Pain & analgesia

PAIN and ANALGESIA

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Experimental evidence that nociceptive fibersare distinct from other sensory fibers

A-delta vs. C fibers

A-delta: myelinated; intermediate velocity (20m/s)C: unmyelinated; slower velocity (2m/s); polymodal

AnterolateralPathway

1. Lissauer’s tract2. substantia gelatinosa3. nucleus proprius4. anterior commissure5. anterolateral tract

2 sensory pathways:Anterolateral

andDorsal Column

3 Types of Pain:

Free Nerve Ending

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

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)

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.

Pain Modulation:

- Descending Pathway- Inhibitory Interneurons (Gate Theory)

Overview of Descending Pathways:

Midbrain

Medulla

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)

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

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

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

Summary: Analgesic Targets

Sources:

- Purves Neuroscience textbook- Pharm textbook- Woolf lecture notes & articles- Rainville paper cited in Purves’s ‘Pain’ chapter

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