PAIN and ANALGESIA

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PAIN and ANALGESIA
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Experimental evidence that nociceptive fibers are
distinct from other sensory fibers
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A-delta vs. C fibers
A-delta myelinated intermediate velocity
(20m/s) C unmyelinated slower velocity (2m/s)
polymodal
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Anterolateral Pathway
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1. Lissauers tract 2. substantia gelatinosa 3.
nucleus proprius 4. anterior commissure 5.
anterolateral tract
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2 sensory pathways Anterolateral and Dorsal
Column
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3 Types of Pain
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Free Nerve Ending
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Peripheral Sensitization
1. Tissue damage leads to release of
inflammatory/sensitizing agents bradykinin,
protons, histamine, PGE2, nerve growth factor 2.
Bind receptors (TrkA, EP), leads to G-protein
cascade, releasing PKA, PKC 3. PKA
phosphorylates Nav1.8/1.9 PKC phosphorylates
noxious stimuli receptors (TRPV, ASIC) 4.
Result increased ion influx per depolarization
lowered activation threshold
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(No Transcript)
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Central Sensitization
1. At presynapse(s), glutamate release, plus
substance P, CGRP, BDNF 2. Bind to postsynaptic
AMPA, NMDA, mGluR, NK1, trigger ion influx and
depolarization, or to signal cascade that
activates kinases 3. Immediate phosphorylation
of AMPA receptors increases glutamate signaling
phosphorylation of NMDA relieves Mg2 block 4.
Later phosphorylation of gene regulatory
proteins can alter gene expression (e.g. DREAM, a
repressor of the endogenous opioid dynorphin, is
activated)
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Analgesia

• Analgesia absence of pain sensation
• Anesthesia absence of sensation
• Analgesic possibilities suggested by
  anterolateral tract
• inhibitors of Na channels (anticonvulsants,
  local anesthetics, etc.)
• inhibitors of inflammatory mediators (NSAIDS,
  etc.)
• inhibitors of NMDA receptors (NMDA antagonists)
• inhibitors of other targets AMPA, Nav1.8/1.9,
  NK1, TRPV, etc.

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Pain Modulation - Descending Pathway -
Inhibitory Interneurons (Gate Theory)
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Overview of Descending Pathways
Midbrain
Pons
Medulla
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Inhibitory Neurotransmission 1. Inhibitory
interneurons or descending projections release
various NTs GABA, NE, or endogenous opioids 2.
Bind receptors on presynapse of afferent pain
fiber, inhibit Ca2 channels, leading to reduced
vesicle release 3. Also bind post-synaptically
can signal via G-proteins to cause K efflux
or Cl- influx (both are hyperpolarizing)
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Opioids
Clinically morphine, codeine, oxycodone,
fentanyl, methadone, (heroin) Endogenous beta-
endorphins mu receptors 1 2 (endogenous
morphine) enkephalins delta receptors dynorphin
s kappa receptors Receptor Location mu
supraspinal (insula, amygdala, hypothalamus, PAG,
medulla) kappa spinal cord delta spinal cord
and supraspinal
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Ongoing studies to determine conditions leading
to endogenous opioid release. Emotional
states seem to play a role, especially fear/stress
as relates to pain. Some implicated areas PAG,
medulla, cingulate, nucleus accumbens
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• Opioid agonists, like morphine, have broader
  systemic effects due to opioid receptors in other
  siginificant areas
• - chemoreceptor trigger zone (CTZ) in medullary
  area postrema
• vomiting center in medullary lateral reticular
  formation
• respiratory control center in medulla
• GI tract

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Summary Analgesic Targets
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• Sources
• Purves Neuroscience textbook
• Pharm textbook
• Woolf lecture notes articles
• Rainville paper cited in Purvess Pain chapter