Neural mechanisms of pain MEDI 6100 Fremantle Broome

Neural mechanisms of pain MEDI 6100 Fremantle Broome Sydney 1

Prof Eric Visser Dr Natalie Morellini © Eric J. Visser 2017 UNDA. All rights

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 © EJ Visser and UNDA 2018 all rights reserved 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 and UNDA 2018 all rights reserved 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 © EJ Visser and UNDA 2018 all rights reserved 5

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. ” Data = nociception © EJ Visser and UNDA 2018 all rights reserved 6

Pain is nature’s tissue-damage ‘alarm’ © EJ VISSER AND UNDA 2018 ALL RIGHTS RESERVED

Pain alarm o Pain motivates us to avoid tissue damage in real time o

Nociceptive (pain) pathways Limbic system Brainstem Dorsal horn Rene Descartes http: //ars. els-cdn. com/content/image/1 -s 2. 0 -S 1877117315000046 -f 01 -01 -9780128013892. jpg

Inflammation Galen & Celsus o Dolor (pain) o Calor (heat) o Rubor (redness) o Tumor (swelling) o Functio laesa (loss of function)

Inflammatory soup © EJ Visser and UNDA 2018 all rights reserved 11

Transduction Converting (chemical, thermal, mechanical) energy of tissue damage into electro-chemical nerve signals Heat Acid (H+) TRPV 1 DRG nociceptors Cold TRPV 8 Aδ C Mechanical © EJ Visser and UNDA 2018 all rights reserved Spinal cord Dorsal horn

TRPV 1 transduction © EJ Visser and UNDA 2018 all rights reserved

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 and UNDA 2018 all rights reserved 14

Voltage-gated Na+ channels transmission o Local anaesthetics o Anticonvulsants o Neuroma ectopics 15

Na+ channels polymorphisms o SCN 9 A gene o Nav 1. 7 o Erythromelalgia

Dorsal horn modulation The ‘CPU’ of nociceptive system © EJ Visser and UNDA 2018

Dorsal horn © EJ Visser and UNDA 2018 all rights reserved

Dorsal horn first-order synapse Nuclear changes © EJ Visser and UNDA 2018 all rights

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 © EJ Visser and UNDA 2018 all rights reserved © ERIC J. VISSER 2017 UNDA. ALL RIGHTS RESERVED 20

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 © EJ Visser and UNDA 2018 all rights reserved 21

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 © EJ Visser and UNDA 2018 all rights reserved © ERIC J. VISSER 2017 UNDA. ALL RIGHTS RESERVED 22

Wind-up amplifier effect IIIIIIIIIIIIIIIIIIIIIIIIII © EJ Visser and UNDA 2018 all rights reserved Stimulus

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 © EJ Visser and UNDA 2018 all rights reserved

Nociceptive (pain) modulation Pain Inhibitory Control “Damping” Central Sensitization “Amplifier” © EJ Visser and

Pain inhibition ‘flight or fight’ © ERIC J. VISSER 2017 UNDA. ALL RIGHTS RESERVED

‘Pain gate’ inhibition in dorsal horn © EJ Visser and UNDA 2018 all rights

‘Pain gate’ dorsal horn

Descending inhibition o Flight (or fight) o Midbrain to dorsal horn 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 © EJ Visser and UNDA 2018 all rights reserved © ERIC J. VISSER 2017 UNDA. ALL RIGHTS RESERVED 29

Descending inhibition NE © EJ Visser and UNDA 2018 all rights reserved 30

Biphasic pain response Analgesia: Allows ‘flight’ from danger Twin Towers DI: NE, endorphins ‘Pain gate’ Hyperalgesia Tissue damage Analgesia Hyperalgesia: Rest injured body part (healing) Conditioning; learn to avoid injury © EJ Visser and UNDA 2018 all rights reserved Simonnet & Rivat Neuroreport 2003 46

Spinal cord nociceptive 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 © EJ Visser and UNDA 2018 all rights reserved Spinothalamic pathway o lateral tract o fast transmission o well localised pain o somatic > visceral pain o evolution: ‘newer’ 32

The bane of pain is mainly in the brain Loesser © EJ Visser and

Pain ‘matrix’ 22 loci There is no pain centre in the brain Somatosensory cortex

Emotional, autonomic, visceral Limbic system Pain ‘relay station’ Autonomic Cingulate gyrus Fear & anxiety

Localization Somatosensory cortex Sensory homunculus (body-map) © EJ Visser and UNDA 2018 all rights

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 © EJ Visser and UNDA 2018 all rights reserved 37

Don’t forget the neuroimmune system! Glia Interleukin 1, 6, TNF Toll-like receptor 4

Key learning objectives 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 © EJ Visser and UNDA 2018 all rights reserved 39

Key learning objectives 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 (CS) ‘amplifies’ nociception o Understand that descending inhibition ‘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 © EJ Visser and UNDA 2018 all rights reserved 40

Questions? © EJ Visser and UNDA 2018 all rights reserved 41

Extra slides and information © EJ Visser and UNDA 2018 all rights reserved 42

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 © EJ Visser and UNDA 2018 all rights reserved

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 © EJ Visser and UNDA 2018 all rights reserved

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. ” © EJ Visser and UNDA 2018 all rights reserved

Peripheral nociception http: //stahlonline. cambridge. org/content/ep 4/images/02598 fig 10_1. png © EJ Visser and

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 47

Dorsal horn convergence T 2/3 dorsal horn level T 2/3 dermatome © Eric J.

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 © EJ Visser and UNDA 2018 all rights reserved Gosselin et al. , (2010) Neuroscientist. 16(5): 519– 531 49

Afferent & efferent pathways o Afferents Arrive o Carry CNS inputs o Efferents Exit

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 © EJ Visser and UNDA 2018 all rights reserved 51

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 © EJ Visser and UNDA 2018 all rights reserved 52

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 Noradrenaline • 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 © EJ Visser and UNDA 2018 all rights reserved 53

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 © EJ Visser and UNDA 2018 all rights reserved 54

Red heads & pain o MCR 1 receptor gene (RR) (CS 16) o MSH receptor polymorphism o Less pricking & pressure pain o More cold sensitive o More sensitive to morphine o Less sensitive to GA, LA 55