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

Somatosensory cortex localization Sensory homunculus (body-map) © Eric J. Visser 2017 UNDA. All rights

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

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.

Immune modulation of nociception in the nervous system Interleukin 1, 6, TNF Toll-like receptor 4