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
give examples of opioid antagonists (4)
- naloxone
- naltrexone
- alvimopan
- methylnaltrexone
what are used to treat mild/moderate inflammatory pain?
NSAIDs
non-selective NSAIDs have what kinds of actions?
analgesic, antipyretic and anti-inflammatory
what do NSAIDs do?
largely inhibit the synthesis and accumulation of prostaglandins by cyclo-oxygenase (COX) enzymes COX-1 and COX-2.
when are COX1 and COX2 active?
COX-1 is constitutively active, COX-2 is induced locally at sites of inflammation by various cytokines
how do NSAIDs act peripherally and centrally? (3)
- Suppress the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by prostaglandins.
- Decrease recruitment of leukocytes that produce inflammatory mediators.
- If they cross the BBB, suppress the production of pain-producing prostaglandins in the dorsal horn of the spinal cord (that, for example, reduce action of the inhibitory neurotransmitter, glycine).
why is paracetamol not an NSAID?
because it lacks anti-inflammatory activity and acts only centrally
why do NSAIDs have limited analgesic efficacy?
because multiple signalling pathways, several of which do not involve arachidonic acid metabolism, cause nociceptor sensitisation
how can long term administration of non-selective NSAIDs produce gastrointestinal damage?
- NSAIDs inhibit COX-2
- PGE2 produced by COX-2 protects against the acid/pepsin environment
