만성통증의 이해(감작 sensitization)

[문형철]

통증은 오래되면 말초신경에서부터 시냅스, 대뇌피질까지 통증의 역치가 낮아지는 방향으로 송두리째 변한다.

놀랍게도 통증이외의 모든 감각은 감작의 반대인 적응을 한다. 예를들어 뜨거운 목욕탕에 들어갈때 처음에는 뜨거운 감각이 시간이 흐르면서 적응하여 온몸이 시원해지는 느낌과 같은 것이다.

1998년 수련의할때 너무도 많은 환자들이 정형외과교과서에서는 존재하지 않는 만성통증(교통사고환자, fibromyalgia환자 등)을 호소하는 것을 보고, 처음에는 꾀병인줄 알았다가 통증의 감작이라는 것을 알고 그 사람들이 진짜  아픈 사람이구나하는 것을 알고나서 만성통증을 호소하는 사람들을 처음으로 환자로 인정할 수 있었다.

문제는 그 다음이었다. 왜 유독 통증만 적응과 반대현상인 감작을 일으키는가? 화장실에서 골똘히 생각하다가 무릎을 탁쳤다. 아~~ 만약에 통증이 적응한다면 우리의 관절은 어떻게 될까? 다치면 다칠수록 덜 아프다는 이야기다. 관절이 망가져도 보호할 방법이 없구나. 아~~ 그렇구나.

그 과정을 간단하게 살펴보면 다음과 같다.

tissue injury로 염증이 발생하여 급성통증 -> 염증물질이 통증역치를 떨어뜨리면서 action potential을 증폭 -> 시냅스에서도 수용야를 넓히고 통증 임펄스를 증폭 -> 대뇌에서 통증이 과장됨.

약간 복잡하게 정리하면

tissue injury로 염증이 발생하여 급성통증 -> various inflammatory and pain mediators resulting in peripheral sensitization ->" Sensitization of the primary afferent sensory fibers by mediators of the pain response results in greater, more frequent transmission of action potentials to the nociceptive neurons than in 'normal' pain responses -> At the synapse level, sensitized primary afferent sensory fibers decrease the threshold for activation of nociceptor neurons which become hyperexcitable and transmit frequent action potentials -> Central sensitization results and the individual perceives greater and more prolonged pain

-> 이렇게 하여 allodynia, hyperalgesia, neuropathic pain 등 통증의 과민으로 진행한다.

더 복잡한 것은 구글에서 찾은 아래 자료 참조.

View Module 1

	Sequence 1: Tissue injury Injury Tissue injury occurs
	Pain inflammatory mediators Tissue injury causes the release of various inflammatory and pain mediators resulting in peripheral sensitization 1,2,3 Pain response mediators: ATP, acetylcholine and serotonin are released from damaged endothelial cells and platelets; prostaglandin E2 is synthesized by Cyclooxygenase I and II enzymes in damaged cells; bradykinin is released from plasma from damaged vessels 1,2 Inflammatory response mediators: Histamine is released from mast cells in response to Substance P and calcitonin gene-related peptide (CGRP) released by primary afferent sensory fibers; additional mediators are released from blood cells (cytokines, complement factors C3a and C5a, serotonin, platelet-activating factor, neutrophil chemotactic factor, fibrinopeptides, leukotrienes) 1,2 Together with bradykinin and prostaglandins, these inflammatory mediators cause peripheral vasodilation, increased vascular permeability, plasma extravasation, migration of leucocytes to the site of injury, and clotting responses 1
	Peripheral senstization Bradykinin stimulates further synthesis/release of prostaglandins, and, together with the prostaglandins, sensitizes the primary afferent sensory fibers in response to stimulation by ATP, acetylcholine, serotonin and mechanical and thermal stimuli 1,2,3 Substance P and CGRP released by the primary afferent sensory fibers contribute to the pain response by triggering the release of histamine from mast cells which, in turn, excites the peripheral afferent sensory fibers 1,2,3 " Sensitization of the primary afferent sensory fibers by mediators of the pain response results in greater, more frequent transmission of action potentials to the nociceptive neurons than in 'normal' pain responses 1,2,5
	Hyperexitation At the synapse level, sensitized primary afferent sensory fibers decrease the threshold for activation of nociceptor neurons which become hyperexcitable and transmit frequent action potentials 1,2
	Central sensitization Central sensitization results and the individual perceives greater and more prolonged pain 1,2,3.
	Sequence 2: Nociceptive pain Allodynia Tissue injury often results in nociceptive pain, in which persistent pain is felt in response to direct activation of peripheral nerve terminals in the skin by pain response mediators from the damaged tissue 1,2 Nociceptive pain: Following tissue injury, Substance P, CGRP and glutamate are released by peripheral afferent sensory fibers and act on peptide and glutamate receptors on the post-synaptic membrane to cause greater excitability of nociceptive neurons. Nociceptive neurons become hyperexcitable, resulting in central sensitization and thus greater perception of pain in the higher centers 1,2,3 Nociceptive pain may involve the abnormal pain states of allodynia or hyperalgesia which result from both peripheral and central hypersensitivity 1,2,3 Allodynia: Certain types of noxious stimulus (e.g. sunburn, injury, post-surgical wounds) may result in the individual perceiving pain in response to stimuli that are not normally painful, such as a light stroking of the skin 1,2,4
	Hyperalgesia Hyperalgesia: Certain noxious stimuli (e.g. severe bruising) can result in the individual perceiving abnormally high levels of pain in response to normal noxious stimuli such as a small scratch; in such cases, patients often perceive spontaneous pain 1,2,4
	Greater transmission of AP's Allodynia and hyperalgesia result in greater and continued transmission of action potentials along the peripheral afferent sensory fibers 1,3
	Perception in higher centers Allodynia and hyperalgesia result in greater perception of pain in the higher centers 1,3.
	Sequence 3: Nueropathic Pain Partial Nerve Severance Neuropathic pain occurs following direct injury to the nerves in the peripheral or central nervous systems. Neuropathic pain can result from complete or partial nerve transection, nerve compression, infiltration or infectious/inflammatory/ischemic etiologies 1,2,4 Partial severance of peripheral afferent sensory fibers results in neuropathic pain in the form of ectopic activity4
	Ectopic Activity Ectopic activity: Nerve damage results in the accumulation of sodium channels 2,5 The accumulation of sodium channels generates action potentials in the damaged peripheral afferent sensory fibers proximal to the injury site 2,5
	Hyperexitability The focus of excitability in the damaged sensory fibers causes the stimulation of the higher centers to perceive spontaneous pain (e.g. phantom pain, sciatica) 2,4,5.
	Sequence 4: Nueropathic pain: Ephaptic Ephaptic activity In addition to ectopic activity, direct nerve injury can cause a different form of neuropathic pain due to ephaptic activity 4
	Cross talk Ephaptic transmission: Complete severance of peripheral afferent sensory fibers results in hyperexcitability of damaged nerves and transmission of action potentials along adjacent, undamaged unstimulated sensory fibers, or cross talk 4
	Receptive field expands Cross-talk between damaged, stimulated peripheral afferent sensory fibers and adjacent unstimulated fibers results in an expansion of the area in which pain is perceived in and around the area of the damaged nerve 4.
	Section 5: Wind up Tissue injury/nerve damage Both the tissue injury and nerve damage responsible for severe/persistent nociceptive and neuropathic pain can result in a process termed wind-up 1,3,4
	Repeated firing of PAF's During wind up, the peripheral afferent sensory fibers fire repeatedly, there is increased transmitter release into the spinal cord, and the response by spinal cord neurons increases progressively 1,3,4
	Ion channels In the synapse, repeated firing from peripheral afferent sensory fibers and consequent release of glutamate results in the prolonged opening of post-synaptic ion channels gated by N-methyl-D-aspartate (NMDA)-type glutamate receptors 1,2,3
	Wind up Prolonged opening of the ion channels enables greater influx of calcium and sodium across the post-synaptic membrane and greater excitation of nociceptive neurons 2,3 Wind-up causes long-term changes in nociceptive neurons, which become hyperexcitable such that they respond to lower stimuli; central sensitization results. NMDA-type glutamate receptors play an important role in this process 1,2,3,4
	Receptive field expands The hyperexcitability resulting from wind-up causes a higher perception of pain, such that weak stimuli cause pain, spontaneous pain may be perceived, and the receptive field expands 1,2,4.

References:

1. Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science (Fourth Edition). New York: McGraw Hill (Health Professions Division). 2000;472-491.

2. Millan MJ. Progress in Neurobiology 1999;57:1-164.

3. Dickenson AH. Brit J Anaesthesia 1995;75:193-200.

4. Suzuki R and Dickenson AH. Neuroreport 2000;11:R17-21.

5. Waxman S. Pain 1999;6:S133-140.

[풍림화산]

면역반응의 감작과 차이가 있다고 하셨는데 어떤점이 다른지 잘 이해가 안됩니다. 만성통증의 감작이 인체의 보호를 위해 통증의 과민반응을 유도한다는 점과 감작과 재감작으로 이루어지는 면역반응 역시 인체의 보호를 위한 반응인데요...

[문형철]

봉약침에 의한 감작, 재감작은 반복적으로 봉약침의 양을 늘려가면서 소거할 수 있습니다. 하지만 통증은 반복되면 될수록 통증의 길은 열릴 뿐입니다. 또 한가지 "기전"이 많이 다른거 같습니다. 부분적으로 비슷하다는점 인정!!