Pain 1_2022_Student(1).pptx

Physiology of pain 1 Professor Andrew Dilley What is pain? “It’s an unpleasant sensory experience associated with tissue damage” • Pain is accompanied with an emotional reaction E.g. Negative effect, fear, anxiety Why do we feel pain? What are the sensations of pain? Pain mechanisms The...

Physiology of pain 1 Professor Andrew Dilley What is pain? “It’s an unpleasant sensory experience associated with tissue damage” • Pain is accompanied with an emotional reaction E.g. Negative effect, fear, anxiety Why do we feel pain? What are the sensations of pain? Pain mechanisms The mechanism of pain are very complicated • Peripheral and central components Classification of pain Nociceptive Normal functioning of nociceptors In response to tissue injury Neuropathic Pain in response to injury to the nervous system Nociceptors • Nociceptors are primary sensory neurons that detect pain Skin Muscle Joints Viscera Meninges Dorsal horn Cell body (in dorsal root/cranial nerve ganglion) Sensory nerve fibre classification • Sensory nerve fibres can be classified by diameter and myelin content Myelinated (30-75m/sec) Large diameter Light touch, proprioception Thinly myelinated (5-30m/sec) Medium diameter Light touch, temperature, nociception PAIN TRANSMISSION Unmyelinated (0.5-2m/sec) Small diameter Temperature, nociception Sensory nerve endings • Nociceptors have free nerve endings in the periphery Glabrous skin: Hairy skin: Meissner’s corpuscles (Aβ) stroking/fluttering Free nerve Endings (Aδ/C) Pacinian corpuscles (Aβ) vibration Merkel discs (Aβ) pressure Free nerve Endings (Aδ/C) Ruffini endings (Aβ) stretch Nociceptors are also in muscles, joints, viscera Nociceptor responses What does it feel like when nociceptors are activated? • Aδ fibres: Sharp pricking pain • C fibres: Slow dull ache Burning pain In the lab… • Recordings can be made from all sensory fibre types in a whole nerve Electrical stimulation of axons in nerve Very fast Voltage Peripheral nerve (compound action potential) Medium 0 ms Very slow (following electrical stimulation) Recording Pain transduction Pain intensity • Two pain responses: Fast sharp pricking pain Slow dull ache - Poorly localised Voltage - Well localised - Activation of reflex arcs Visceral pain – no first response Activation of nociceptors Pressure Heat Cold Chemical Tissue damage/inflammation Polymodal nociceptors • Most C-fibre nociceptors are polymodal Respond to pressure, temperature and chemical “Our ability to distinguish pain sensations resulting from heat, cold or pressure must involve decoding within the central nervous system” Julius & Basbaum, 2001 Pressure transduction • Mechanically sensitive ion channels respond to pressure • Precise channels not yet identified (Possibly acid sensing ion channels, transient receptor potential channels) Temperature transduction • Transient receptor potential family of channels transduce different temperatures Temp Agonist TRPV1 HOT TRPM COLD Capsaicin (Chilli) Menthol TRPA1 V COLD Cinnamon • Detect different temperatures Vanilloid (TRPV1) subtype responds to heat Inflammation and pain hypersensitivity Inflammation and tissue injury • Chemicals released as part of tissue injury and inflammation have excitatory effects on nociceptors ATP H+ Serotonin/5-HT (from platelets) Histamine (from mast cells) Bradykinin Prostaglandin* Nerve growth factor * Prostaglandins are produced from the conversion of arachidonic acid by cyclooxygenase (COX) enzymes Activation of nociceptors by inflammation • For example, ATP, protons and serotonin can activate nociceptors Bind to: ATP Purinergic receptors (P2X) H+ Acid sensing ion channels Serotonin 5-HT3 receptors “Switch on” nociceptors = PAIN E.g. In runners – lactic acid build up, leads to tissue acidosis (↑ protons) Neurogenic inflammation • Activation of one branch of a nociceptor by inflammation, triggers the release of substance P and calcitonin gene related peptide (CGRP) from another • Leads to: Vasodilation Activation of mast cells Release of histamine = More Inflammation • Called neurogenic inflammation Modulation of nociceptors by inflammation • Inflammation can modulate nociceptors and cause hypersensitivity Important terms Hyperalgesia Noxious stimuli produce an exaggerated pain response = Allodynia Non-noxious stimuli produce a painful response = “Pain hypersensitivity after an injury helps healing by ensuring that contact with the injured tissue is minimized until repair is complete” Mechanisms of pain hypersensitivity • Peripheral and central sensitisation lead to hypersensitivity 1. Peripheral sensitization [Hyperalgesia] 2. Central sensitization [Allodynia] tissue damage/ Inflammation (Next lecture) Central sensitization is a major mechanism in neuropathic pain Peripheral sensitization • Peripheral sensitisation is an increase in the responsiveness of the peripheral ends of nociceptors • Driven by tissue injury or inflammation Bradykinin NGF Reduce the threshold of heatactivated channels (TRPV1) Prostaglandins Reduce the threshold of sodium and TRPV1 channels Sunburn can cause peripheral sensitization Mechanisms of action of bradykinin • Bradykinin indirectly acts on TRPV1 Bradykinin binds to receptor (metabotropic G protein-coupled) Activation of protein kinase Phosphorylation of TRPV1 Phosphorylation of channel reduces its threshold (i.e. it fires more easily) Central pain pathways Spinothalamic tract • Pain information ascends the spinothalamic tract • First-order neurons (nociceptors): Enter dorsal horn Form tract of Lissauer Synapse in substantia gelatinosa (lamina I and II) Glutamate and Substance P Excites second-order neurons Second order neurons • Second-order neurons: Cross in dorsal horn at each level Ascend in anterolateral column to thalamus Referred pain • Due to convergence of visceral and cutaneous nociceptors on same second order neurons in the spinal cord Where pain is perceived (left arm) • Brain perceives visceral pain as cutaneous pain e.g. Angina perceived as pain in upper chest wall and left arm Cutaneous nociceptors Visceral nociceptors Myocardial infarction Angina More of these afferents Sensory component • Third-order neurons: Cerebrum Primary somatosensory cortex Ascend to primary somatosensory cortex Midbrain Sensory homunculus Thalamus Pons Lower body = medial Upper body = lateral Medulla Encode the sensory components - Tells you “where” it hurts - Modality Cervical Lumbar Emotional component • Third-order neurons: Project to insula and cingulate cortex Insula Pain network Cingulate cortex Many cortical regions activated (limbic system, prefrontal cortex) Encode the emotional components - Unpleasantness - Negative affect Thalamus Pain experience • The pain experience is determined by many factors Memories Expectation Emotions Stress induced analgesia • For survival it may be necessary to supress pain • Called stress-induced analgesia E.g. - Battle victims - Endurance athletes (swimming, running etc) • Higher cortical regions can activate descending modulatory pathways Descending regulation of pain • Two important regions: Cingulate cortex Cortical regions Insula Periaqueductal gray matter (PAG) Hypothalamus Project to Amygdala Rostral ventromedial medulla (RVM) Midbrain PAG Projects to Medulla • Modulates activity of spinothalamic tract Can be inhibitory and excitatory RVM Projects to Dorsal horn Inhibition of pain • Periaqueductal grey matter neurons excite serotonergic neurons, which excite inhibitory interneurons • Inhibitory interneurons inhibit spinothalamic tract neurons - Also parallel noradrenalin pathway via locus coeruleus (pons) Spinothalamic tract PAG RVM Serotonergic neuron - Inhibitory interneuron Nociceptor Dorsal horn Endogenous opioid system • Opioids play an important role in the inhibition of pain (E.g. Endorphins, enkephalins) • Released from interneurons at multiple sites - Endogenous opioid system • Opioids are inhibitory Act on inhibitory metabotropic receptors - In PAG and RVM: Opioids Inhibit inhibitory interneurons that would otherwise stop the pathway In dorsal horn: Opioids inhibit second order neurons Spinothalamic tract - X PAG - X RVM Dorsal horn - - Nociceptor Summary • Nociceptors and their responses to noxious stimuli • Transduction of painful stimuli • Role of tissue injury and inflammation • Hypersensitivity (hyperalgesia and allodynia) • Peripheral sensitisation (mechanism of hyperalgesia) • Ascending pain pathways • Descending inhibition of pain and role of opioids