pain & analgesia
TRANSCRIPT
![Page 1: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/1.jpg)
PAIN and ANALGESIA
www.freelivedoctor.com
![Page 2: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/2.jpg)
Experimental evidence that nociceptive fibersare distinct from other sensory fibers
www.freelivedoctor.com
![Page 3: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/3.jpg)
A-delta vs. C fibers
A-delta: myelinated; intermediate velocity (20m/s)C: unmyelinated; slower velocity (2m/s); polymodal
www.freelivedoctor.com
![Page 4: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/4.jpg)
AnterolateralPathway
www.freelivedoctor.com
![Page 5: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/5.jpg)
1. Lissauer’s tract2. substantia gelatinosa3. nucleus proprius4. anterior commissure5. anterolateral tract
www.freelivedoctor.com
![Page 6: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/6.jpg)
2 sensory pathways:Anterolateral
andDorsal Column
www.freelivedoctor.com
![Page 7: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/7.jpg)
3 Types of Pain:
www.freelivedoctor.com
![Page 8: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/8.jpg)
Free Nerve Ending
www.freelivedoctor.com
![Page 9: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/9.jpg)
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
Peripheral Sensitization
www.freelivedoctor.com
![Page 10: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/10.jpg)
www.freelivedoctor.com
![Page 11: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/11.jpg)
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 cascadethat activates kinases
3. Immediate: phosphorylation of AMPA receptorsincreases glutamate signaling; phosphorylation of NMDArelieves Mg2+ block
4. Later: phosphorylation of gene regulatory proteinscan alter gene expression (e.g. DREAM, a repressor ofthe endogenous opioid dynorphin, is activated)
www.freelivedoctor.com
![Page 12: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/12.jpg)
Analgesia
Analgesia = absence of pain sensationAnesthesia = 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.
www.freelivedoctor.com
![Page 13: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/13.jpg)
Pain Modulation:
- Descending Pathway- Inhibitory Interneurons (Gate Theory)
www.freelivedoctor.com
![Page 14: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/14.jpg)
Overview of Descending Pathways:
Midbrain
Pons
Medulla
www.freelivedoctor.com
![Page 15: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/15.jpg)
Inhibitory Neurotransmission
1. Inhibitory interneurons or descendingprojections release various NTs: GABA, NE, or endogenous opioids
2. Bind receptors on presynapse ofafferent pain fiber, inhibit Ca2+ channels,leading to reduced vesicle release
3. Also bind post-synaptically: can signalvia G-proteins to cause K+ efflux orCl- influx (both are hyperpolarizing)
www.freelivedoctor.com
![Page 16: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/16.jpg)
Opioids
Clinically: morphine, codeine, oxycodone, fentanyl, methadone, (heroin)
Endogenous:
beta-endorphins: mu receptors 1 & 2 (endogenous morphine)enkephalins: delta receptorsdynorphins: kappa receptors
Receptor Location:mu: supraspinal (insula, amygdala, hypothalamus, PAG, medulla)kappa: spinal corddelta: spinal cord and supraspinal
www.freelivedoctor.com
![Page 17: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/17.jpg)
Ongoing studies to determineconditions leading to endogenousopioid release. Emotional statesseem to play a role, especiallyfear/stress as relates to pain.
Some implicated areas:PAG, medulla, cingulate, nucleusaccumbens
www.freelivedoctor.com
![Page 18: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/18.jpg)
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
![Page 19: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/19.jpg)
Summary: Analgesic Targets
www.freelivedoctor.com
![Page 20: Pain & analgesia](https://reader033.vdocument.in/reader033/viewer/2022061601/557aaa91d8b42a6f378b4ada/html5/thumbnails/20.jpg)
Sources:
- Purves Neuroscience textbook- Pharm textbook- Woolf lecture notes & articles- Rainville paper cited in Purves’s ‘Pain’ chapter
www.freelivedoctor.com