Neural mechanism of pain MEDI 6100 Fremantle Broome
Neural mechanism of pain MEDI 6100 Fremantle Broome Sydney 1
Prof Eric Visser Dr Natalie Morellini Post-doctoral pain research fellow 2
Student learning outcomes o Describe 'pain pathways' in depth o Outline central nervous system [CNS] control over pain perception o See learning suggestions at the end of this slide show o Main reference to read Schug SA, et al. APM: SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2015), Acute Pain Management: Scientific Evidence (4 th edn) ANZCA & FPM, Melbourne, pages 1 -7 o http: //fpm. anzca. edu. au/documents/apmse 4_2015_final 3
What is pain? o ‘Pain is an unpleasant sensory & emotional experience associated with actual or potential tissue damage’ (IASP 2012) o Pain is generated by the conscious brain in response to perceived tissue damage o Pain is more than just a sensation o Pain is a subjective, multidimensional, whole-person experience o Pain is what the person-in-pain says it is o Pain always occurs in a ‘context’ -bio-medical-psycho-social-environmental EJ Visser Churack Chair UNDA 2017 copyright 4
Nociception o ‘The process of encoding & transmitting noxious stimuli in the nervous system’ (IASP 2012) o Converting the ‘energy’ released by tissue damage into electro-chemical signals in the nervous system -chemical (‘inflammatory soup’) -mechanical -thermal o Pain & nociception are not the same thing o Nociception is the sensory processing ‘bit’ (a brain input) o Pain is the sensory & emotional experience (a brain output) o Nociception is the (main) trigger & driver of pain o CAN have pain without nociception & vice versa 5
Pain is nature’s tissue-damage ‘alarm’
Pain alarm o Pain motivates us to avoid tissue damage in real time o Acute stress response o Pain behaviours
Pain pathways Rene Descartes
Nociceptive (pain) pathways Limbic system Brainstem Dorsal horn http: //ars. els-cdn. com/content/image/1 -s 2. 0 -S 1877117315000046 -f 01 -01 -9780128013892. jpg
Peripheral nociception http: //stahlonline. cambridge. org/content/ep 4/images/02598 fig 10_1. png EJ Visser Churack Chair UNDA 2017 copyright 10
Inflammation Galen & Celsus o Dolor (pain) o Calor (heat) o Rubor (redness) o Tumor (swelling) o Functio laesa (loss of function)
Inflammatory soup Visser UNDA pain 2017 12
Nociceptors transduction Converting the (chemical, thermal, mechanical) energy of tissue damage into electro-chemical nerve signals Heat Acid (H+) TRPV 1 DRG Cold TRPV 8 Mechanical
TRPV 1 transduction
A & C fibres transmission o o o A fibres Thick Myelinated Fast Localised ‘Sharp’ pain o o o C fibres Thin Unmyelinated Slow Poorly localised Dull, aching or burning pain http: //stahlonline. cambridge. org/content/ep 4/images/02598 fig 10_1. png EJ Visser Churack Chair UNDA 2017 copyright 15
Voltage-gated Na+ channels transmission o Local anaesthetics o Anticonvulsants o Neuroma ectopics E Visser Churack Chair UNDA 2016 16
Na+ channels polymorphisms o SCN 9 A gene o Nav 1. 7 o Erythromelalgia o Congenital insensitivity to pain E Visser Churack Chair UNDA 2016 17
Dorsal horn modulation The ‘CPU’ of nociceptive system
Dorsal horn
Dorsal horn first-order synapse Nuclear changes
Glutamate o Most abundant neurotransmitter in body (90%) o Excitatory (neurotoxic in high amounts) o Amplification o Sensitization o Learning o Memory o Wind-up o Long term potentiation o Glia mops up glutamate
NMDA channel It’s the nervous system’s ‘chemical transistor’ (amplifier) o Mediates central sensitization -’wind-up’ -memory (hippocampus) o Glutamate is the agonist o Blocked by ketamine VISSER MED 200 UNDA PAIN PHARMACOLOGY 2016 22
Central sensitization amplifier Increased nociceptive output for a given nociceptive input Capacitance effect ‘memory’ Amplifier effect NMDA 1 1 1 1 3 Hz Wind-up lllllllllll 50 Hz Dorsal horn VISSER MED 200 UNDA PAIN PHARMACOLOGY 2016 23
Wind-up amplifier effect IIIIIIIIIIIIIIIIIIIIIIIIII Stimulus 3 Hz
Allodynia ‘touch pain’ Greek for ‘other pain’ Allodynia is the clinical sign for central sensitization If any of these non-painful stimuli feels painful, you have detected allodynia…. . . and therefore central sensitization
Pain inhibition ‘flight or fight’ E VISSER CHURACK CHAIR UNDA 2016 26
Conditioned pain modulation o Descending inhibition of nociception o Flight (or fight) o Neuroplasticity o Inhibitory transmitters -norepinephrine -serotonin -endorphins o CPM allows us to escape danger o CPM allows us to sit on our bottoms -45 kg/cm 2 pressure VISSER MED 200 UNDA PAIN PHARMACOLOGY 2016 27
Pain gate in dorsal horn
Biphasic pain response Analgesia: allows ‘flight’ from danger Tissue damage Hyperalgesia Analgesia Hyperalgesia -rests injured body part (healing) -teaches ‘caveman’ not to get injured again EJ Visser Churack Chair UNDA 2017 copyright Simonnet & Rivat Neuroreport 2003 29
Nociceptive (pain) modulation Pain Inhibitory Control “Damping” Central Sensitization “Amplifier” EJ Visser Churack Chair UNDA 2017 copyright 30
Red heads & pain • MCR 1 receptor gene (RR) (CS 16) • MSH receptor polymorphism • Less pricking & pressure pain • More cold sensitive • More sensitive to morphine • Less sensitive to GA, LA E Visser Churack Chair UNDA 2016 31
Nociceptive (pain) pathways Descending inhibition DRG NE Aδ & C fibres transduction tissue damage TRPV channels Inflammatory soup transmission Dorsal horn Central sensitization ‘amplification’ modulation voltage gated Na ion channels Visser UNDA pain 2017 copyright 32
Spinal cord pathways © Future Neurol 2007 Thalamocortical system Limbic system Primitive emotional brain Spinal-midbrain-limbic pathway o midline tract o slower transmission o poorly localised pain o visceral > somatic pain o evolution: primitive © Eric J. Visser 2017 UNDA. All rights reserved Spinothalamic pathway o lateral tract o fast transmission o well localised pain o somatic > visceral pain o evolution: ‘newer’ 33
Descending inhibition NE © Eric J. Visser 2017 UNDA. All rights reserved 34
The bane of pain is mainly in the brain Loesser E VISSER CHURACK CHAIR UNDA 2015 35
Pain in the brain ‘matrix’ 22 loci Somatosensory cortex Pre frontal cortex Amygdala RAS EJ Visser Churack Chair UNDA 2017 copyright 36
Emotional & autonomic response Pain ‘relay station’ Autonomic Cingulate gyrus Fear & anxiety panic Memory of pain © Eric J. Visser 2017 UNDA. All rights reserved 37
Somatosensory cortex localization Sensory homunculus (body-map) © Eric J. Visser 2017 UNDA. All rights reserved 38
Questions? 39
Learning suggestions o Know the definitions of pain & nociception o Understand differences between them o Appreciate that pain is a complex, multi-dimensional experience generated by the conscious brain, and not just a sensation o Understand that pain is a tissue damage ‘alarm’ system o Know that a person can experience pain when there’s NO tissue damage o Understand the basic anatomy of nociceptive (‘pain’) pathways o Understand the transduction, transmission & modulation of nociceptive signals in the nervous system 40
Learning suggestions o Understand the concept of the ‘pain gate’ in the dorsal horn o Understand the concept of neuroplasticity & its role in pain o Understand that central sensitization ‘amplifies’ nociception o Understand that conditioned pain modulation ‘dampens’ nociception o Understand the concept of pain ‘wind-up’ o Know that allodynia (touch pain) is the main clinical sign of CS o Understand that nociception activates the (emotional) limbic system o Understand that there is no specific ‘pain centre’ in the brain o Understand the roles of the neuroimmune (glia) & adrenergic systems in nociception & pain Visser MED 200 UNDA pain pharmacology 2016 41
Glia and nociception • Glia are non-neuronal cells in the central (CNS) and peripheral (PNS) nervous systems, that maintain homeostasis, form myelin, and provide support and protection for neurons. • Glia in PNS • Schwann cells- nerve • Satellite cells-DRG • Glia in CNS • • * Activated after PNS injury Astrocytes- involved in “normal” nociception Microglia Oligodendrocytes Ependymal cells • Glia can be activated by; • • Peripheral nerve injury Trauma- physical or psychological Hypoxia Infection Gosselin et al. , (2010) Neuroscientist. 16(5): 519– 531
Immune and glial response after nerve injury Schwann cells Transient activation Satellite cells Resident Microglia and Astrocytes Promotes healing Limits injury Active Microglia and Astrocytes Pro-inflammatory events Chronic activation Neuronal death Chronic pain Scholz and Woolf (2007) Nature Neuroscience 10: 11; 1361
Neuroinflammation • Neuroinflammation is defined as inflammation of a nerve or parts of the nervous system (CNS and PNS) Pro-inflammatory mediators • Caused by activation of glia and infiltration of immune cells • Can modulate excitatory and inhibitory synaptic transmission leading to enhanced chronic pain Chronic pain
Adrenergic receptors • G-protein coupled receptors • Bind catecholamines- e. g. adrenaline, noradrenaline • Several types- beta and alpha expressed throughout body • Alpha- 1 and 2 expressed in neurons and implicated in nociception and pain • Alpha-2 agonists are used to treat pain – inhibit release of noradrenaline • Alpha-1 receptors expressed in keratinocytes, nerve fibres and blood vessels of skin- implicated in maintenance of chronic pain Noradrenaline
Alpha 1 -adrenergic receptors and neuropathic pain Peripheral nerve injury Activation of sympathetic nervous system Up-regulation of alpha 1 -adrenoceptors on nociceptive nerves and keratinocytes Heightened nociceptor excitability and inflammation Functional changes in sympathetic activity Release of inflammatory mediators from keratinocytes Breaching of blood-nerve barrier permits alpha 1 - adrenoceptor activation on nociceptive afferents
Nociception vs pain explained in a movie Terminator II-Judgment Day (1991) John Connor “Does it hurt when you get shot? ” The Terminator “I sense injuries… The data could be called pain. ” EJ Visser Churack Chair UNDA 2017 copyright 47
Extra slides and information 48
Acute pain o Pain of recent onset & limited duration (<3 M) o Clear relationship to injury or disease o Physiological pain o Nociceptive, inflammatory o Protective & adaptive o Pain ≈ amount of tissue damage o Pain improves with healing EJ Visser Churack Chair UNDA 2017 copyright 49
Pain is nature’s tissue damage alarm o Acute pain signals a ‘tissue damage emergency’ o Unpleasant sensory & emotion experience -aversive conditioning (learning) o Pain behaviours -escape -signals risk of tissue damage to others o Pain (nociception) has protected Earth’s life-forms for millions of years o Evolutionary survival advantage o Highly preserved in phylogeny
Pain alarm o Pain conditions us (and others in our social group) to avoid future tissue damage o Learn from our mistakes o Especially in childhood o Nocebo response
Fear (anxiety) is also an alarm o Pain ≈ fear (anxiety) o Both protect tissues from damage o Shared facial expressions & behaviours o Shared neurochemistry -serotonin, nor-epinephrine o Shared neuroanatomy & function o Anxiety = chronic pain & disability -catastrophizing, hypervigilance -3 Ps: panic, PTSD, phobias EJ Visser Churack Chair UNDA 2017 copyright 52
Pain behaviours EJ Visser Churack Chair UNDA 2017 53
Pain behaviours o Signals ‘distress’ o Defensive: fight & flight, feign & freeze (play-dead) o Protective: splinting, limping, rubbing o Adaptive: crawl to cave, call an ambulance o Social signalling: facial expressions, crying, swearing o ‘I need help’, ‘stay away from danger’ EJ Visser Churack Chair UNDA 2017 copyright 54
Pain pathways Rene Descartes "Particles of heat activate a spot of skin attached by a fine thread to a valve in the brain… this opens the valve allowing animal spirits to flow from a cavity into the muscles causing them to flinch, and turn the head and eyes toward the affected body part, also moving the hand turn the body protectively. ”
https: //previews. 123 rf. com/images/hfsimaging 1411/hfsimaging 141100007/33426526 -Noxious-and-pain-receptors-inskin-and-the-nerve-pathways-to-the-brain-via-the-spinal-cord-and-thala-Stock-Vector. jpg
Afferent & efferent pathways o Afferents Arrive o Carry CNS inputs o Efferents Exit o Carry CNS outputs © ERIC J. VISSER 2017 UNDA. ALL RIGHTS RESERVED 57
Pain gate dorsal horn
Comparing visceral & somatic pain Visceral pain Somatic pain Few nociceptors (15%) Many nociceptors (75%) C-fibres A-δ fibres Function: homeostasis > nociception Function: nociception > homeostasis Transmission with autonomic nerves Transmission in somatic nerves Terminates in superficial dorsal horn (I, II, V) Terminates in deeper dorsal horn (II, V, X) Medial (slow) spinal cord pathways Lateral (fast) spinal cord pathway Spino-parabrachial-limbic, dorsal columns Spinothalamic Terminates in limbic brain Termination in thalamus & cortex ‘Primitive’ mid-brain Limbic-hypothalamic-autonomic system Pain: slow onset & offset Pain ≠ tissue damage burning, aching, gripping, colicky © Eric J. Visser 2017 UNDA. All rights reserved Neocortex Pain: fast onset & offset Pain ≈ tissue damage sharp, throbbing 59
Comparing visceral & somatic pain Visceral pain Somatic pain Pain is poorly localised (midline, torso) Pain is well localised (‘lateralized’) Referred pain Minimal referred pain ↑ Emotion & pain behaviour (distress) ↓ Emotion & pain behaviour Pain more likely to be remembered Pain less likely to be remembered ↑ Autonomic response ↓ Autonomic response ‘Vegetative’ motor response ‘Reactive’ motor response Localised with flat of hand (Limbic system) Sympathetic & parasympathetic ‘Rest & recover’ (rest & digest) Localised with tip of finger Flight, run away from danger Evolutionary primitive pain system Evolutionary advanced pain system Monitors internal environment Monitors external environment © Eric J. Visser 2017 UNDA. All rights reserved 60
Referred pain Definition: Pain experienced in a different part of the body to the site of nociception o Sensory afferents from viscera & somatic tissues share a common connection in spinal dorsal horn o Dorsal horn convergence © Eric J. Visser 2017 UNDA. All rights reserved 61
Dorsal horn convergence T 2/3 dorsal horn level T 2/3 dermatome © Eric J. Visser 2017 UNDA. All rights reserved 62
Immune modulation of nociception in the nervous system Interleukin 1, 6, TNF Toll-like receptor 4
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