pharmacology of pain

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pharmacology of pain
2012-12-09 07:35:32
pharmacology pain nhb neuro

pharmacology of pain
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  1. 2 types of sensitisation
    • eg on burning
    • local: thermal - 'primary hyperalgesia': pro-inflammatory mediators eg bradykinin, PGE
    • central: mechanical - 'secondary hyperalgesia': change in strength of connections to 2nd order neurons in dorsal horn
  2. Exciting stimuli (8)
    • External: heat, cold, mechanical, chemical
    • Internal: ATP (released from damaged cells), bradykinin (formed when proteolytic enzymes are released from damaged cells), high potassium (prolonged electrical excitation), acid (anoxia)
  3. Sensitising stimuli (8)
    Histamine, NO, 5-HT, prostaglandins, NGF, bradykinin, ATP, acid
  4. What is neurogenic inflammation?
    When nociceptive nerve terminals are stimulated, they release substance P by exocytosis, causing vasodilatation and an increase in the permeability of blood vessels.
  5. 6 ion channels involved in nociceptor excitation
    • TRPV1: heat, capsaicin, H+, anandamide (endogenous neurotransmitter)
    • TRPV2: extreme heat
    • ?TRPV4: mechanical stimuli
    • TRPA1 (/TRPM8): cold (and isothiocyanates in wasabi, mustard, horseradish)
    • P2X: ATP
    • ASICs: protons
  6. Which sodium channels are found at nociceptive nerve terminals?
    Nav1.7 and 1.8
  7. Which sodium channels are widespread?
    Nav1.1, 1.6
  8. Describe TRPV1: activators, sensitisers, structure
    • heat >45, acid, anandamide, capsaicin
    • 6 TM
    • pore loop between 5 and 6
    • 2 proton sensors (glutamate) either side of pore
    • intracellular capsaicin binding site (Capsaicin is lipophilic)
    • sensitised by phosphorylation: PKA (prostaglandins) and PKC (bradykinin)
  9. 2 Drugs acting on transduction of pain
    • Capsaicin: desensitisation (After initial pain). Used in topical creams (eg muscle pain) and to relieve chronic inflammation of urinary tract
    • Local anaesthetics eg cocaine: block all Na channels
  10. 3 Potentials for drugs to act on transduction of pain
    • Nav1.7 and Nav1.8
    • Specific ion channels
    • Blocking sensitising kinases
  11. Mechanisms for sensitisation at peripheral nociceptive terminal
    • PGE2: Gs: cAMP: PKA: phosphorylation of Nav1.8 lowers its threshold of activation.
    • ALSO cAMP: activates Ih inward current (sim to If)
    • Bradykinin: PLC: DAG: PKC: phosphorylation of TRPV1 lowers the heat threshold at which the channels are activated
  12. Exp for sensitisation
    • Bradykinin periodically injected as a test nociceptive stimulus
    • Prostaglandin increased response
    • Also, bradykinin increases response to heat stimulus
  13. 4 Drugs acting on sensitisation
    • NSAIDs: eg aspirin, ibuprofen, diclofenac: inhibit COX1 and COX2: stop prostaglandin synthesis/release
    • Opiates: eg morphine, fentanyl: antagonise prostaglandins by decreasing cAMP via u opioid receptor
    • Bradykinin antagonists: eg icatabant (specific B2, but not in clinical use)
    • Steroidal anti-inflammatory drugs: eg dexamethasone: downregulate transcription of genes for proteins like COX2 and bradykinin B1 and B2 receptors
  14. Describe COX pathway for prostaglandin production
    • arachidonic acid produced from membrane phospholipids by phospholipase A2
    • arachidonic acid converted to prostaglandins and thromboxanes by cyclo-oxygenases
    • esp important in pain are PGE2 and PGI2
  15. different COX roles, consequences for NSAIDs
    • COX1: constitutively expressed and inhibit stomach acid production - non selective NSAIDs can cause stomach ulcers by releasing inhibition
    • COX2: upregulated in inflammation. Specific drugs inc celecoxib (but was withdrawn due to cardiac effects)
    • maybe, but probably not COX3?: in brain, preferentially inhibited by paracetemol (explains why it is a good antipyretic, but a poor anti-inflammatory/analgesic)
  16. 3 Substances involved in transmission at the first synapse (in substantia gelatinosa)
    • Glutamate: to AMPA and NMDA
    • Substance P: to GPCR NK1 receptors
    • Opiates: u opioid pre- and post-synaptically:
  17. Role of opiates at first nociceptive synapse
    • INHIBITORY: u opioid pre and post-synaptically: Gi - reduces cAMP
    • K currents activated, VGCC (N type) suppressed
    • Enkephalin containing interneurons activated by pathways originating in PAG
  18. 4 Drugs acting on transmission at first synapse
    • Opiates: eg morphine: mimic endogenous opiates (im analgesic and sedative last for 4-6 hours): euphoria and addiction, excitement, vomiting
    • NMDA antagonists: eg ketamine. CNS effects to do with memory and cognition.
    • NK1 antagonists: shown to be ineffective in humans
    • N type VGCC blockers: eg ziconotide: showing promise (no addictive side effects); and antiepileptics gabapentin and pregabalin
  19. Describe endogenous opiates and name 3
    • short polypeptides, homology esp at terminus
    • endorphins, enkephalins, nociceptin
  20. Describe opiate receptors
    • u, delta, kappa
    • Gi (7TM)
    • most analgesics work at u
    • all show receptor specific tolerance (increasing amounts needed to stimulate with use) eg via betaARK phosphorylation, internalisation, down-regulation
  21. Describe descending inhibitory pain pathway
    • PAG to raphe magnus nucleus (NRM) to dorsal horn (inhibitory interneurons)
    • may also be direct
  22. Describe neuropathic pain (4 eg)
    • damage to peripheral nerves
    • eg phantom limb, diabetic neuropathy, post-herpetic neuralgia, tic doloueux
  23. 4 Drugs effective against neuropathic pain
    • Opiates: but receptors are downregulated in neuropathic pain
    • Tricyclic antidepressants: eg imipramine
    • Antiepileptic gabapetnetin or descendant pregabalin: inhibit N type VGCC
    • Ziconotide: blocks N type VGCC. Needs to be injected intrathecally, used in extreme cases eg pain of terminal cancer