Pathophysiology of Pain Wound Inflammatory response Chemical mediators Activity in Pain Path PAIN http://neuroscience.uth.tmc.edu/s2/chapter08.html Chris Cohan, Ph.D. Dept. of Pathology/Anat Sci University at Buffalo
Objectives 1. Describe the mechanisms that cause tissue inflammation and that lead to pain. 2. Describe the types, causes, and consequences of sensitization. 3. Describe the intrinsic pathways that modulate pain. 4. Describe the different clinical treatments for pain.
Overview 1. Peripheral mechanisms that initiate pain are diverse. Involve inflammatory response crucial in understanding how to treat pain. 2. Physiological changes (sensitization) in pain pathways increase magnitude and duration of pain. 3. Unlike touch, built-in anatomical, physiological, and pharmacological mechanisms decrease pain sensation. 4. Clinical treatments for pain require an understanding of 1,2,3 inflammatory response, sensitization, built-in control.
First Order Neurons Nerve endings in skin/viscera contain specialized channels/receptors that respond to noxious stimuli: Mechanical - excess deformation Thermal - Temp > 45 C or < 5 C TRPV1 receptors on thermal nociceptors also bind the active ingredient in hot peppers (capsaisin). Capsaisin creme isused to desensitive nociceptors. Polymodal - mechano, thermo, chemical Encoding mechanisms similar to tactile stimuli
Pain and Inflammatory Response 2. Injured tissue releases inflammatory molecules. 3. Nociceptor terminals release inflammatory molecules that affect blood vessels. 4. Nociceptor terminals release inflammatory molecules that affect mast cells. RESULT: the inflammatory molecules lower threshold for action potentials in nociceptors and increase their activity. neurogenic inflammation
Inflammatory Response (2) Injured tissue releases inflammatory molecules that bind to receptors on nociceptors, depolarizing nociceptors and increasing their activity. Nociceptor terminal This image cannot currently be displayed. P~ heat H + ATP ionotropic receptors Inflammatory molecules K +, H +, ATP
Inflammatory Response (3, 4) As nociceptor activity increases, their terminals release inflammatory neuropeptides: substance P and CGRP tachykinins
Inflammatory Response (3, 4) substance P and CGRP Blood Vessels vasodilation/increased vascular permeability released from terminals Mast Cells Secrete histamine, serotonin, NGF, prostaglandins Leak bradykinin, histamine Activate nociceptors
Inflammatory Response (3, 4) Peptides released by blood vessels and mast cells bind to receptors on nociceptors, depolarizing them and and increasing their activity. Nociceptor terminal This image cannot currently be displayed. P~ Bradykinin ATP Histamine heat H + PDE 5-HT 2 metabotropic receptors ionotropic receptors
Inflammatory Response Inflammatory molecules produce a cycle of events: 1. Release more inflammatory molecules from blood vessels and mast cells 2. Bind to nociceptors and increase their activity These inflammatory molecules contribute to the swelling, redness, and increased pain of tissue that spreads beyond the site of injury a protective response.
Neurogenic Inflammation directly affects the immune system to further potentiate the inflammatory response 1. Mast cell activation, leukocyte chemotaxis 3. Immune System: activate dendritic and T-cells, release molecules that recruit neutrophils, monocytes 2. Blood vessels: blood flow, permeability, leakage of inflammatory molecules Nature, 15:1063, 2012
Sensitization Increased pain sensitivity to stimuli caused by inflammation. Characteristics: 1. Allodynia Stimuli that were not painful previously, now evoke pain. 2. Hyperalgesia Noxious stimuli evoke more intense pain than normal.
Sensitization - Components Sensitization has both peripheral and central components. Peripheral Sensitization - Increased activity in the pain pathway caused by activated nociceptors. Central Sensitization Increased activity in the pain pathway caused by changes in central synapses.
Peripheral Sensitization A large variety of inflammatory molecules can bind to receptors on nociceptors. Activity of ionotropic ion channels is changed directly by ligands or through second messenger systems. Na + Na + K + This image cannot currently be displayed. ~P ~P 3 microtubules 4 P~ NGF Bradykinin ATP Histamine heat H + PDE 5-HT 2 H + 2 Nociceptor terminal 5 1 cations TNF NGF inflammatory molecules
Peripheral Sensitization Consequences: 1. Decrease action potential threshold 2. Increase frequency of AP 3. Induce spontaneous activity COX inhibitors, which decrease prostaglandin synthesis, can reduce the effects of inflammatory molecules. Na + Na + K + This image cannot currently be displayed. ~P ~P 3 microtubules 4 P~ NGF Bradykinin ATP Histamine heat H + PDE 5-HT 2 H + 2 Nociceptor terminal 5 1 cations TNF NGF inflammatory molecules
Central Sensitization Sustained nociceptor activity in the periphery alters synaptic function in the central nervous system. Excitability of 2 neurons is increased by enhanced efficacy of postsynaptic potentials decreased threshold for action potentials
1 axon terminals release substance P and Glutamate onto 2 neurons. Substance P and Glutamate together activate SubstP and NMDA receptors: Ca ++ influx Central Sensitization prostaglandin synthesis Ca ++ changes in synaptic function Mg + + substp provides additional depol to open NMDA-R NMDA-R receptor
Sensitization - Clinical Implications Central Sensitization caused by increased activity from nociceptors causes: Neuropathic pain - prolonged increase in CNS excitability. Postsurgical pain cutting through skin can cause excessive nociceptor activity. Local anesthetics and NSAIDS can reduce sensitization.
Intrinsic pathways can inactivate pain pathways.
Activated by hypothalamus and cortex Intrinsic Pain Modulation Regions that modulate pain 1. Midbrain periaqueductal grey 2. Pons locus ceruleus 3. Medulla raphe nuclei PAG Locus ceruleus Medulla Reticular Formation serotonin Spinal Cord NE Spinal Cord in stressful/emotional situations
Pain Modulation Descending brainstem axons excite opiate interneurons in spinal cord Opiate interneurons cause: presynaptic inhibition of 1 neuron Decreased Ca++ influx Neuropeptides long-lasting effect 5-HT NE Ca Ca postsynaptic inhibition of 2 neuron Neuron is hyperpolarized in substantia gelatinosa
Clinical Treatment of Pain A. Electrical stimulation Periaqueductal grey Tactile sensory pathway can inhibit pain pathway used therapeutically to decrease pain activity dorsal columns 1 tactile 1 pain to ALS
Clinical Treatment of Pain A. Electrical stimulation Tactile Fibers A - Stimulate Fasc. Gracilis/Cuneatus axons B - TENS stimulates peripheral nerve 1 tactile fibers (transcutaneous electrical nerve stimulation) A dorsal columns A B 1 tactile 1 pain acupuncture? to ALS
Clinical Treatment of Pain Spinal cord stimulator For TENS
Clinical Treatment of Pain B. Pharmacological i. ß inflammation - NSAIDS ii. Increase inhibition of pain pathway Opiates - neuropeptides with long-lasting effects Norepinephrine via a1 and a2 adrenergic receptors Antidepressants 5-HT/NE reuptake inhibitors Antiseizure meds GABA activity; (ß Na activity) iii. Capsaisin creams - hot peppers desensitize receptors C. Surgery ALS tractotomy - transient relief D. Acupuncture can be an effective treatment E. Meditation and relaxaion techniques
Molecular/Genetic Aspects of Pain Channelopathies Specific Na + channel isoform used by Ad, C fibers to conduct action potentials. LOF mutations inability to feel pain study analyszed Pakastani family who were street performers GOF mutations ß threshold, ß Na inactivation warm stimuli cause burning pain paroxysmal pain disorder