pain physiology 2015

PAIN PHYSIOLOGY FIFTEEN APRILA FAJRIN

BAG FKK-FFUJ

Learning Object???

DeniBon Nociceptor Nerves types Pain types Allodynia vs Hyperalgesia Pain pathway

Pain DeniBon?

An unpleasant sensory and emoBonal experience associated with actual or potenBal Bssue damage or described in terms of such damage

(The InternaBonal AssociaBon for the Study of Pain/IASP)

Why Pain is Important? Pain protects humans by warning of

occurrence of biologically harmful processes

Pain can interfere with daily funcBoning of a person when it prevents people from performing their social roles, vocaBonal roles, and impacts their psychological well-being.

Noxious SBmulus?

Pain causing Chemical Mechanical Thermal

Heat (>42 oC) Cold (

Nociceptor Pain detecBng

Found throughout the body NOCICEPTION the detecBon of Bssue damage by

specialised transducers a^ached to nociceptor (A delta and C bres)

Nociceptor Nociceptors are unspecialized, free, unmyelinated nerve endings that

convert (transduce) a variety of sBmuli into nerve impulses, which the brain interprets to produce the sensaBon of pain.

Dierent types of nociceptors have been idenBed that respond to dierent causes

A-delta dan C

14 Nilesh B. Patel

and (2) larger diameter, lightly myelinated nerves that conduct nerve impulses faster (20 m/sec = 72 km/h) termed A fi bers. Th e C-fi ber nociceptors respond poly-modally to thermal, mechanical, and chemical stimuli; and the A-fi ber nociceptors are of two types and re-spond to mechanical and mechanothermal stimuli. It is well known that the sensation of pain is made up of two categoriesan initial fast, sharp (epicritic) pain and a later slow, dull, long lasting (protopathic) pain. Th is pattern is explained by the di erence in the speed of propagation of nerve impulses in the two nerve fi ber types described above. Th e neuronal impulses in fast-conducting A-fi ber nociceptors produce the sensation of the sharp, fast pain, while the slower C-fi ber nocicep-tors produce the sensation of the delayed, dull pain.

Peripheral activation of the nociceptors (trans-duction) is modulated by a number of chemical sub-stances, which are produced or released when there is cellular damage (Table 1). Th ese mediators infl uence the degree of nerve activity and, hence, the intensity of the pain sensation. Repeated stimulation typically causes sensitization of peripheral nerve fi bers, causing lower-ing of pain thresholds and spontaneous pain, a mecha-nism that can be experienced as cutaneous hypersensi-tivity, e.g., in skin areas with sunburn.

Hypersensitivity may be diagnosed by taking history and by careful examination. Certain conditions may be discriminated:

a) Allodynia: Pain due to a stimulus that does not normally provoke pain, e.g., pain caused by a T-shirt in patients with postherpetic neuralgia.

b) Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked. (Note: a dysesthesia should always be unpleasant, while paresthesia should not be unpleasant; e.g., in patients with diabetic poly-neuropathy or vitamin B1 defi ciency.)

c) Hyperalgesia: An increased response to a stimu-lus that is normally painful. (Note: hyperalgesia refl ects increased pain on suprathreshold stimulation; e.g., in patients with neuropathies as a consequence of pertur-bation of the nociceptive system with peripheral and/or central sensitization.)

d) Hyperesthesia: Increased sensitivity to stimula-tion, excluding the special senses, e.g., increased cuta-neous sensibility to thermal sensation without pain.

With the knowledge of pain pathways and sen-sitization mechanisms, therapeutic strategies to inter-act specifi cally with the pain generation mechanisms can be developed.

Central pain pathwaysTh e spinothalamic pathway and the trigeminal pathway are the major nerve routes for the transmission of pain and normal temperature information from the body and face to the brain. Visceral organs have only C-fi ber noci-ceptive nerves, and thus there is no refl ex action due to visceral organ pain.

Th e spinothalamic pathwayThe nerve fibers from the dorsal root ganglia en-ter the spinal cord through the dorsal root and send branches 12 segments up and down the spinal cord

In addition, local release of chemicals such substance P causes vasodilation and swelling as well as release of histamine from the mast cells, further in-creasing vasodilation. Th is complex chemical signaling protects the injured area by producing behaviors that keep that area away from mechanical or other stimuli. Promotion of healing and protection against infection are aided by the increased blood fl ow and infl ammation (the protective function of pain).

Fig. 1. Some chemicals released by tissue damage that stimulates nociceptors. In addition release of substance-P, along with hista-mine, produce vasodilation and swelling.

SkinReleased bytissue damage:BradykininK+Prostaglandins

Histamine

C fibersA fibers

To spinal cordInjury

MastCell

Table 1Selected chemical substances released with stimuli

su cient to cause tissue damageSubstance Source

Potassium Damaged cellsSerotonin PlateletsBradykinin PlasmaHistamine Mast cellsProstaglandins Damaged cellsLeukotrienes Damaged cellsSubstance P Primary nerve a erents

Nerve Types Aerent (sensory)

A Beta sensory, large diameter with myelin (30-50 m/s Fastest)

A Delta pain bers, smaller with less myelin (5-25

m/s)

C pain, smallest, non myelinated (

Allodynia vs Hyperalgesia

Allodynia pain due to a sBmulus that does not normally provoke pain

Hyperalgesia An increased response to a sBmulus that is normally painful.

Intensity

The intensity of pain oers perhaps the least desirable system for classifying pain, because intensity varies for most paBents over Bme and is uniquely subjecBve.

A paBent might rate the experience of pain resulBng from some pathologic condiBon as a 10,

whereas another paBent with the same pathology might describe the intensity of pain only as a 5, both using a 0 to 10 scale (with 0 signifying no

pain at all and 10 represenBng the worse pain imaginable)

Pain CHART

Remember???

Cell body (in ganglion) nucleus Dendrites

axon

Dendrite

Body

Synapse

PAIN Acute

Chronic

Acute and Chronic Pain CharacterisBc

Karakteris)k Nyeri akut Nyeri kronik

Lama Singkat (maksimal 1 bulan)

Hingga 6 bulan/>

Peredaan nyeri Sangat diinginkan Sangat diinginkan

Ketergantungan thd obat

Tidak biasa sering

Komponen psikologis

Umumnya Bdak ada

Sering merupakan masalah utama

Kontribusi lingkungan dan keluarga

Kecil signikan

Insomnia Jarang sering

Tujuan pengobatan Kesembuhan fungsionalisasi

Acute vs Chronic Pain???

First pain: carried in A-delta bers, larger diameter bers contain myelin, reex to get o source, goes

to cogniBve level (more discrete - very localized)

Second Pain: carried in C bers, smaller diameter, non myelinated, slower. (less discrete - more

diuse)

Acute A-delta and C bers Chronic C bers

PAIN NocicepBve

Inammatory

NeurophaBc

NocicepBve Pain This nocicepBve pain system is a key early warning device,

an alarm system that announces the presence of a potenBally damaging sBmulus.

This nociceptive pain system is a key early warningdevice, an alarm system that announces the presence of apotentially damaging stimulus. Nociceptive pain must becontrolled only under specific clinical situations, such asduring surgery or medical procedures that damage tissueand after trauma. It is important that this system not bechronically disabled, because loss of its protective functioninevitably leads to tissue damage, including self-inducedmutilation of the tongue and lips, destruction of joints, lossof the tips of fingers, and pressure ulcers. Nociceptive pain

is therefore a vital physiologic sensation. Lack of it in pa-tients with congenital insensitivity to pain due to a muta-tion of the nerve growth factor tyrosine kinase A receptor,which results in a loss of high-threshold sensory neurons,reduces life expectancy (6).

If tissue damage occurs despite the nociceptive defen-sive system (for example, through trauma, surgery, or in-flammatory diseases), the bodys imperative shifts fromprotecting against noxious, potentially damaging stimuli topromoting healing of the injured tissue. Inflammatory pain

Figure 1. The 4 primary types of pain.

Review The Possibility of Mechanism-Specific Pharmacologic Management of Pain

442 16 March 2004 Annals of Internal Medicine Volume 140 Number 6 www.annals.org

Inammatory Pain In this state, sensiBvity is increased such that sBmuli to the

aected part that would normally not cause pain now do so. As a result, we prevent contact with or movement of the injured

part unBl repair is complete, minimizing further damage. Inammatory pain typically decreases as the damage and inammatory response resolve







Neuropathic Pain Neuropathic pain may result from lesions to the peripheral

nervous system, as in paBents with diabeBc or AIDS polyneuropathy, post-herpeBc neuralgia, or lumbar radiculopathy, or to the central nervous system, such as in paBents with spinal cord injury, mulBple sclerosis, or stroke







General Mechanism of Pain

NOCICEPTION TransducBon Transmission ModulaBon PercepBon

NocicepBon-TransducBon

- the conversion of a noxious sBmulus into electrical acBvity in the peripheral terminals of nociceptor sensory bers.

- Mediated by specic receptor ion channels expressed only by nociceptors

- Noxious sBmulus converted into Ca2+ mediated electrical depolarizaBon

Nociceptor AcBvators

can be the target of treatment (4), we must develop bothdiagnostic tools to identify these mechanisms as well asmechanism-specific pharmacologic agents.

NociceptionNociception, the perception of noxious stimuli, is ini-

tiated by stimuli that activate the peripheral terminals ofnociceptors, a highly specialized subset of primary sensory

neurons that respond only to intense stimuli. Nociceptorshave unmyelinated (C-fiber) or thinly myelinated (A!-fiber) axons (16). The receptive properties of these sensoryneurons are determined by their expression of transducingion-channel receptors, which have a high threshold of ac-tivation to external stimuli (2). Many (but not all) of thesetransducers have been identified, including those that cause

Figure 2. Contributions of primary sensory neurons to pain.

A. The peripheral terminal of a nociceptor sensory neuron. The different transducing receptor and ion channels that respond to thermal, mechanical, andchemical stimuli are shown. B. The mechanism of peripheral sensitization. Inflammatory mediators, such as prostaglandin E2 (PGE2), bradykinin (BK), and nervegrowth factor (NGF), activate intracellular kinases in the peripheral terminal that phosphorylate transducer channels to reduce their threshold or sodium channelsto increase excitability. C. Transcriptional changes in the dorsal root ganglion. Activity, growth factors, and inflammatory mediators act on sensory neurons toactivate intracellular transduction cascades. These cascades control the transcription factors that modulate gene expression, leading to changes in the levels ofreceptors, ion channels, and other functional proteins. AA ! archidonic acid; ASIC ! acid-sensing ion channel; ATP! adenosine triphosphate; CaMKIV !camkinase IV; COX-2! cyclooxygenase-2; ERK ! extracellular signal-regulated kinase; EP ! prostaglandin E receptor; JNK ! jun kinase; mRNA!messenger RNA; PKA ! protein kinase A; PKC ! protein kinase C; TRP ! transient receptor potential receptor.



Nociceptor AcBvators

TRP transient receptor potential

NocicepBon-Transmission

- The passage of acBon potenBals from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system

- The synapBc transfer - Release of

neurotransmi^er-induced pain Glutamate, substance P

NocicepBon-ModulaBon

Balancing between exitatory mediators and the inhibitory eect of endogenous analgesics

Adjust K inux and Na eux Endogenous analgesics,

including enkephalin (ENK), norepinephrine (NE), and -aminobutyric acid (GABA), acBvate opioid, alpha adrenergic, and other receptors that either inhibit release of Glu

NocicepBon-PercepBon

the conversion of a noxious thermal, mechanical, or chemical sBmulus

into electrical acBvity in the peripheral terminals of nociceptor

sensory bers

A-delta ber C ber

Spinal cord

Brain

Response aduhhh tarik tangan

Drug target for Pain

-To be continued guys-