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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
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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)
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Sensitising stimuli (8)
Histamine, NO, 5-HT, prostaglandins, NGF, bradykinin, ATP, acid
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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.
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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
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Which sodium channels are found at nociceptive nerve terminals?
Nav1.7 and 1.8
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Which sodium channels are widespread?
Nav1.1, 1.6
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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)
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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
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3 Potentials for drugs to act on transduction of pain
- Nav1.7 and Nav1.8
- Specific ion channels
- Blocking sensitising kinases
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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
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Exp for sensitisation
- Bradykinin periodically injected as a test nociceptive stimulus
- Prostaglandin increased response
- Also, bradykinin increases response to heat stimulus
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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
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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
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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)
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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:
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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
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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
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Describe endogenous opiates and name 3
- short polypeptides, homology esp at terminus
- endorphins, enkephalins, nociceptin
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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
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Describe descending inhibitory pain pathway
- PAG to raphe magnus nucleus (NRM) to dorsal horn (inhibitory interneurons)
- may also be direct
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Describe neuropathic pain (4 eg)
- damage to peripheral nerves
- eg phantom limb, diabetic neuropathy, post-herpetic neuralgia, tic doloueux
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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
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