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Modulasi adalah proses interaksi antara rangsangan nyeri dan reaksi inhibisi yang

memasuki kornu posterior. Apabila impuls nyeri yang masuk lebih kuat dibandingkan

inhibisi, maka akan terjadi nyeri. Sedangkan apabila inhibisi lebih kuat, maka nyeri tidak

akan terasa. Adapun reaksi inhibisi dapat berupa inhibisi segmental dan inhibisi

suprasegmental.

Central ModulationFACILITATION

At least three mechanisms are responsible for central sensitization in the spinal cord:

(1) Wind-up and sensitization of second-order neurons. WDR neuronsincrease their frequency of discharge with the same repetitive stimuli, and exhibitprolonged discharge, even after afferent C fiber input has stopped.

(2) Receptor field expansion. Dorsal horn neurons increase their receptivefields such that adjacent neurons become responsive to stimuli (whether noxious ornot) to which they were previously unresponsive.

(3) Hyperexcitability of flexion reflexes. Enhancement of flexion reflexes isobserved both ipsilaterally and contralaterally.

Neurochemical mediators of central sensitization include sP, CGRP, vasoactive

intestinal peptide (VIP), cholecystokinin (CCK), angiotensin, and galanin, as well as the

excitatory amino acids L-glutamate and L-aspartate. These substances trigger changes in

membrane excitability by interacting with G proteincoupled membrane receptors on

neurons, activating intracellular second messengers, which in turn phosphorylate substrate

proteins. A common pathway is an increase in intracellular calcium concentration (Figure

185).

Glutamate and aspartate play an important role in wind-up, via activation of N -

methyl- D-aspartate (NMDA) and non-NMDA receptor mechanisms. These amino acids are

believed to be largely responsible for the induction and maintenance of central sensitization.

Activation of NMDA receptors increases intracellular calcium concentration in spinal neurons

and activates phospholipase C (PLC). Increased intracellular calcium concentration activates

phospholipase A 2 (PLA 2), catalyzes the conversion of phosphatidylcholine (PC) to arachidonic

acid (AA), and induces the formation of prostaglandins. Phospholipase C catalyzes thehydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2) to produce inositol triphosphate

(IP 3) and diacylglycerol (DAG), which functions as a second messenger; DAG, in turn,

activates protein kinase C (PKC).

Activation of NMDA receptors also induces nitric oxide synthetase, resulting in the

formation of nitric oxide. Both prostaglandins and nitric oxide facilitate the release of

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excitatory amino acids in the spinal cord. Thus, COX inhibitors such as ASA and NSAIDs also

appear to have important analgesic actions in the spinal cord.

THIS NEURONAL CIRCUITRY IS PRESENT IN THE POSTERIOR ROOTS OF THESPINAL CORD: AB AND C FIBRES COMING FROM THE SKIN, FOR EXAMPLE,STIMULATE THE NEURON N IMPLICATED IN NOCICEPTION, BUT THISSTIMULATION CANNOT OCCUR WHEN THE PERIPHERAL STIMULUS IS WEAKBECAUSE ENKEPHALINERGIC INTERNEURONS (E) STIMULATED BY SENSORYSOMESTHETIC FIBRES AB INHIBIT NOCICEPTIVE TRANSMISSION. IT IS ONLYWHEN THE STIMULUS IS STRONG THAT THE NOCICEPTOR C FIBRES LOWER THEEFFICACY OF THIS INHIBITORY CONTROL. ACCORDING TO THE THEORY, LAMINAII INHIBITORY INTERNEURONS CAN BE ACTIVATED DIRECTLY OR INDIRECTLY(VIA EXCITATORY INTERNEURONS) BY STIMULATION OF NON-NOXIOUS LARGESENSORY AFFERENTS FROM THE SKIN THAT WOULD THEN BLOCK THEPROJECTION NEURON AND THEREFORE BLOCK THE PAIN. THUS RUBBING APAINFUL AREA RELIEVES THE PAIN.

INHIBITION

Transmission of nociceptive input in the spinal cord can be inhibited by segmental

activity in the cord itself, as well as descending neural activity from supraspinal centers.

Segmental Inhibition

Inhibisi Segmental

Aktivasi dari serat afferent yang besar akan menghambat neuron WDR dan aktivitas

jaras spinotalamikus. Selain itu, aktivasi rangsangan berbahaya di bagian noncontiguous

tubuh menghambat neuron WDR pada tingkat lain, yaitu, sakit pada satu bagian tubuh

menghambat rasa sakit di bagian lain. Terdapat gate theory untuk proses modulasi nyeri

di sumsum tulang belakang. Teori ini menyatakan bahwa nyeri adalah hasil dari balans

antara informasi yang menuju medulla spinalis melalui serat otot besar dengan yang

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melalui serat otot yang kecil. Apabila jumlah relative dari stimulus pada serat saraf besar

lebih besar, maka tidak akan terasa nyeri, dan sebaliknya.

Glycine-aminobutyric acid (GABA) adalah asam amino yang berfungsi sebagai

neurotransmitter penghambat. GABA memiliki peranan penting dalam inhibisi rangsangan

nyeri di tingkat segmental, yaitu di sumsum tulang belakang. Terdapat dua subtype darireseptor GABA, yaitu reseptor GABA A dan GABA B. Inhibisi segmental dimediasi oleh aktivitas

reseptor GABA B, yang meningkatkan konduktansi K + melewati membrane sel. Reseptor

GABAA berfungsi sebagai channel Cl - yang meningkatkan konduktansi Cl - melewati

membrane sel. Benzodiazepin dan aktivasi reseptor glisin juga meningkatkan konduktansi

Cl- melewati membrane sel neuron.

are amino acids that function as inhibitory neurotransmitters. They likely play an important

role in segmental inhibition of pain in the spinal cord. Antagonism of glycine and GABA

results in powerful facilitation of WDR neurons and produces allodynia and hyperesthesia.

There are two subtypes of GABA receptors: GABA A, of which muscimol is an agonist, andGABAB, of which baclofen is an agonist. Segmental inhibition appears to be mediated by

GABAB receptor activity, which increases K + conductance across the cell membrane. The

GABAA receptor functions as a Cl channel, which increases Cl conductance across the cell

membrane. Benzodiazepines potentiate this action. Activation of glycine receptors also

increases Cl conductance across neuronal cell membranes. Strychnine and tetanus toxoid

are glycine receptor antagonists. The action of glycine is more complex than GABA, because

the former also has a facilitatory (excitatory) effect on the NMDA receptor.

Adenosine also modulates nociceptive activity in the dorsal horn. At least two

receptors are known: A 1 , which inhibits adenylcyclase, and A 2 , which stimulates

adenylcyclase. The A 1 receptor mediates adenosine's antinociceptive action.

Methylxanthines can reverse this effect through phosphodiesterase inhibition.

Inhibisi Supraspinal

Beberapa struktur supraspinal mengirimkan serat-serat ke sumsum tulang belakang untuk

menginhibisi nyeri di dorsal horn. Lokasi penting tempat bermulanya serat-serat yang turun

ke medulla spinalis adalah area abu-abu periaquadectal, formatio retikula, dan nucleus

raphe magnus (NRM). Stimulasi dari area abu-abu periaquadectal di midbrain menghasilkan

efek analgesia yang meluas pada manusia. Akson dari jaras ini bekerja pada afferentneuron primer di presinapsnya dan pada postsinaps bekerja di second-order neurons (atau

interneurons). Mekanisme antinosiseptik ini dimediasi melalui mekanisme reseptor 2adrenergik, serotonergik, dan opiate. Peranan monoamine dalam menginhibisi nyeri dapat

menjelaskan efek analgesi dari antidepresan yang memblok reuptake dari katekolamin dan

serotonin. Aktivitas dari reseptor ini mengaktivasi intraselular messenger sekunder,

membuka gerbang K + dan menginhibisi peningkatan konsentrasi kalsium intraseluler.

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Jalur inhibisi adrenergic berasal dari area abu-abu periaqueductal dan formatio

retikula. Norepineprin memperantarai aksi ini dengan mengaktivasi reseptor 2 adrenergik.

Setidaknya sebagian dari inhibisi descenden dari periaqueductal dikirim ke NRM dan

formation retikula medulla spinalis, kemudian ke serat serotonergik yang mengirimkan

inhibisi ke neuron di kornu dorsalis lewat funikulus dorsolateral.

Sistem opiate endogen (NRM dan formation retikularis) beraksi melalui methionine

enkephalin, leucine enkephalin, dan endorphin. Opioid ini bekerja di presinaps dan

menyebabkan hiperpolarisasi neuron aferen primer dan menginhibisi pelepasan subtansi P.

Sebaliknya, opioid eksogen lebih banyak bekerja di postsinap yaitu pada second order

neuron atau interneuron di substansia gelatinosa.