Neurobiology of Pain

Transcription

1 Neurobiology of Pain What the Ratologists have taught me!!!! Dr Diarmuid McCoy MB BCh BAO (NUI) FFARCSI FFPMANZCA FANZCA FFPMCAI Specialist Pain Medicine Physician The Geelong Hospital Barwon Health Pain Matrix HealthScope Geelong Private Hospital

2 Pain Sensory and Emotion Experience Actual /Potential Tissue Damage

3 PAIN Subjective response to nociceptive input to brain Components Motivational-Affective: Emotional Sensory-Discriminative Nociception Awareness of the stimulation of nociceptors by a noxious stimulus

4 Pain is Sensory-discriminative dimension Intensity location quality behavior Cognitive Evaluative dimension Anticipation attention and influence of previous experience Motivational-affective dimension Fear anxiety

5 Nociception is not Pain Nociception refers to a neural process of encoding and processing noxious stimuli Loeser /Treede 2008 Pain is not a stimulus it is the final product of a complex information processing network (Pain Updated review 2008)

6 Complex regional Pain Syndrome Type 1 and 2 RSD Causalgia Chronic pain syndrome Somatoform type pain Pain patient

7 What is a Nociceptor? A number of receptors/channels that sense damage VR1 vanilloid receptor family - capsaicin/atp ASICs - respond to low ph/mechanical? P2X receptors - respond to ATP Chemical sensors - prostaglandins, 5HT, Bk etc - peripheral sensitization & inflammation

8 Nociception is not Pain Nociception refers to a neural process of encoding and processing noxious stimuli Loeser /Treede 2008 Pain is not a stimulus it is the final product of a complex information processing network (Pain Updated review 2008)

9 Perceptual categories Pricking (First pain) Quality: Sharp Temporal: Initial pain sensation; Brief PNS axons: Aδ fibers CNS pathway: Somatosensory to thalamus & cortex Burning (Second pain) Qualities: Dull; Aching; Unpleasant Temporal: Later, more long-lasting pain sensation PNS axons: C fibers CNS: Reticular formation; Periaqueductal gray; Hypothalamus; Central thalamus

10 Transduction Mechanical (pinch) Thermal (heat) Chemical (acid/ sting) Electrical Mechanical nociceptors (high threshold stimuli activate) Polymodal nociceptive neurones

11 Temporal Acute Definition Understanding Chronic (persistent) Definition Understanding Not the duration that is important but rather the inability of the body to restore the homeostatic function

12 INFLAMMATION/NOCICEPTIVE Peripheral Sensitization Central Sensitization Damaged Zone ALLODYNIA HYPERALGESIA Sensitization and activation COX1 - COX2 BK2 - BK1 PGs, H+ ATP NGF C-fibre CNS blood vessel 5HT BK SP, CGRP Vasodilation+plasma extravasation Transmitter release - neuronal excitability

13 Inflammatory Soup Threshold of the Aσ& C fibres is lowered Increased receptive field Activation of silent receptors Spontaneous activity of peripheral nociceptors

14 Vanilla flavour TRP family V1-V5 Na and Calcium channels Temperature specific TRP menthol cool temperatures Clinical correlation Familial episodic pain syndromes ppt cold fatigue fasting HR and Resp diff

15 Mechanical version Degenerin / epithelial Na channel ASIC 1-3? Not as clearly defined as TRP Na v 1.7/1.8/1.9 Voltage gated sodium channels TTX (1.7)sensitive identified as having a role in erythromelalgia TTX 1.8 redistributed along axons in peripheral nerve injuries TTX 1.9 decreased in these

16 Calcium channels Voltage gated calcium channels Types N type and T type Casade of events Release of SP CGRP glutamate (N type) Blocked by conotoxin T type close proximity to NMDA receptor and NK1

17 INFLAMMATION/NOCICEPTIVE Peripheral Sensitization Central Sensitization Damaged Zone ALLODYNIA HYPERALGESIA Sensitization and activation COX1 - COX2 BK2 - BK1 PGs, H+ ATP NGF C-fibre CNS blood vessel 5HT BK SP, CGRP Vasodilation+plasma extravasation Transmitter release - neuronal excitability

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19 Multiple mediators at the site of injury J Pain 2000;1:344.

20 Peripheral Sensitization Skin 6h 12h Mast cell Macrophage IL1b, IL6 TNFa Tissue damage TRPV1 H + Ca 2+ PG PKC PGS EP/IP Cox-2 AA COX-2 Sensitive PKA (SNS/SNS2) Primary sensory neuron peripheral terminal There are both prostanoid and non-prostanoid sensitizers

21 Tissue damage Hyperalgesia Spontaneous pain Allodynia PERIPHERAL ACTIVITY CENTRAL SENSITIZATION Nerve damage Decreased threshold to peripheral stimuli Expansion of receptive field Increased spontaneous activity

22 Pain Intensity Pain Sensitization 10 Hyperalgesia 8 Injury Normal Pain Response 6 Allodynia 4 2 Stimulus Intensity Gottschalk and Smith. Am Fam Physician

23 Nociceptive primary afferents terminate in the dorsal horn Project on to second order neurons Nociceptive specific Wide Dynamic range (WDR)

24 SENSATIONS peripheral endings dorsal root ganlgia SP & CGRP I IIo IIi III low intensity non-noxious stimuli high intensity noxious stimuli heavily myelinated fast conducting thinly myelinated intermediate conducting unmyelinated slow conducting Ab A C VII WDR IV V VI X INPUTS REFLEXES VIII IX

25 Ascending Tracts Spinothalamic Spinomesencephalic tract Spinoreticular tract Neospinal thalamic tract Dorsal Columns Pyramidal?

26 Referred Pain Projection convergence theory

27 Neuropathic pain Difficult to explain. Why Difficult to describe.why Difficult to measure Why Difficult to treat Why An injured nerve should not work properly Negative (symptoms/signs) Positive signs Spontaneous pain /allodynia /Hyperpathy

28 Neuropathic Pain Peripheral Central Spinal Brain

29 ATP capsaicin heat COX1 COX2 mechanical? DRG H+ PGs cold warm ATP Na +, K +, Ca 2+ channels VRs ASICs EPs TRPs P2X sensitize, activate C-fibre

30 NEUROPATHY Central Sensitization Nerve Injury Ectopic activity Sympathetic sprouting Neurochemical alterations HYPERALGESIA ALLODYNIA CNS Na + channels Transmitter release Ephaptic transmission

31 Neuropathic Pain Sprouting (neuroma formation) Phenotyic change (Transcriptional change in gene expression) Expansion or creation of receptive field Following transcetion of nerve or cord alteration in somatic map Loss if inhibition Function of GABA ergic inhibition NMDA activation

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33 NMDA activation SP/NKA/Mg plug/ca influx/no increased excitability

34 Activation of Glial cells Neurones: Glial 1:10 Physical support Nutrition Homeostasis Myelin production (Oligodendrocytes) Signal transmission Protection for neurons (remove dead nerve cells /immune ) Microglia astrocytes oligodendrocytes Importance emerging

35 Microglia Immune defence CNS Specialized macrophages Cell extensions are not static but constantly sampling the environment Oligodendrocytes myelin Astrocytes BBB Regulate vasoconstriction

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37 Pain perception: Located in Thalamus & Cortex Psychophysical features Components: Location; Intensity; Character; Duration Location: 1 & 2 somatosensory cortex Affective features Components: Unpleasantness & Rejection Location: Limbic cortex (Cingulate & Insula) Ascending pathway: Dorsal horn; Parabrachial nucleus; Amygdala

38 Monoamines & GABA after Nerve Injury Spinal transmission can also be modulated from supraspinal mechanisms Use a wide range of neurotransmitters Midbrain Brainstem 5-HT 5HT 1 inhibitory 5HT 2 & 3 excitatory Noradrenalin e a 2 -adrenergic Rs inhibitor Spinal cord GABA Tonic inhibition, GABA A

39 S Weir Mitchell April 21, 1864 [The patient] will allow no one to touch his skin with a dry hand, and even then is careful to exact a tender manipulation. He keeps a bottle of water about him and carries a wet sponge in the right hand. This hand he wets always before he handles anything; used dry, it hurts the other limb. At one time, when the suffering was severe, he poured water into his boots % of patients with partial amputations in American Civil War CAUSALGIA

40 ...The part itself is not alone to an intense burning sensation,, but becomes exquisitely hyperaesthetic, so exquisitely hyperaesthetic, so that a touch or tap of the fingers increases the pain. Exposure too increases the pain. Exposure to the air is avoided with a care which seems almost absurd......the seat of burning pain is very various... its intensity very various... its intensity varies from a most trivial burning to a state of torture burning which hardly can be credited but which reacts of the whole economy until the general economy until the general health is seriously affected

41 Complex Regional Pain Syndrome Causalgia CRPS II Reflex Sympathetic dystrophy CRPS I CRPS I classically limb following surgery or injury but may be associated with SCI CVA or AMI CRPS II classically identifiable nerve injury Symptoms of burning pain disproportionate to the inciting event Intense allodynia dynamic static and deep. Autonomic dysfunction Trophic changes Hair nail skin Dystonic movements

42 Classification Neuropathic pain? Pain initiated or caused by a primary lesion or dysfunction in the nervous system Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. No diagnostic criteria (Definite Probable Possible) neuropathic pain OK for CRPS I? CRPS II but it neither have a distinct neuroanatomical distribution

43 Diagnostic Criteria Sensory abnormality Spontaneous pain Mechanical Hyperalgesia Deep somatic hyperalgesia Vascular abnormalities Vasodilation Vasoconstriction Skin temp asymmetry Colour changes Oedema sweating abnomalities Hyper hypohydrosis Motor / trophic changes Weakness Tremor Dystonia Coordination deficits Nail / hair / skin Joint stiffness Soft tissue changes 1 symptom in > 3 category AND 1 sign in 2 categories Sensitivity 0.85 Specificity 0.60

44 Aspects of CRPS Neuropathic pain decrease in small fibre density in affected target area but also in adjecent non target area in comparason with contralateral limb (glabrous and non glabrous) large individual variation Some features suggest an inflammatory aspect eg heat swelling redness? Steroids in the early stage Antioxidents as early as possible Immune Cell mediated: higher level of TNFα and IL6 in blister fluid and increase in Langerhans cells in skin biopsy but no direct coorelation? Infliximab Autoimmune aspect in 30-40% Neurogenic inflammation increase in cgrp in acute stage Increased intensity of axon reflex vasodilatation WELL NAMED

45 Contributory Factors Genetic Injury Rehabilitation Operative Tourniquets Time Approach Acute pain (regional anaesthesia)

46 Paracetamol Treatments NSAIDS:? In early stage to enable mobilisation Opioids: may have a role in some aspects (neuropathic pain) Peripheral administration? TCA: have a role in neuropathic pain no data in CRPS Na Channel blockers: lamotrigine Carbamezepine and GABA Agonists: IT application for dystonia but not extensively studied

47 Treatments Chemical Sympathectomy poor evidence Surgical Sympathectomy

48 Treatments Steroid: High dose tapering rapidly studied in CRPS I following stroke in acute stage Gaba / Pregabalin: mild effect on pain and some significant effect on evoked pain and sensory dysfunction Immune Modulators: two cases with Infliximab Immunoglobulins: 1 case report 50% reduction in pain. In a mixed pain group?70 relief in all major pain groups NMDA antagonist: ketamine as a sole agent minimal effect. With sympathetic blockade relief of allodynia Others agents? Calcitonin: some promising data. Free radical scavengers DMSO or NAC mixed results. Acute vrs Chronic stage SCS What about Paediatrics

49 Pain Sensory and Emotion Experience Actual /Potential Tissue Damage