Professional Documents
Culture Documents
Steven Stanos, DO Center for Pain Management Rehabilitation Institute of Chicago Dept. of PM&R, Northwestern University Medical School Feinberg School of Medicine
Nociceptive vs. Neuropathic Receptors and channels Inflammation Peripheral Sensitization Central Sensitization Temperature Sensation Plasticity & Brain Changes Muscle Pain Cytokines: the Future
Postoperative pain
Mechanical low back pain
*Complex regional pain syndrome type II. 1. Portenoy RK, Kanner RM. In: Pain Management: Theory and Practice. Philadelphia, PA: FA Davis Company; 1996:4. 2. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994. 3. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000.
Melzack R. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Philadelphia, Penn: Lippincott Williams & Wilkins; 1998.
Enteroceptive Sensations
Pain Thirst Hunger Thermoception
Physiological Pain
Initiated and by specialized sensory nociceptors innervating peripheral tissues and responding only to noxious stimuli Projects to spinal cord and cortex Activates reflex withdrawal, increase in arousal, emotional, autonomic and neurohumoral responses
Normal Healing
Pain Relief
Hyperalgesia
Allodynia
Chronic Pain
Pain Pathophysiology
Nociceptive pain
Believed to be related to ongoing activation of an intact nervous system by tissue injury
Somatic Visceral
Neuropathic pain
Believed to be related to aberrant somatosensory processing in the peripheral nervous system, the central nervous system, or both
Nociception
Transduction: detection of noxious or damaging stimuli Conduction: passage of resulting sensory input from peripheral terminals to the spinal cord Transmission: synaptic transfer of input to neurones within specific laminae of DH
Perception
Ascending Pathway C-Fiber - Fiber - Fiber Dorsal Horn Dorsal Root Ganglion
Spinal Cord
Conduction
Peripheral Nerve
Transmission/ Modulation
Transduction
Injury
1. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000. 2. Irving GA, Wallace MS. Pain Management for the Practicing Physician. New York, NY: Churchill Livingstone; 1997. 3. Woolf CJ, et al. Ann Intern Med. 2004;140:441-451.
A-
+ + +
Muscle spindle primary endings Golgi Tendon organs Muscle efferents (extrafusal) Encapsulated endings;Merkel Muscle efferents (intrafusal) A- specific & polymodal; cold; hair; visceral (+/-) Preganglionic autonomic
C-nociceptors; C-polymodal; warmth, mechano;postganglioic autonomic; enteric nerve fibers
6-12+
2-10 1-6 <3 <1.5
A-
A- A- B C
30-70
10-50 5-30 3-15 0.5-2.0
+
+ + + No
1. Julius D, Basbaum A, Nature 2001(413). 2. Chakour M,, et al. Pain 1996; 64:143.
Receptors
Non-painful stimuli:
Specificity for a particular stimulus High degree of gain to amplify weak signals Rapid adaptation to increasing intensities
Painful stimuli:
Specificity less important High threshold receptors: thermal, chemical and mechanical stimuli (polymodal) Threshold for firing may decrease
Kidd, Urban. Br J of Anaesth 87, 2001.
Cutaneous
C-fiber Small diameter Slow conducting Unmyelinated 1. Proinflammitory peptides Subst P CGRP Lamina I/II * tissue inflammation (NGF) 2. Specific enzymes/ Lectin IB4 *chronic neuropathic pain (GDNF)
Caterina, Cur Op in Neurobiology (9), 1999.
Low
EAA
G-protein linked
Ion Channels
Dynamic, constantly changing Plasticity reflects sensitivity needed for survival Injury: amygdala, hippocampus, and DRG Normal peripheral nerves (resist) Demyelination: density
Receptors
Capsaicin/ Vanilloid Purinergic (P2X)
Calcium
Visceral Pain
Psychophysics Not evoked from all viscera Not always linked to injury Referred to body wall Diffuse & poorly localized Intense motor & autonomic reactions Neurobiology Not all innervated by sensory receptors Functional properties of afferents Viscerosomatic convergence in CNS Few sensory visceral afferents, diverge CNS Warning system, capacity for amplification
Siddal, Cousins. Neural Blockade in Clinical Anesthesia and Management of Pain, Third Ed.,1998.
Inflammation
Redness (rubor) Heat (calor) Swelling (tumor) Loss of function (function lasea) Pain (dolor)
Inflammation
Macrophages: Cytokines(IL1, IL6, TNF-) Nerve Growth Factor Damaged Cells: ATP and protons Mast Cells: Histamine, serotonin, prostaglandins, arachidonic acid metabolites Upregulation of receptors VR1, SNS, SNS-2 & Peptides Phenotypic Switch ( A-fiber into C-fiber)
Jensen et al. Acat Anaesthesiol Scand 45, 2001.
Inflammation
Short-term
Modifications in excitation & sensitization of peripheral sensory terminals
Longer-term
Changes in properties of afferents Decrease in threshold for firing Increase in excitability of spinal neurons
Hyperalgesia
pain threshold pain to suprathreshold stimuli Spontaneous pain
Sensitization
threshold for response response to suprathreshold stimuli Spontaneous activity
Peripheral Sensitization
Tissue Damage Inflammation Sympathetic Terminals
SENSITIZING SOUP
Hydrogen Ions Noradrenaline Bradykinin Leukotrienes Histamine Potassium Prostaglandins 5-HT Purines Cytokines NGF Neuropeptides
Peripheral Sensitization
Plasma Extravasation Vasodilation Macrophage
SKIN
TNF- IL-6 LIF
Tissue Damage Pressure ?
Mast Cell
Heat
H+
Ca2+ (PKC) PKA PKC TTXr (SNS/SNS2) Sub P Gene Regulation TTXr TTXs
1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994. 2. Backonja MM. Anesth Analg. 2003;97:785-790.
Central sensitization occurs as a result of increased nociceptor drive or disinhibition after nerve injury, leading to exaggerated dorsal horn response
Inhibitory Input Is Downregulated
To Brain Innocuous Stimulus Dorsal Horn Neuron Innocuous or Noxious Stimulus Dorsal Horn Neuron
Disinhibition
Temperature
Thermosensation
Thermosensation
TRP channel family
TRV2 TRPV1 (Vanilloid) >53 C >43 C Noxious heat Heat, capsaicin, acid
TRPV3/TRPV4
TRPM8 (CMRI) TRPA1
>30-40 C Warm
>25 C <17 C Cold, menthol Noxious cold
Thermosensation
Cold
10-15% C & A-delta Specificity vs. modulation of excitatory & inhibitory channels K, Na, Ca channels CMRI (cold- and mentholsensitive receptor) cloned TRP (transient receptor potential)
Heat
Capsaicin Vanilloid receptor subtype 1 (VR1 or TRPV1) Thermal activation threshold ~43C Polymodal, influenced by a variety of substances
Capsaicin
genus Capsicum:
mildest (bell) to hottest (habanero) Capsaicin: 16,000,000 SHU Classic: habanero: 200,000 SHU
Activates, desensitize (Ca), and exert neurotoxic effects on polymodal nociceptors release of Subst P & CGRP, nerve degeneration (NGF), loss of intraepidermal fibers pharmacological & functional desensitization via VR1 receptor
Anand P. Gut 52, 2003. W. Clin J Pain 16(2), 2000. Robbins
TRPV Channels:
Pain Neurochemistry
Transmission via spinothalamic tract to brain Dorsal horn Dorsal root ganglion Ion fluxes (H+/ K+) Prostaglandins Leukotrienes Tissue injury Bradykinin
Spinal cord
Substance P
To brain
Histamine
Substance P, aspartate, neurotensin, glutamate
Sensitized nociceptor
Neuromatrix
Pain Matrix
Pain Matrix
Anterior cingulate cortex (ACC) Insular cortex (IC) Thalamus Sensorimotor cortex (SSI, SSII) Cerebellum
Opioid Systems
Reynolds: (1969) Endogenous opioid system PAG & NMM: funnel Homeostatic and behavioral adjustments
Mason P. J Neurophysiol. 2005;94:1659-1663. Finniss DB, Benedetti F. Pain. 2005;114:3-6. Petrovic P, Ingvar M. Pain. 2002;95:1-5.
Tracey, 2008
INJURY
Tissue Damage
SYMPTOMS
Spontaneous Hyperalgesia Pain Allodynia
PERIPHERAL ACTIVITY
CENTRAL
SENSITIZATION
Nerve Damage