BS42025 L5 Flashcards
what does electrical excitation of PAG produce?
profound analgesia
what do activated PAG neurons that project onto the NRM/LC do?
NRM- excite serotonergic and enkephalinergic neurons projecting to the dorsal horn resulting in suppression of nociceptive transmission
LC- LC noradrenergic neurons projecting to the dorsal horn are also excited and inhibit nociceptive transmission.
what are the mechanisms of suppression of nociceptive transmission in the dorsal horn? (3)
- Direct presynaptic inhibition- inhibition of neurotransmitter released from nociceptors. Works via G-protein coupled receptors (GPCRs) suppressing the opening of voltage-gated Ca2+ channels and Ca2+ influx required for transmitter exocytosis.
- Direct postsynaptic inhibition- works via GPCRs opening K+ channels in the projection neuron causing hyperpolarisation and reduced excitability.
- Indirect inhibition- works by activation of inhibitory interneurons (enkephalinergic and GABAergic) that suppress transmission by both pre-and post-synaptic mechanisms.
what do opioid agonist drugs mimic the activity of?
enkephalinergic interneurons
Analgesics may reduce nociception and pain by; (5) (+examples)
- Acting at the site of injury: decrease nociceptor sensitisation in inflammation (e.g. NSAIDs).
- Blocking nerve conduction: (e.g. local anaesthetics)- not considered here.
- Suppressing transmission of nociceptive signals in the dorsal horn of the spinal cord (e.g. opioids and some anti-depressant drugs).
- Activating (or potentiating) descending inhibitory controls (e.g. opioids)
- Targeting ion channels upregulated in nerve damage (e.g. antiepileptics)
what stages is the WHO pain ladder made up of?
3- strong opioid (eg. morphine, oxycodone, hydromorphone, heroin, fentanyl)
2- weak opioid (eg. codeine, tramadol, dextropropoxyphene)
1- paracetamol, NSAID (eg. aspirin, diclofenac, ibuprofen, naproxen, indometacin)
what combinations of the WHO pain ladder are used in moderate/severe pain?
1+2 or 1+3
how is opioid action mediated?
by G protein-coupled opioid receptors, all of which signal, preferentially to Gi/o
what actions do opioid GPCRs have to create analgesia? (3)
- Inhibition of opening of voltage-activated Ca2+ channels (presynaptic effect eg- suppresses excitatory neurotransmitter release from nociceptor terminals- mediated by the Gi/oBy subunit)
- Opening of K+ channels (postsynaptic effect eg- suppresses excitation of projection neurons- mediated by the Gi/oBy subunit)
- Inhibition of adenylate cyclase (important in long-term effects (mediated by the Gi/oa subunit)
what are the general roles of the three types of opioid receptors?
- U (mu, aka MOP) responsible for most of the analgesic action of opioids but unfortunately, also some major adverse effects.
- D (delta, aka DOP) contributes to analgesia but activation can be proconvulsant.
- K (kappa, aka KOP) contributes to analgesia at the spinal and peripheral level and activation associated with sedation, dysphoria and hallucinations.
what is the respiratory adverse effect and mechanism of opioids?
apnoea- blunting of medullary respiration centre to CO2; involves u and d receptors
what is the cardiovascular adverse effect and mechanism of opioids?
orthostatic hypotension- reduced sympathetic tone and bradycardia, histamine-evoked vasodilation.
what are the gastrointestinal adverse effect and mechanism of opioids?
nausea, vomiting, constipation, increased intrabiliary pressure- action of CTZ (in medulla), increased smooth muscle tone, decreased motility, via enteric neurons. involves u and d receptors
what are the CNS adverse effects and mechanisms of opioids?
confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia- these occur to different degrees depending on the specific opioid drug and receptor subtypes activated
give examples of opioid agonists (9)
- morphine
- diamorphine (heroin)
- codeine
- fentanyl
- pethidine
- buprenorphine
- tramadol
- methadone
- etorphine
