) Neuropeptides released in CNS EM / ENK / β-ep Opioid receptors μ δ κ DYN Fig. 4. Schematic diagram showing the opioid mechanisms of EA-induced analgesia (Modified from Han s model). EA; electroacupuncture, EM; Endomorphin, ENK; Enkephalin, β-ep beta endorphin, DYN; Dynorphin. 침자극의항 stress 효과에관련된연구는진통 (analgesic effect) 관련연구에비해상대적으로많지않았으나, 최근에는이와관련된연구등이국내외로증가되고있다. stress 관련동물연구들에따르면, 침자극은혈액이나뇌의특정영역에서 Norepinephrine이나 Adrenal hormone의분비를감소시키고 34,35), 다양한 stress task에노출된이후발생하는일련의 stress 관련행동도감소시킨다 36). 특히, 3 Hz의전기침자극은 immobilization stress task에노출된쥐의혈압, 심박수, 혈중 Norepinephrine, 혈중 Epinephrine의증가를감소시킨다 13). Han 등은 stress task로 100 Hz의 tooth-pulp stimulation(stress Task) 을사용하여혈중 Norepinephrine, Epinephrine, Dopamine, Corticosterone, ACTH가증가됨을확인하였고, 3 Hz의전기침자극을통해이러한증가를억제시킬수있다고하였다. 이러한전기침의효과는 opioid antagonist인 Naloxone의주입을통해감소된다고하였다. 고 찰 Catecholamine과 Glucocorticoids 등의부신 hormone이스트레스상황하에서분비되어, 인체가 stress에대처하는데중요한역할을하고있다. 이러한 hormone들은뇌의변연계 (limbic system) 를통해기억에도영향을주고있는데, Epinephrine혹은 Norepinephrine 등은기억의응고화 (memory consolidation) 를증가시킨다고하였지만, Glucocorticoids에대한역할에는상반된주장이많았다 4-6). 이는Glucocorticoids 역시기억에많은영향을주고있지만, 기억의각단계에따라상반된효과를보이기때문에여러상이한주장들이제기되어오고있다 7). 기억은 acquisition, consolidation, retrieval 등의다양한과정으로구성되어있고 1-3), 이러한기억의다양한단계에따라 stress hormone은각각다른효과를보일수있다. Glucocorticoids를 training 직후 (post-training) 주입하면, 정서적으로각성된경험에대한기억의 consolidation을증가시키지만 19), Glucocorticoids를 retention test 직전 (pre-test) 주입하면 inhibitory avoidance task 혹은water-maze spatial task에서수행능력이손상되고, 이러한효과는 Metyrapone(Corticosterone - 1545 -
이상관 김민수 안련섭 김문수 성강경 synthesis inhibitor) 의전처치 (pre-treatment) 로사라진다 7,22). 흥미로운것은 Glucocorticoid receptor agonist를주입하거나, stress task(restraint task 혹은 footshock task) 를사용하여 Glucocorticoids와유사한기억조절효과를보여주는연구 21,22) 들은많았지만, Glucocorticoids의증가를완화시키거나관해시키는 Task나처치 (Treatment) 를이용한실험은거의없었다. 그러므로 stress hormone을조절할수있는한방임상적처치중하나인전기침자극 (electroacupuncture) 을이용한기억조절효과를연구할필요가있다. 기억의각단계에따른다양한 opioid hormone의처치역시각각특징적인효과를보이고있다. Beta endorphin이나 Enkephalin의 training 직후 (post-training) 주입은기억의 consolidation을손상시키고, Naloxone (μ opioid receptor antagonist) 의 training 직후 (post-training) 주입은기억의 consolidation을증가시킨다 8,9). Dynorphin의주입은낮은 footshock(0.2 ma) task에서는기억의 consolidation과 retrieval 을모두증가시키지만, 높은footshock(0.4 ma) task에서는별다른영향을주지않는다. 이러한효과는 stress hormone과밀접한관계가있는데, 각각의 opioid hormone은기억의조절에중요한해부학적구조인 Basolateral Amygdala (BLA) 에서의 Norepineprhine 수준과높은연관성을보이고, 이러한기억조절효과는부신 (adrenal grand) 을제거하면사라지게된다 8,9). 침자극은자율신경계와 hormone시스템 (HPA system) 의활성을조절하는것으로제안되어왔고 30,31), 최근에는전기침자극의진통효과와항 stress 효과등에많은연구들이시행되어오고있다. 전기침자극의진통효과의기전은 opioid system과관련되어다양하게연구되고있는데, low frequency 에의해 Met-enkephalin, Beta endorphin, Endomorphin의분비가증가되고, high frequency 에의해 Dynorphin A의분비가증가된다 10-12). 또한 low frequency 에의한진통효과는 Naloxone에의해억제될수있다 13). 전기침자극의항 stress 효과관련연구들에따르면, 침자극은혈액이나뇌의특정영역에서 Norepinephrine이나 Glucocorticoids의분비를감소시키고 34,35), 다양한 Stress task에노출된이후발생하는일련의 stress 관련행동도감소시킨다 35). 특히, low frequency인 3 Hz의전기침자극은 immobilization stress task에노출된쥐의혈압, 심박수, 혈중 Norepinephrine, 혈중 Epinephrine의분비증가를감소시킨다 13). Han 등의연구결과에의하면, high frequency인 100 Hz의 tooth-pulp stimulation에의해혈중 Norepinephrine, Epinephrine, Dopamine, Corticosterone, ACTH의분비가증가되고, 3 Hz의전기침자극을통해이러한효과는억제되며, opioid antagonist 인 Naloxone의주입을통해이러한모든효과는감소된다 14). 이는 high frequency에의해 stress hormone이증가되고, low frequency 에의해증가된 stress hormone이감소됨을의미하고있다. 이상의실험결과들로보아전기침자극의진통효과와항 stress 효과는서로독립적으로보여지기보다는상호의존적이거나매우밀접한관계하에보여지고있음을시사하고더나아가부분적으로동일시스템이관여되고있음을시사하고있다. 그러므로기억조절에중요한역할을하고있는 stress hormone 이나 opioids 등을통해진통효과와항 stress 효과를보이고있는전기침자극역시기억조절에중요한역할을할수있을것으로사료된다 (Fig. 5). Low Frequency of EA High Frequency of EA SH Han 14) JS Han 10,33) SH Han 14) JS Han 10,33) Stress H β-end & Enk Stress H Dynorphin Roozendaal 3,5-7) McGaugh 8) Quirare 23) Hatfeld 24) Memory consolidation 3,5-7) Roozendaal Ilyutchenok 25) Cerro 26) Memory consolidation Memory consolidation or not Fig. 5. Schematic diagram showing the hypothesis that Electroacupuncture can be involved in modulating of memory. EA; Electroacupuncture, Stress HStress hormone, Corticosterone, β-end; Beta-endorphin, Enk Enkephalin 결 론 기존의전기침자극의효과로알려진진통효과와항 stress 효과와관련된실험결과들을종합한결과다음과같은결과를얻었다. stress hormone은특정뇌부위및기억의단계에따라특이적인기억조절효과가있다. 다양한 opioid hormone은각각특이적인기억조절효과가있다 high frequency의전기침자극은 stress hormone의수준을증가시킨다. low frequency의전기침자극은 stress hormone의수준을감소시킨다. high frequency 의전기침자극은β-Endorphin과 Enkephalin의수준을감소시킨다. low frequency의전기침자극은β-endorphin과 Enkephalin의수준을증가시킨다. 그러므로기억조절효과가있는stress hormone과 opioid hormone의조절을통해전기침자극역시기억조절효과가있을것으로사료된다. 감사의글 이논문은 2006학년도원광대학교숭산학술연구재단의지원에의해서연구됨. 참고문헌 1. Belanoff, J.K., Gross, K., Yagar, A., Schatzberg, A.F. Corticosteroids and cognition. J. Psychiat. Res, 35: 127-145, 2001. 2. Lupien, S.J., McEwen, B.S. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res. Rev. 24: 1-27, 1997. - 1546 -
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