近代生理學大師 Cannon 提出所有生理機能的主要目的是要讓動物體大都經 由負回饋(negative feedback)的機制維持其內環境(internal environment)
恆定狀態(homeostasis)(Cannon, 1929)。Sterling 和 Eyer(1988)進一步提 出應變恆定狀態(allostasis)的概念,強調生物體在外界變化的環境中會透過多 種模式來維持內環境的恆定狀態(McEwen and Wingfield, 2003; Romero et al., 2009)。近年來生物科技發展迅速,對於生物體各種機能在分子生物學層面運作 機轉的了解已有大幅度的進展。然而,根據這些生理機轉所研發出來的藥物,縱 然能使生物體失調的病理狀態得以控制,但生理機能環環相扣,恢復生理狀態的 恆定,仍需靠自身各個系統的自行調適。
動物體對外界刺激產生反應、恢復生理機能恆定的過程中,大至器官系統,
小至分子化學成分都有一定的運作機轉。多年來從分子生物學角度探討生理機轉 所花費的經費人力非常龐大,但所獲得實際應用於改善健康的成果卻仍然有限。
因此,回歸最原始的觀察,從整體醫療(integrated medicine)大架構重新省 思動物的自然調適機制,從另一個角度來研究,或許比較有機會找到突破點。
本研究乃基於此種策略性思考,將重心放在動物對刺激產生反應的這個機 轉,並以動物最重要的自動調適功能「自律神經調控血液循環」為研究目標。因 此,本研究的基本構想就是探討刺激反應過程中神經與血液循環的變化,以此建 立一套研究模式,以利於後續探討動物為何對於刺激失去調適能力,以至於無法 恢復生理恆定狀態而導致各種疾病的發生。在了解動物如何藉由神經與循環系統 來達成對刺激的調適,以及其失調時所產生的病理現象後,則將有機會發展成為 一套完整的神經調節醫學,藉由物理性的人為施予刺激,來產生預期的反應,以 達到調控神經功能與改善生理機能的目的。
本研究主要的目的為建構探討動物生理病理的刺激反應所需的方法學,聚焦
62
63
並評估此辣椒素刺激所產生的效應。
影響局部熱充血反應最大的因素是感覺神經的功能,故此測試法具有應用於 感覺神經功能評估的潛力。先前的方法採用隨機選取測試的部位,因此微血管密 度變異大,且感覺神經纖維的分佈也不同,故儘管經由最大血管擴張血流量校正 處理,其再測信度仍然不佳,因此無法應用於感覺神經功能之測試。本研究採用 預先界定測量部位的選取規則來降低感覺神經纖維分佈的變異性,於間隔一段時 間後重新定位測試部位,則其 peak CVC 及 peak CVC 改變量在測試前環境適應 達 30 分鐘時,於人體右側前臂可獲得良好的再測信度。而如果將環境適應期增 長到 60 分鐘後,也可以在左側前臂獲得可接受的再測信度。因此後續可針對正 常人與特定病人族群的特定身體部位,建立正常值範圍,並探究可否用於評估特 定病人族群的感覺神經功能,或作為長期追蹤病人感覺神經功能變化的指標。
本研究的第三個部份是利用辣椒素體表刺激,進行了上下肢解剖對稱部位的 刺激反應關聯驗證。結果顯示辣椒素刺激右下肢(小腿)30 分鐘會增強右上肢
(前臂)對應部位的局部熱充血反應,但對右上肢非對應部位及左上肢的局部熱 充血反應則不影響。在左下肢給予辣椒素刺激則對左右兩側上肢的局部熱充血反 應都不影響。如能進一步證明其確為局部交感神經興奮所致,則此刺激反應模式 建立後,便可用在驗證各刺激部位與反應部位的關聯性上,用以建立完整的刺激 反應對應圖譜。除此之外,本研究也藉助此方法,顯示上下肢之間可能存有體交 感神經反射作用,其作用不僅具有解剖上特異性之對應關係,且左右側的反應並 不相同。
以辣椒素刺激體表,在預期的對應部位可測得局部熱充血反應發生顯著改變 後,接著可反過來利用電刺激在疾病的預測對應部位作治療,以觀察電刺激對目 標部位所產生的血流量變化。本研究的第四部份採用大鼠後肢缺血之動物模式,
以電刺激大鼠前肢觀察其效應。結果顯示在兩側後肢缺血後,前肢電刺激可以造
64
65
可以因電刺激而產生血流量的特異性改變,且其對應規則在左側與右側也不相 同。因此,利用此兩種實驗模式,未來有機會建立刺激反應的對應規則,進而發 展實用的標靶神經調節技術(targeted neuromodulation),臨床上將可運用於 治療各種與神經與血液循環系統功能失調有關的疾病。
66
參考文獻
Agarwal, S.C., et al., 2010. Comparative reproducibility of dermal microvascular blood flow changes in response to acetylcholine iontophoresis, hyperthermia and reactive hyperaemia. Physiol. Meas. 31, 1–11.
Allen, R.J., 2006. Physical agents used in the management of chronic pain by physical therapists. Phys. Med. Rehabil. Clin. N. Am. 17, 315–345.
Barie, P.S., Mullins, R.J., 1988. Experimental methods in the pathogenesis of limb ischemia. J. Surg. Res. 44, 284–307.
Bell, C., et al., 1985. Differentiation of vasodilator and sudomotor responses in the cat paw pad to preganglionic sympathetic stimulation. J. Physiol. 364, 93–104.
Bickel, A., et al., 2009. C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies. J. Peripher. Nerv. Syst. 14, 294–299.
Binder, M.D., Mendell, L.M., 1990. The Segmental Motor System. Oxford, Oxford University Press.
Blaisdell, F.W., 2002. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc. Surg. 10, 620–630.
Bland, M., 2000. An Introduction to Medical Statistics, third ed. Oxford University Press, London.
Bonelli, R.M., Költringer, P., 2000. Autonomic nervous function assessment using thermal reactivity of microcirculation. Clin. Neurophysiol. 111, 1880–1888.
Boushel, R., 2010. Muscle metaboreflex control of the circulation during exercise.
Acta. Physiol. (Oxf). 199, 367–383.
Braverman, I.M., et al., 1990. Correlation of laser Doppler wave patterns with underlying microvascular anatomy. J. Invest. Dermatol. 95, 283–286.
Brunt, V.E., et al., 2011. 17-β estradiol and progesterone independently augment
67
cutaneous thermal hyperemia but not reactive hyperemia. Microcirculation 18, 347–355.
Cannon, W.B., 1929. Organization for physiological homeostasis. Physiol. Rev. 9, 399–431.
Carter, S.J., Hodges, G.J., 2011. Sensory and sympathetic nerve contributions to the cutaneous vasodilator response from a noxious heat stimulus. Exp. Physiol. 96, 1208–1217.
Caselli, A. et al., 2003. Local anesthesia reduces the maximal skin vasodilation during iontophoresis of sodium nitroprusside and heating. Microvasc. Res. 66, 134–139.
Charkoudian, N., et al., 1999. Influence of female reproductive hormones on local thermal control of skin blood flow. J. Appl. Physiol. 87, 1719–1723.
Chau, D., et al., 1997. Sympathetically Correlated Activity of Dorsal Horn Neurons in Spinally Transected Rats. J. Neurophysiol. 77, 2966–2974.
Chau, D., et al., 2000. Ongoing and Stimulus-Evoked Activity of Sympathetically Correlated Neurons in the Intermediate Zone and Dorsal Horn of Acutely Spinalized Rats. J. Neurophysiol. 83, 2699–2707.
Chen, X.H., Han, J.S., 1992. Analgesia induced by electroacupuncture of different frequencies is mediated by different types of opioid receptors: another cross-tolerance study. Behav. Brain Res. 47, 143–149.
Choi, E.M. et al., 2012. Point specificity in acupuncture. Chin. Med. 7, 4
Chou, R., Huffman, L.H., 2007. American Pain Society; American College of Physicians. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann. Intern. Med. 147, 505–514.
Ciplak, M., et al., 2009. The vasodilatory response of skin microcirculation to local heating is subject to desensitization. Microcirculation 16, 265–275.
68
Clough, G., et al., 2009. Evaluation of a new high power, wide separation laser Doppler probe: potential measurement of deeper tissue blood flow. Microvasc.
Res. 78, 155–161.
Cracowski, J.L., et al., 2006. Methodological issues in the assessment of skin microvascular endothelial function in humans. Trends Pharmacol. Sci. 27, 503–508.
Craig, A.D., 2005. Forebrain emotional asymmetry: a neuroanatomical basis? Trends Cogn. Sci. 9, 566–571.
Cramp, A.F., et al., 2000. The effect of high- and low-frequency transcutaneous electrical nerve stimulation upon cutaneous blood flow and skin temperature in healthy subjects. Clin. Physiol. 20, 150–157.
Cramp, F.L., et al., 2002. Transcutaneous electric nerve stimulation: the effect of intensity on local and distal cutaneous blood flow and skin temperature in healthy subjects. Arch. Phys. Med. Rehabil. 83, 5–9.
Cravo, S.L., et al., 1995. Cardiovascular adjustments in limb retraction provoked by noxious stimulation in decerebrate and spinal cats. Evidence for a somatotopic organization. Braz. J. Med. Biol. Res. 28, 385–396.
Cravo, S.L., et al, 2003. Rostral ventrolateral medulla: an integrative site for muscle vasodilation during defense-alerting reactions. Cell Mol. Neurobiol. 23, 579–595.
Deluze, C., et al., 1992. Electroacupuncture in fibromyalgia: results of a controlled trial. Brit. Med. J. 305, 1249–1252.
den Uil, C.A., et al., 2008. The microcirculation in health and critical disease. Prog.
Cardiovasc. Dis. 51, 161–170.
Donald, A. E., et al., 2008. Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J. Am. Coll. Cardiol. 51, 1959–1964.
69
Dong, Z. et al., 2011. Evaluation of influence of acupuncture and electro-acupuncture for blood perfusion of stomach by laser Doppler blood perfusion imaging. Evid.
Based Complement Alternat. Med. 2011, 969231.
Drummond P.D., 2009. Alpha-1 adrenoceptor stimulation triggers axon-reflex vasodilatation in human skin. Auton. Neurosci. 151, 159–163.
Drummond, P.D., Lipnicki, D.M., 1999. Noradrenaline provokes axon reflex hyperaemia in the skin of the human forearm. J. Auton. Nerv. Syst. 77, 39–44.
Dubin, A.E., Patapoutian, A., 2010. Nociceptors: the sensors of the pain pathway. J.
Clin. Invest. 120, 3760–3772.
Dubinsky, R.M., Miyasaki, J., 2010. Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 74, 173–176.
Field, K.J., et al., 1993. Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats. Lab. Anim. 27, 258–269.
Frantz, J., et al., 2012. Desensitization of thermal hyperemia in the skin is reproducible. Microcirculation 19, 78–85.
Ge, H.Y., Arendt-Nielsen, L., 2011. Latent myofascial trigger points. Curr. Pain Headache Rep. 15, 386–392.
Gibbins, I. L., Morris, J. L., 2000. Pathway specific expression of neuropeptides and autonomic control of the vasculature. Regul. Peptides 93, 93–107.
Gibbins, I. L., et al., 2003. Functional organization of peripheral vasomotor pathways.
Acta. Physiol. Scand. 177, 237–245.
Goats, G.C., 1994. Massage--the scientific basis of an ancient art: Part 2.
Physiological and therapeutic effects. Br. J. Sports Med. 28, 153–156.
70
Groetzner, P., Weidner, C., 2010. The human vasodilator axon reflex - an exclusively peripheral phenomenon? Pain 149, 71–75.
Guyatt, G., et al., 1987. Measuring change over time: assessing the usefulness of evaluative instruments. J. Chronic Dis. 40, 171–178.
Hahm, T.S., 2007. The effect of 2 Hz and 100 Hz electrical stimulation of acupoint on ankle sprain in rats. J. Korean Med. Sci. 22, 347–351.
Han, Z., et al., 1999. Endomorphine-1 mediates 2 Hz but not 100 Hz electroacupuncture analgesia in the rat. Neurosci. Lett. 274, 75–78.
Hippisley-Cox, J., et al., 2005. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ.
331, 1310-1316.
Hodges, G.J., et al., 2008. The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans. J.
Appl. Physiol. 105, 233–240.
Hodges, G.J., et al., 2009. The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming. Am. J. Physiol. Heart Circ.
Physiol. 296, H51–56.
Holzer, P., 1992. Peptidergic sensory neurons in the control of vascular functions:
mechanisms and significance in the cutaneous and splanchnic vascular beds. Rev.
Physiol. Biochem. Pharmacol. 121, 49–146.
Hornyak, M. E., et al., 1990. Sympathetic activity influences the vascular axon reflex in the skin. Acta Physiol. Scand. 139, 77–84.
Houghton, B.L. et al., 2006. Nitric oxide and norepinephrine contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin. J. Physiol. 572,811–820.
71
Huang, C., 2004. Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain. Brain Res. Bull. 63, 99–103.
Huang, C.S., Tsai, Y.F., 2009. Somatosympathetic reflex and acupuncture-related analgesia. Chin. J. Physiol. 52, 345–357.
Huang, C. S., et al., 2012. Axon reflex-related hyperemia induced by short local heating is reproducible. Microvasc. Res. 84, 351–355.
Huang, C.S., et al., 2013. Increasing acclimation period improves the reproducibility of short-heating local thermal hyperemia. Microvasc. Res. 85, 93–98.
Iellamo, G., et al., 1996. Evaluation of reproducibility of spontaneous baroreflex sensitivity at rest and during laboratory tests. J. Hypertens. 14, 1099–1104.
Izumi, H., 1999. Nervous control of blood flow in the orofacial region. Pharmacol.
Ther. 81, 141–161.
Jänig, W., 1988. Pre- and postganglionic vasoconstrictor neurons: differentiation, types, and discharge properties. Annu. Rev. Physiol. 50, 525–539.
Jänig, W., Szulczyk, P., 1981. The organization of lumbar preganglionic neurons. J.
Auton. Nerv. Syst. 3, 177–191.
Jenelle, D.R., Michael, R.V., 2002. Cellular Mechanisms of Neurogenic Inflammation.
J. Pharmacol. Exp. Ther. 302, 839–845.
Jette, A. M., et al., 2007. Interpreting rehabilitation outcome measurements. J. Rehabil.
Med.39, 585–590.
Johnson, J.M., Kellogg, D.L. Jr., 2010. Local thermal control of the human cutaneous circulation. J. Appl. Physiol. 109, 1229–1238.
Juvin, L., et al., 2005, Propriospinal circuitry underlying interlimb coordination in mammalian quadrupedal locomotion. J. Neurosci. 25, 6025–6035.
Kagitani, F., et al., 2010. Afferent nerve fibers and acupuncture. Auton. Neurosci. 157,
72
2–8.
Kellogg D.L. Jr., 2006. In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J. Appl. Physiol.
100, 1709–1718.
Kellogg, D.L. Jr., et al., 1999. Role of nitric oxide in the vascular effects of local warming of the skin in humans. J. Appl. Physiol. 86, 1185–1190.
Kellogg, D.L. Jr., et al., 2009. Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans. J. Appl. Physiol. 107, 1438–1444.
Kerman, I. A., Yates, B. J., 1999. Patterning of somatosympathetic reflexes. Am. J.
Physiol. Regul. Integr. Comp. Physio. 277, 716–724.
Kimura, A., Sato, A., 1997. Somatic regulation of autonomic functions in anesthetized animals--neural mechanisms of physical therapy including acupuncture. Jpn. J.
Vet. Res. 45, 137–145.
Koo, S.T., et al., 2002. Acupuncture analgesia in a new rat model of ankle sprain pain.
Pain 99, 423–431.
Koo, S.T., et al., 2008 Electroacupuncture-induced analgesia in a rat model of ankle sprain pain is mediated by spinal alpha-adrenoceptors. Pain 135, 11–19.
Kramer, H.H., et al., 2004. Electrically stimulated axon reflexes are diminished in diabetic small fiber neuropathies. Diabetes 53, 769–774.
Krishnan, S. T., Rayman, G., 2004. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care 27, 2930–2935.
Krishnan, S. T., et al., 2009. Abnormal LDIflare but normal quantitative sensory testing and dermal nerve fiber density in patients with painful diabetic neuropathy.
Diabetes Care 32, 451–455.
Kumada, M., et al., 1978. Hemodynamic similarities between the trigeminal and
73
aortic vasodepressor responses. Am. J. Physiol. Heart Circ. Physiol. 234, H67–73.
Lao, L., et al., 2001. Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal fos protein expression in rats with persistent inflammation. J. Pain 2, 111–117.
Lao, L., et al., 2004. A parametric study of electroacupuncture on persistent hyperalgesia and Fos protein expression in rats. Brain Res. 10, 18–29.
Landis, J.R., Koch, G.G., 1977. The measurement of observer agreement for categorical data. Biometrics 33, 159–174.
Lee. J.H., Beitz, A.J., 1993. The distribution of brain-stem and spinal cord nuclei associated with different frequencies of electroacupuncture analgesia. Pain 52, 11–28.
Liao, J.M., et al., 2002 Electroacupuncture at Hoku elicits dual effect on autonomic nervous system in anesthetized rats. Neurosci. Res. 42, 15–20.
Lin, J.G., et al, 2002. The effect of high and low frequency electroacupuncture in pain after lower abdominal surgery. Pain 99, 509–514.
Lin, J.G., Chen, W.L., 2008. Acupuncture analgesia: a review of its mechanisms of actions. Am. J. Chin. Med. 36, 635–645.
Lipman, A.G., 2005. Pain as a human right: the 2004 Global Day Against Pain. J. Pain Palliat. Care Pharmacother. 19, 85–100.
Lockhart, C.J., et al., 2009. End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation. Clin. Sci. (Lond). 116, 175–190.
Long, D. A., 1994. Hand differences and reported intensity of nociceptive stimuli.
Percept. Mot. Skills 79, 411–417.
Lugo, M., et al., 2002. Sensory lateralization in pain subjective perception for noxious heat stimulus. Somatosens. Mot. Res. 19, 207–212.
Lugo, M., et al., 2002. Sensory lateralization in pain subjective perception for noxious heat stimulus. Somatosens. Mot. Res. 19, 207–212.