1. Nociceptive fibers that detect painful stimuli are distinct from other sensory fibers, and can be classified as myelinated A-delta fibers or unmyelinated C fibers. 2. Pain signals travel through two main pathways in the spinal cord - the anterolateral pathway and dorsal column pathway. 3. Pain processing involves peripheral sensitization at the site of injury, and central sensitization in the spinal cord which can amplify pain signaling.

1. PAIN and ANALGESIA www.freelivedoctor.com

2. Experimental evidence that nociceptive fibers are distinct from other sensory fibers www.freelivedoctor.com

3. A-delta vs. C fibers A-delta : myelinated; intermediate velocity (20m/s) C : unmyelinated; slower velocity (2m/s); polymodal www.freelivedoctor.com

4. Anterolateral Pathway www.freelivedoctor.com

5. 1. Lissauer’s tract 2. substantia gelatinosa 3. nucleus proprius 4. anterior commissure 5. anterolateral tract www.freelivedoctor.com

6. 2 sensory pathways: Anterolateral and Dorsal Column www.freelivedoctor.com

7. 3 Types of Pain: www.freelivedoctor.com

8. Free Nerve Ending www.freelivedoctor.com

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. www.freelivedoctor.com

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. 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, Na v 1.8/1.9, NK1, TRPV, etc. www.freelivedoctor.com

13. Pain Modulation: - Descending Pathway - Inhibitory Interneurons (Gate Theory) www.freelivedoctor.com

14. Overview of Descending Pathways : Midbrain Pons Medulla www.freelivedoctor.com

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. 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. 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. 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 www.freelivedoctor.com

19. Summary: Analgesic Targets www.freelivedoctor.com

20. Sources: Purves Neuroscience textbook Pharm textbook Woolf lecture notes & articles Rainville paper cited in Purves’s ‘Pain’ chapter www.freelivedoctor.com