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Primary hyperalgesia caused by
Pro-inflammatory mediators: PGE2 and bradykinin
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Secondary hyperalgesia caused by
changes in the strength of connections to 2nd order neurons in the dorsal horn of the SC
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Internal factors exciting nociceptors (4)
ATP, bradykinin, high [K+], acid
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Sensitizing agents (5)
NO, NGF, prostaglandins, serotonin, histamine
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Both sensitise and excite nociceptors
bradykinin, ATP, H+
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Ion channel: extreme heat
TRPV2
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Ion channel: acid
ASID (acid sensitive ion channel)
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Ion channel: extreme cold
TRPA1
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Ion channel: mechanical stimuli
TRPV4
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Na channels in nociceptive nerve terminals
Nav1.7 and 1.8
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Sensitisation mechanism of PGE2
- Gs -> AC -> cAMP -> PKA -P-> Nav1.8 (lowers threshold of activation
- or cAMP -> activates Ih (inward Na current)
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Sensitisation mechanism of bradykinin
-> Gq -> PLC -> PIP2 -> DAG -> PKC -P-> TRPV1 (at 2 sites, lowers heat threshold at which channels are activated)
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NSAIDs: method, 3 egs
- Inhibit COX 1 and 2 -> inhibit prostaglandin release
- eg aspirin, ibuprofen, diclofenac
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Opiates: method, egs (2)
- Decrease cAMP via u opioid receptor
- eg morphine, fenatyl
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Icatabant
bradykinin B2 receptor antagonist (not used)
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dexamethasone
- steroidal anti-inflammatory drug
- downregulates transcription of genes for proteins like COX 2 and bradykinin B1 and B2 receptors (involed in inflammation)
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diclofenac
NSAID: inhibits COX1+2 and therefore prostaglandin release
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fenatyl
opioid: decreases cAMP via u opioid receptor
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celecoxib
COX-2 specidic inhibitor: fewer GI side effects, but had cardic side effects -> mostly withdrawn
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ketamine
NMDA receptor antagonist (effects on memory and cognitive functions)
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ziconotide
blocks N type Ca channels (similar to opiates but without addictive side effects)
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3 types of opioid receptor
mu, sigma, kappa
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amitriptyline
tricyclic antidepressent, seems to be effective against neuropathic pain
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imipramine
tricyclic antidepressent, seems to be effective against neuropathic pain
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gabapentin
antiepileptic drug, off-target effect of inhibiting N-type Ca channels
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pregabalin
antiepileptic drug, off-target effect of inhibiting N-type Ca channels
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