PAIN and ANALGESIA www.freelivedoctor.com
Experimental evidence that nociceptive fibers are distinct from other sensory fibers www.freelivedoctor.com
A-delta vs. C fibers A-delta : myelinated; intermediate velocity (20m/s) C : unmyelinated; slower velocity (2m/s); polymod...
Anterolateral Pathway www.freelivedoctor.com
1. Lissauer’s tract 2. substantia gelatinosa 3. nucleus proprius 4. anterior commissure 5. anterolateral tract www.freeliv...
2 sensory pathways: Anterolateral and Dorsal Column www.freelivedoctor.com
3 Types of Pain: www.freelivedoctor.com
Free Nerve Ending www.freelivedoctor.com
1. Tissue damage leads to release of inflammatory/sensitizing agents: bradykinin, protons, histamine, PGE2, nerve growth f...
www.freelivedoctor.com
Central Sensitization 1. At presynapse(s),  glutamate  release, plus  substance P , CGRP, BDNF 2. Bind to postsynaptic  AM...
Analgesia <ul><li>Analgesia  = absence of pain sensation </li></ul><ul><li>Anesthesia  = absence of sensation </li></ul><u...
Pain Modulation: - Descending Pathway - Inhibitory Interneurons (Gate Theory) www.freelivedoctor.com
Overview of Descending Pathways : Midbrain Pons Medulla www.freelivedoctor.com
Inhibitory Neurotransmission 1. Inhibitory interneurons or descending projections release various NTs:  GABA,  NE, or endo...
Opioids Clinically : morphine, codeine, oxycodone, fentanyl, methadone, (heroin) Endogenous : beta-endorphins:  mu recepto...
Ongoing studies to determine conditions leading to endogenous opioid release.  Emotional states seem to play a role, espec...
<ul><li>Opioid agonists, like morphine, have broader systemic effects due to  opioid receptors in other siginificant areas...
Summary: Analgesic Targets www.freelivedoctor.com
<ul><li>Sources: </li></ul><ul><li>Purves Neuroscience textbook </li></ul><ul><li>Pharm textbook </li></ul><ul><li>Woolf l...
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Pain & analgesia

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Pain & analgesia

  1. 1. PAIN and ANALGESIA www.freelivedoctor.com
  2. 2. Experimental evidence that nociceptive fibers are distinct from other sensory fibers www.freelivedoctor.com
  3. 3. A-delta vs. C fibers A-delta : myelinated; intermediate velocity (20m/s) C : unmyelinated; slower velocity (2m/s); polymodal www.freelivedoctor.com
  4. 4. Anterolateral Pathway www.freelivedoctor.com
  5. 5. 1. Lissauer’s tract 2. substantia gelatinosa 3. nucleus proprius 4. anterior commissure 5. anterolateral tract www.freelivedoctor.com
  6. 6. 2 sensory pathways: Anterolateral and Dorsal Column www.freelivedoctor.com
  7. 7. 3 Types of Pain: www.freelivedoctor.com
  8. 8. Free Nerve Ending www.freelivedoctor.com
  9. 9. 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 Na v 1.8/1.9 ; PKC phosphorylates noxious stimuli receptors (TRPV, ASIC) 4. Result: increased ion influx per depolarization; lowered activation threshold Peripheral Sensitization www.freelivedoctor.com
  10. 10. www.freelivedoctor.com
  11. 11. 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 Mg 2+ block 4. Later: phosphorylation of gene regulatory proteins can alter gene expression (e.g. DREAM, a repressor of the endogenous opioid dynorphin, is activated) www.freelivedoctor.com
  12. 12. Analgesia <ul><li>Analgesia = absence of pain sensation </li></ul><ul><li>Anesthesia = absence of sensation </li></ul><ul><li>Analgesic possibilities suggested by anterolateral tract: </li></ul><ul><li>inhibitors of Na + channels (anticonvulsants, local anesthetics, etc.) </li></ul><ul><li>inhibitors of inflammatory mediators (NSAIDS, etc.) </li></ul><ul><li>inhibitors of NMDA receptors (NMDA antagonists) </li></ul><ul><li>inhibitors of other targets: AMPA, Na v 1.8/1.9, NK1, TRPV, etc. </li></ul>www.freelivedoctor.com
  13. 13. Pain Modulation: - Descending Pathway - Inhibitory Interneurons (Gate Theory) www.freelivedoctor.com
  14. 14. Overview of Descending Pathways : Midbrain Pons Medulla www.freelivedoctor.com
  15. 15. 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 Ca 2+ 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 ) www.freelivedoctor.com
  16. 16. Opioids Clinically : morphine, codeine, oxycodone, fentanyl, methadone, (heroin) Endogenous : beta-endorphins: mu receptors 1 & 2 ( endo genous m orphine ) enkephalins: delta receptors dynorphins: kappa receptors Receptor Location: mu: supraspinal (insula, amygdala, hypothalamus, PAG, medulla) kappa: spinal cord delta: spinal cord and supraspinal www.freelivedoctor.com
  17. 17. 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 www.freelivedoctor.com
  18. 18. <ul><li>Opioid agonists, like morphine, have broader systemic effects due to opioid receptors in other siginificant areas : </li></ul><ul><ul><li>- chemoreceptor trigger zone (CTZ) in medullary area postrema </li></ul></ul><ul><ul><li>vomiting center in medullary lateral reticular formation </li></ul></ul><ul><ul><li>respiratory control center in medulla </li></ul></ul><ul><ul><li>GI tract </li></ul></ul>www.freelivedoctor.com
  19. 19. Summary: Analgesic Targets www.freelivedoctor.com
  20. 20. <ul><li>Sources: </li></ul><ul><li>Purves Neuroscience textbook </li></ul><ul><li>Pharm textbook </li></ul><ul><li>Woolf lecture notes & articles </li></ul><ul><li>Rainville paper cited in Purves’s ‘Pain’ chapter </li></ul>www.freelivedoctor.com

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