Physiological Analgesia + Analgesic Drugs Flashcards
What is the decending pain pathway?
Brain regions involved in pain perception (e.g. cortex, amygdala) and the spinomesencephalic pathway project to the periaqueductal grey (PAG) in the midbrain.
The PAG projects to brainstem nuclei that project to the spinal cord, modifying nociceptive transmission. These include:
- the locus coeruleus (in pons), which sends noradrenergic projections
- the nucleus raphe magnus (in medulla) that sends serotonergic projections
What does stimulation of the PAG do?
Excitation produces profound analgesia
Excitation can also be caused by enkaphalins (enogenous opioids), morphine
This is through inhibition of inhibitory GABA (aka disinhibition)
How does suppression of descending nociceptive transmission work?
- Direct presynaptic inhibition - inhibition of presynaptic neurotransmitter release from nociceptors (via GPCRs supressing VGCCs)
- Direct postsynaptic inhibition - GPCRS open K+ channels -> hyperpolarisation
- Indirect inhibition - activation of inhibitory interneurons (enkephalinergic, GABAergic) that suppress transmission pre- and post-synaptically (opioid agonists mimic enkaphalinergic neuron actions) (enkephalin acts on mu receptors presynaptically -> blocks VGCCs -> prevents neurotransmitter release OR acts on mu receptors post-synaptically -> activates K+ channels -> hyperpolarisation)
How do analgesics reduce nociception/pain?
- NSAIDs (decrease nociceptor sensitisation in inflammation)
- Block nerve conduction
- Suppress nociception signals in dorsal horn
- Activate descending inhibitory pathways
- Target ion channels upregulated in nerve damage
Describe the analgesic ladder by The WHO
Analgesics are placed on rungs according to clinical efficacy. Rungs:
- Strong opioids (morphine, fentanyl, heroin)
- Weak opioids (codeine, tramadol)
- NSAID (aspirin, diclofenac, ibuprofen, naproxen)
What neurotransmitter do neurons from the nucleus raphe magnus use?
Noradrenaline
Noradrenergic pathway
What neurotransmitter do neurons from the locus coeruleus use?
Serotonin (5HT)
Serotonergic pathway
What are the 3 types of opioid receptors?
Mu - analgesic, rewarding
Delta - analgesic, proconvulsant
Kappa - analgesic at spine/periphery, sedation, dysphoria, hallucinations
Why are opioids rewarding?
Presynaptic mechanims -> blocks GABA release at interneurons that project onto VTA dopaminergic cells -> disinhibition + increased excitation of dopamine neurons -> DA released into nucleus accumbens -> rewarding plus addictive
What systems can be affected by opioid use?
- Respiratory (nausea)
- Cardiovascular (orthostatic hypotension - like when you stand up suddenly)
- Gastrointestinal (nausea, vomiting, constipation)
- CNS (confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia)
Morphine
Mu agonist
For acute severe and chronic pain
Metabolised by liver
Can be given IV, IM, SC, and orally
Oral most appropriate in chronic pain
Epidural provides profound analgesia
Diamorphine
More lipophilic than morphine
IV works rapidly
For severe post-operative pain
Codeine
Weaker opioid for milf/moderate pain
Metabolised in liver by demethylation to morphine by CYP2D6 + CYP3A4
Orally
Reduces gut motility (anti diarrhoea)
Semi-synthetic derivatives with higher potency (oxycodone + hydrocodone)
Fentanyl
75-100 fold more potent than morphine
IV as maintenance anaesthesia (can reduce amount of anaesthetic needed)
Okay for chronic, not acute
Pethidine (meperidine)
Acute pain, like labour
Given IV, SC, IM - rapid but short duration of action, not for chronic pain
Not used with MOA inhibitors (excitement, convulsion, hyperthermia)
Norpethidine is neurotoxic metabolite (seizures)
