Darwin Amir Bgn Penyakit Saraf FK-Unand / RS DR. M. Djamil MEKANISME NYERI Darwin Amir Bgn Penyakit Saraf FK-Unand / RS DR. M. Djamil

Pendahuluan Nyeri adalah pengalaman sensorik dan emosional yang tidak menyenangkan terkait kerusakan jaringan, baik aktual maupun potensial atau yang digambarkan dalam bentuk kerusakan tersebut.

Pendahuluan Nyeri adalah anugerah Sesungguhnya nyeri adalah anugerah yg besar dari maha pencipta (Allah SWT) “Pain is alarm protection tell us that something wrong in our body”. Sulit dibayangkan seandainya tubuh kita tidak dilengkapi dgn “reseptor nyeri”, sehingga kita tidak pernah menyadari kalau tubuh kita telah terancam kerusakan.

Potential tissue damage --- > Physiological Pain Pendahuluan Pain can occur due to Potential tissue damage --- > Physiological Pain Actual tissue damage ----- > Nociceptive pain or Acute pain or inflammation pain Described in term of such damage ----- > Chronic Pain

1. PHYSIOLOGICAL PAIN Pain that occur to stimulate withdrawals reflex To prevent tissue damage To prevent our body from hatmful things.

2. Acute or Nociceptive Pain Acute Pain or Nociceptive Pain is pain that elicited by activation of nociceptors There are 4 distinct process involved: 1. Transduction 2. Transmission 3. Modulation and 4. Perception

The Pain Pathway Pain Perception Brain Dorsal Horn Dorsal Root Ganglion Dorsal Horn 2:1981 3:55 Activation of peripheral pain receptors, also called nociceptors, by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord via the dorsal root ganglion. From the dorsal horn, the signals are carried along the ascending pain pathway or the spinothalamic tract to the thalamus and the cortex. Pain can be controlled by pain-inhibiting and pain-facilitating neurons. Descending signals originating in supraspinal centers can modulate activity in the dorsal horn by controlling spinal pain transmission.1,2 Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63:1979-1984. Fields HL, Martin JB. Pain: pathophysiology and management. In: Fauci AS, Braunwald E, Isselbacher KF, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:53-58.    2:1979 3:55 Spinal Cord Nociceptor Gottschalk A et al. Am Fam Physician. 2001;63:1979-84. Fields HL et al. Harrison’s Principles of Internal Medicine. 1998:53-8.

Stage of Nociception Transduction 1. Transduction Conversion of noxious stimuli (mechanical, thermal, chemical into electrical activation 2 Transmission Communication of the nerve impulse from the periphery to the spinal cord, up to spinothalamic track to the thalamus and cerebral cortex 3 Modulation Process by which impulse travel from the brain back down to the spinal cord to selectiveley inhibit (or sometimes amlpify) pain impulse 4 Perception Net result of three events – the subjective experience of pain

Pain perception much depend on modulation ---- > 3 possibilities Nociception without pain (ada nosisepsi tanpa nyeri) Nociception with pain (ada nosisepsi dengan nyeri). Pain without Nociception (ada nyeri tanpa nosisepsi)

The Somatosensory System Somatosensory cortex Frontal cortex Thalamus Hypothalamus Descending pathway Ascending tracts Periaqueductal gray matter Midbrain Medulla Dorsal horn area Spinal cord Noxious stimuli activate receptors in periphery

The Pain Response Pain Activation of the Peripheral Nervous System Tissue Damage Activation of the Peripheral Nervous System Activation of the Central Nervous System at the Spinal Cord Level Transmission of the Pain Signal to the Brain <<Animated slide: Please advance to view entire sequence.>> The pain response is a complex process that involves both the peripheral nervous system (PNS) and the central nervous system (CNS). Tissue injury results in the activation of the PNS. Signals from the PNS travel into the CNS. They move through the spinal cord before traveling to the brain, where pain perception occurs. In addition, pain perception can be transmitted directly from the site of injury to the CNS via a humoral signal (probably via interleukin [IL]-6), which then induces cyclooxygenase (COX)-2 in the CNS.1 This concept will be discussed in greater detail later in the presentation. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471-475. Pain 1:471-2 Samad TA et al. Nature. 2001;410:471-5.

Pendahuluan Nyeri dibedakan atas: Nyeri Neuropatik: Nyeri yang disebabkan oleh lesi (kerusakan) sistem saraf. Nyeri Nosiseptif: Nyeri yang disebabkan oleh proses inflamasi dan kerusakan jaringan

Pendahuluan Pd keadaan sakit, tubuh merasakan nyeri Nyeri merupakan mekanisme pertahanan tubuh sehingga individu memindahkan stimulus nyeri Ada 2 jenis rasa nyeri: ☼ Nyeri cepat: tajam, menusuk, rasa kesetrum dan akut. ☼ Nyeri lambat: rasa terbakar, pegal, berdenyut, nyeri mual dan khronik

Peripheral Activation VR1 External Stimuli Heat Voltage-Gated Sodium Channels Ca2+ Mechanical 4:1766 Chemical Action Potentials Transducer receptor/ion channel complexes on peripheral nociceptor terminals respond to noxious stimuli from mechanical, chemical, or heat sources by generating depolarizing currents. If the current is sufficient, action potentials are initiated and then conducted to the CNS, where they invade central nociceptor terminals and cause the release of neurotransmitters, thus eliciting pain perception. Depicted here is the activation of vanilloid receptor VR1 by noxious heat stimuli, resulting in the generation of action potentials that travel to the spinal cord to cause the release of transmitters.1 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768. 4:1766 Adapted from Woolf CJ et al. Science. 2000;288:1766.

Pendahuluan Reseptor nyeri dan rangsangannya: Semua reseptor adalah ujung saraf bebas. Tersebar dipermukaan kulit dan jaringan seperti: - periosteum - dinding dalam arteri - permukaan sendi - falks / tentorium serebri Ada 3 macam stimulus: - mekanik - suhu - kimiawi

Peripheral Modulation External Stimulus VR1 HEAT PKA Sensitizing Stimulus EP Receptor SNS/PN3 TTX-Resistant Sodium Channel 4:1766 PGE2 PKCe Modulation is a result of receptor/ion channel phosphorylation, which causes a change in the expression of channels on the surface of primary sensory neurons. Sensitizing agents such as prostaglandin E2 (PGE2) and bradykinin released during tissue damage or by inflammatory cells sensitize nociceptor terminals. Nociceptors undergo modulation as a result of simultaneous activation of the intracellular kinase protein kinase A (PKA) or protein kinase C (PKC), the phosphorylation of a tetrodotoxin (TTX)-resistant sensory neuron–specific sodium ion channel (SNS; also referred to as SNS/PN3), and possibly the phosphorylation of VR1. Phosphorylation of SNS channels causes an influx of sodium ions. Consequently, the excitability of nociceptor terminal membranes increases, and peripheral nociceptors become more sensitive to subsequent stimuli.1 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768. Bradykinin BK Receptor 4:1765-6 EP = prostaglandin E; BK = bradykinin. Adapted from Woolf CJ et al. Science. 2000;288:1766.

Sensasi Nyeri Nyeri berperan melindungi tubuh Nosiseptor adalah suatu reseptor nyeri pada ujung saraf bebas yg ditemukan pada jaringan tubuh, kecuali otak. Rangsangan termal, kimia dan mekanik akan mengaktifkan nosiseptor, dengan jalan melepaskan prostaglandin, kinin dan ion kalium

Jenis Nyeri: ☻Impuls nyeri cepat - berlangsung cepat (0,1 dtk pasca rangsangan - disepanjang saraf tipe A bermielin - nyeri bersifat akut, tajam atau menusuk - tdk dijumpai pd struktur dalam

Jenis Nyeri: ☻ Impuls nyeri lambat terjadi disepanjang saraf tipe C tdk bermielin - nyeri sangat menyiksa, dan menjadi khronik spt; rasa terbakar, tumpul dan berdenyut. spt sakit gigi dan infeksi kuku, - nyeri pd rangsangan reseptor kulit disebut dgn; superficial somatic pain - pd rangsangan otot skeletal, sendi, tendon disebut; deep somatic pain

Jenis Nyeri: - nyeri viseral; akibat rangsangan nosiseptor organ pd viseral spt distensi abdomen dan iskhemia organ internal. - zat kimia yg merangsang nyeri adalah bradikinin, serotonin, ion kalium, asetil kholine dan enzim proteolitik

Jaras rangkap penjalaran sinyal nyeri Dua jaras penyaluran sinyal nyeri ke sistem saraf pusat ☻Nyeri cepat dan tajam dirangsang oleh mekanik dan suhu. - disalurkan ke medula spinalis oleh serabut tipe Aδ - kecepatan 6-10 m/detik. ☻Nyeri lambat dirangsang secara kimia, mekanik dan suhu - disalurkan melalui saraf tipe C - kecepatan 0,5-2 m/dtk

There are Two Sensory Afferent Neurons Large myelinated A fibers, very fast conduction velocity. Respond to innocuous stimuli Small myelinated A & C unmyelinated fibers, have slow conduction velocity. Respond to noxious stimuli Large fibers A Dorsal root ganglion Dorsal Horn A Small fibers C Peripheral sensory Nerve fibers LYRICA Neuropathic Pain Slide Kit: February 2005 Update

Physiological Pain A C fiber A Touch Tactile Pressure NOXIOUS STIMULUS INNOCUOUS STIMULUS A C fiber A DHN DHN PAIN INNOCUOUS SENSATION Touch Tactile Pressure First Pain Second Pain LYRICA Neuropathic Pain Slide Kit: February 2005 Update

Jaras nyeri di MS dan batang otak Dari kornu dorsalis menuju otak, sinyal nyeri disalurkan di MS melalui: ☻Tr. Neo-spinotalamikus - untuk nyeri cepat berakhir di lamina I (lamina marginalis) – kolumna anterolat. - sebgn berakhir di kompleks ventrobasal dan sebgn lagi di korteks somatosensorik

Jaras nyeri di MS dan batang otak ☻Tr. Paleo-spinotalamikus - utk nyeri lambat dan khronik melalui saraf tipe C dan sebgn saraf tipe Aδ - berakhir di lamina II dan III subs. Gelatinosa dan lamina V dan VII kornu dorsalis - Neurotransmiternya Subst. P dan Glutamat - Berakhir di tiga tempat ■ Nc. Retikularis medula, pons dan mesensefalon ■ Area tekt. mesensefalon dan kol. Sup dan Inf ■ Subst. grisea peri akuadukt

Activation of Central Neurons C-Fiber Terminal Glutamate (-) NMDA P Substance P AMPA P Ca2+ (+) Dorsal Horn Neuron 4:1765 8:1547-8 Following mild noxious stimuli, dorsal horn neurons are activated primarily by fast excitatory postsynaptic potentials (EPSPs) produced by unmyelinated nociceptive C-fibers. These fast EPSPs signal the onset, duration, intensity, and location of the stimulus. More intense stimuli generate higher frequency inputs and cause the synaptic release of glutamate and other neuromodulators, such as substance P, from the C-fibers to act on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). This produces slow EPSPs lasting tens of seconds.1 Repeated stimulation allows for temporal summation of slow EPSPs, resulting in the removal of the magnesium blockade on N-methyl D-aspartate (NMDA) channels.1 The increased current through the NMDA channels enhances the cumulative depolarization caused by slow EPSPs. The result is a “windup” of action potential discharge on central pain-projecting neurons and neuronal modulation.1,2 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768. Schwartzman RJ, Grothusen J, Kiefer TR, et al. Neuropathic central pain: epidemiology, etiology, and treatment options. Arch Neurol. 2001;58:1547-1550. (+) PKC 4:1765 4:1765 8:1548 Woolf CJ et al. Science. 2000;288:1765-8. Schwartzman RJ et al. Arch Neurol. 2001;58:1547-50.

Introduce Hypothesis of 1965 MELZACK and WALL Introduce Hypothesis of “GATE CONTROL THEORY” Brain GATE CONTROL SYSTEM Aβ - + + SG DHN ACTION SYSTEM - - + C The beginning of “MODULATION” LYRICA Neuropathic Pain Slide Kit: February 2005 Update

Sistim Inhibisi Sensasi Nyeri Reaksi seseorang terhadap nyeri bervariasi. Dipengaruhi otak melakukan inhibisi (sistem analgesia). Ada 3 komponen: Area periakuadukt grisea dan periventr. mesensefalon., sinyal dikirim ke 2. Nukl. Raphe magnus dibawah pons diatas medula obl. Dan disalurkan ke 3. Kompleks penghambat rasa nyeri radiks dorsalis MS kemudian dipancarkan ke-otak

Sistim Inhibisi Sensasi Nyeri Enkefalin disekresikan oleh nc. periventrik, area peri akuadukt dan raphe magnus. menghambat pd pre dan post sinaps serabut nyeri tipe C dan Aδ Serotonin oleh radiks dorsalis MS menghambat pd pre-sinaptik terhadap ion kasium.

Sistim Inhibisi Sensasi Nyeri Sistim Opium Otak, Endorfin dan Enkefalin ☻Morphin like subst. bekerja pd sebagian sistem analgesia. Ada 12 macam opium like subst di-otak Berasal dari pemecahan 3 mol. Protein, y.i pro-opiomelanokortin, pro-enkefalin dan pro-dinorfin. Bhn yg penting adalah β-endorfin, met-enkefalin dan leu-endorfin.

Proses Sensasi Nyeri Pd reseptor sensasi diseleksi dan di-olah jadi 4 tahap 1. Rangsangan reseptor sensorik - Hrs tepat dan adekuat hingga terjadi respons. 2. Transduksi stimulus. - terjadi pd kornu dorsalis MS (dikonversi) menjadi energi rangsangan (gradasi pot tergantung kuat rangsangan dan ampl

Proses Sensasi Nyeri 3. Membangkitkan impuls saraf. - Pd grad. potensial mencapai ambang tercetus 1 impuls atau lebih, kmdian menyebar ke pusat. 4. Integrasi input sensorik. Daerah tertentu di-otak akan menerima dan meng-integrasikan impuls sensorik dan diterima pd area tertentu di korteks

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