Introduction to Pain Ed Bilsky, Ph.D. Phone: 602.2707 Department of Pharmacology University of New England E-mail: ebilsky@une.edu
Clinical Cases • 63 year old white female presents to the emergency room with an acute outbreak of shingles following a recent episode of flu. She reports some itching at the site of the rash (lower right side of her trunk) that has progressed into a burning/stabbing pain (7/10) over the past two days. • A 23 year old African-American male presents to the ER claiming to be having an acute sickle cell crisis. He is visible agitated and reports that his pain is a 10/10 and wants an injection of 150 mg of Demerol (meperidine). • A 38-year-old man (70 kg) suffered for 48 h from an acute pain in the lumbar region that was not improved with common drugs available at home (acetaminophen 1000 mg3/day). The pain was paroxystic with no analgesic position The patient reported a previous history of renal acute pain. Clinical examination showed a maximal pain to pressure of the right lumbar region, a microscopic haematuria, no elevated temperature, and VAS or NS equal to 5 (0=no pain, 10=maximal pain). The X-ray of the abdomen showed a small opaque object in the projection of the fourth right lumbar vertebra. The ultrasonographic exam showed a moderate dilatation of the right urinary tract. The diagnosis was a right acute renal colic.
Introduction to Pain • Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” • Physiological pain serves an important protective and reparative function
Peripheral Nerve Fibers A α A d C C
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pain Normal Abnormal Protective Non-protective Acute Prolonged Chronic (Pain as Disease) Inflammation Reflexes and Repair Healing of injured tissue can occur but pain continues Therapeutic goal: return sensitivity to normal thresholds without loss of protective function (anti hyperalgesia/anti-allodynia)
Impact of Chronic Pain • In contrast to normal pain states, pathological chronic pain serves no apparent purpose • Furthermore it poses significant health and social problems in the United States and elsewhere – quality of human life – economic costs
Incidence and Cost of Various Neurological Disorders Disease Cases Cost Cost/Case Chronic Pain 90 million $100 billion $1,100 Addiction 30 million $160 billion $5,333 Alzheimer’s 4 million $90 billion $22,500 Stroke 3 million $25 billion $8,333 Schizophrenia 2 million $32.5 billion $16,250 Parkinson’s 0.5 million $6 billion $12,000 Spinal Injury 0.3 million $10 billion $33,000 National Institutes of Health, 1998
Processing of Pain Signals • Transduction - Noxious stimuli are converted to electrical signals in sensory nerve endings • Transmission - neural events which relay the information from the periphery to the cortex • Modulation - the nervous system can selectively inhibit the transmission of pain signals • Perception - subjective interpretation by the cortex of the noxious stimulus. • Sensory component
Cortex Central Perception Relay and Descending Thalamus Modulation Brain Stem Transmission Spinal Cord Peripheral stimulus Signal Transduction
Descending Modulation in “Top-down” Modulation Chronic Pain States Pain is a Sensory Experience - Emotion - Attention/Distraction - Expectation - Stress Ascending Transmission - Novel Therapies
The Variability of Pain • Pain Detection Threshold – a property of the sensory system – highly reproducible in individuals • Pain Tolerance – Highly variable among individuals – dependent on affective components
Neural Mechanisms of Pain Transduction and Transmission Pain Pain Avoidance Avoidance Emotional Emotional reaction reaction Dorsal Root Ganglia (cell body) Withdrawal Withdrawal Spinal cord Transmission Perception Transduction Conduction
Transduction of Nociceptor Activators Histamine Mechanical Protons Heat Cold ATP force Capsaicin Wasabi Mustard oil H + G s s s e R r ASICs ASICs TRPMs s TRPVs o C a t P n p TRPV1 TRPV4 G e i K c TREK-1 o e n n i i r s u o P r y T Not all receptors are necessarily co-localized on the same cell membrane
Pain Transmission Fibers A d C-Polymodal Type Nociceptors Nociceptors Conduction (0.5 - 2 m/sec) (5 - 20 m/sec) High-Threshold Thermal Mechanoreceptors Modality Pressure Thermal Chemical Pressure Pressure
Peripheral Nociceptors Do Not Adapt • Sensitization of high-threshold mechanothermal nociceptor Spikes Heat 48 ( o C) Stimuli 35
Peripheral Nociceptors Do Not Adapt Non-nociceptive Nociceptor Stimulus thermoreceptor 45 o C Nociceptor Magnitude of afferent Thermoreceptor response 0 40 45 50 Temperature ( o C)
Injury-Induces Changes in Pain Detection and Sensation Secondary Hyperalgesia Nerve Block Hyperalgesia: an increased response (Central Sensitization) No secondary to a normally painful stimulus hyperalgesia Response Pain threshold Primary Hyperalgesia (Peripheral Sensitization) Allodynia Hyperalgesia Stimulus intensity Subjective Pain Intensity 6 post-injury 5 Allodynia: a painful response to a normally innocuous stimulus 4 3 pre-injury 2 Response Pain threshold 1 0 41 43 45 47 49 Stimulus temperature ( o C) Stimulus intensity
Peripheral Nociceptor Sensitization and Neurogenic Inflammation Calor vasodilation --> heat Rubor vasodilation --> redness Tumor plasma extravasation --> swelling Dolor activation of peripheral and adjacent nociceptors Glucocorticoids NSAIDS • Direct activation of nociceptor • Sensitization of nociceptor • Chemicals produced only during tissue injury
Chemical Mediators in Nociceptive Transmission Pain in Man Effect on Primary Substance Source Afferents Potassium Damaged Cells ++ Activate Serotonin Platelets ++ Activate Bradykinin Plasma Kininogen +++ Activate Histamine Mast Cells + Activate Prostaglandins Damaged Cells - Sensitize Leukotrienes Damaged Cells - Sensitize Substance P Primary Afferents - Sensitize
Anterior Cingulate Cortex Somatosensory Cortex Human Brain Imaging of Heat Pain Insular Cortex Thalamus C Thalamus Spinomesen- cephalic Tract Anterior Cingulate Somatosensory Cortex Cortex Spinoreticular Injury Tract Insular Cortex I II III IV Primary V Afferent Prefrontal Nociceptors Cortex Anterolateral System
Windup Induced by Repetitive C-Fiber Stimulation Persistent Nociceptive Input Changes Responses of 2 nd Order Cells in the Spinal Dorsal Horn 25 Spikes per stimulus 20 15 10 5 0 0 2 4 6 8 10 12 14 16 Stimulus number
Mechanisms of Central Sensitization Repetitive C-fiber input Presynaptically: Primary Afferent Neuron • Repetitive C-fiber input • Increased transmitter release NMDA AMPA NK-1 Summation of slow synaptic potentials Postsynaptically: NMDA and neurokinin mediated • Increased response to Alteration in second messengers (Calcium, IP3, DAG etc) transmitter • Strengthening of Protein kinase activation --> Phosphorylation of receptors and ion channels “synaptic efficacy” Increased excitability and synaptic efficacy Second Order Neuron Central sensitization
Gate Theory of Pain A b Low Threshold Mechanoreceptor Inhibitory Interneuron (e.g., GABA?) 2 nd Order Pain Transmission Cell To Thalamus C/A d Nociceptor
Transcutaneous Electrical Nerve Stimulation QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a QuickTime™ and a TIFF (Uncompressed) decompressor TIFF (Uncompressed) decompressor are needed to see this picture. are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Spinothalamic Tracts Paleospinothalamic Neospinothalamic Somato- Lateral sensory Sensation Thalamus Spinal Cortex Cord Reticular Medial Association Affect Formation Thalamus Cortex
Endogenous Opioids Regulate Nociception Increased Decreased Spinothalamic Enkephalin Release Neurotransmission Projection to Thalamus Nociceptive ENK Input Normal release of Activation of Opioid Receptors: glutamate, substance P • Decrease Ca ++ Conductance etc. promotes the transmission of pain • increase K + efflux
Supraspinal Analgesia • Brainstem circuits may inhibit Descending Modulation → PAG indirectly rostral movement of controls pain transmission in the dorsal horn nociceptive information and activate descending pathways ACC that alter nociceptive processing in the spinal cord T H – periaqueductal gray – rostral ventral medulla Amygdala PAG • Parts of the limbic system DLPT Pain Facilitation activated by opioids may alter Pain Inhibition the emotional response to RVM painful stimuli Dorsal Horn – nucleus accumbens/ventral Pain Transmission forebrain Neuron
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