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Pain
| Term | Definition |
|---|---|
| Pain definition | Unpleasant sensory/emotional experience associated w/ or resembling actual/potential tissue damage |
| Nociception definition | Neural process of encoding noxious stimuli |
| Nociceptor fibres | Thinly myelinated A-delta fibres (sharp stabbing pain), unmyelinated C fibres (dull burning pain) |
| Nociception transduction | Ion channels -> receptor potnetial reaches sufficient depolarisation -> open VGNaC -> AP propagation to spinal cord presynaptic terminals -> VGCaC -> Ca2+ influx -> nt release to postsynaptic terminals in spinal cord |
| Heat receptors | TRPV1, TRPM3, anoctamin-1, TRPA1 |
| Cold receptors | TRPM8, TRPA1 |
| Proton receptors | ASICs, TRPV1, TASK-1 (K+ efflux ion channel blocked by H+) |
| ATP receptors | P2X3 (ionotropic) |
| Mechanical stimuli receptors | Piezo1/2, TRPV4, ASICs |
| Nociceptor classes | Polymodal -> respond to many different stimuli, unimodal (only respond to particular type of stimuli), silent (only sensitised/recruited by cytokines during inflammation) |
| Nociceptor sensitisation | If stimulus is sufficient to cause tissue damage, there is increased response to subsequent stimuli -> hyperalgesic (same stimulus = more painful), allodynic (previously innocuous -> painful) |
| What pain stimuli are released during tissue damage? | Intracellular factors from damaged/overstressed cells -> excitatory agents/ATP, bradykinin -> formed by kallikrein cleaving kininogen, acid -> released by anoxic anaerobic/overloaded metabolism |
| What are sensitising agents? | Don't directly activate nociceptors but enhance the responses to excitatory agents -> PG, NGF |
| What is released when nociceptors are stimulated? | CGRP (calcitonin gene-related peptide -> potent vasodilator), substance P (vasodilator/inflammatory mediator - mast cell degranulation) |
| Erenumab | CGRP mAb antagonist -> prevents vasodilation -> prophylactic relief in migraines |
| Arachidonic acid pain pathway | Metabolised to prostanoids via COX-1/2 -> AA cyclised and oxygenated to form PGG2 (endoperoxide) -> hydroperoxyl reduced to form PGH2 -> converted to PGE2 by PGE synthase |
| PGE2 effect on nociceptors | Sensitising agent for 4 PGE2 receptors -> Gs -> increase AC -> increase cAMP -> PKA activation -> Na+ channel phosphorylation (opening) -> Na+ influx -> reduce activation threshold -> smaller depolarisation evokes AP firing |
| Neuropathic pain definition | Pain outlasting initial nerve injury due to phangom limb, infectious disease (HIV, leprosy, hepatitis), diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia |
| Analgesics definition and examples | Inhibit nociceptor sensitisation by decreasing neuronal excitability -> NSAIDs, opioids, antidepressants, GABA analogues, Nav inhibitor, Cav inhibitor |
| NSAIDs | Inhibit COX enzymes -> inhibit PG production -> less nociception sensitisation > enter hydrophobic channel on PGE synthase enzyme -> form H-bonds w/ Arg120 -> prevent AA entrance into catalytic domain -> xcp aspirin |
| Aspirin | NSAID -> enters PGE synthase active site -> acetylates Ser530 -> irreversible acetylation/inactivation of COX -> long-lasting aspiring action -> weakly COX-1 selective -> cardiovascular protection (prevent platelet derived thromboxane) and treat migraines |
| COX-1 vs COX-2 | COX-1 is constitutive (inhibition has unwanted side effects), COX-2 is only induced in activated inflammatory cells via TNF-alpha (inhibition has anti-inflammatory/analgesic effects) |
| NSAID examples | Ibuprofen -> weakly COX-1 selective (RA/gout/soft tissue disorder symptomatic relief), paracetamol -> analgeisc/antipyretic (poor anti-inflammatory - not NSAID), ectoricoxib -> COX-2 selective (osteoarthritis/RA) |
| NSAID side effects | Inhibition of constitutive COX-1 activity -> GI bleeding (PGs inhibit gastric acid secretion/stimulate mucin release), renal insufficiency (PGE/I2 maintain RBF), stroke/MI (inhibit PG vasodilation), bronchospasm |
| Naloxone | Opioid receptor antagonist |
| Opioids | Substance producing morphine-like effects -> mu, kappa, delta, ORL1 receptors -> Gi/o coupled -> betagamma subunit opens GIRK (hyperpolarisation - less likely AP), inhibit Ca2+ channel opening -> decreased Ca2+ influx -> decreased nt release |
| Opioid peripheral inhibitory action | Peripheral -> AC inhibition counteracts PG nociceptor sensitising effects |
| Opioid central inhibitory action | Spinal cord dorsal horn -> presynaptic nociceptor inhibition decreases nt release, postsynaptic nociceptor inhibition decreases dorsal horn excitability, supraspinal -> PAG evokes endogenous inhibitory systems and reduce affective pain (mu-mediated) |
| Opioid examples | Morphine, diamorphine, codeine, buprenorphine, etorphine |
| Morphine and diamorphine | Opioids -> morphine -> acute/chronic pain, diamorphine (heroin) -> prodrug metabolised to 6-monoacetyl/morphine -> higher lipid solubility than morphine when IV administered -> BBB penetration -> subsequent deacetylation gives analgesic effects |
| Codeine | Opioid -> oral absorption (less analgesic effects) -> prodrugs combined w/ NSAID for mild pain |
| Buprenorphine | Opioid -> partial opioid receptor agonist -> patch administration -> slow dissociation + combined high affinity/low efficacy -> antagonises other opioids -> more effective than full agonists as gives moderate analgesia w/ less respiratory depression |
| Etorphine | Opioid -> 1000x more potent than morphine (large animals) |
| Additive analgesia | Drugs inducing analgesia via different mechanisms -> less of each drug needs to be given -> will reduce side effects -> co-codamol = paracetamol (NSAID) + codeine (opioid) |
| Opioid side effects | mu-mediated respiratory depression (inhibit respiratory rhythm/central chemoreceptors), nausea/vomiting (delta/mu-mediated), constipation (mu/delta/kappa-mediated) |
| Antidepressants | 5-HT selective reuptake inhibitors (SSRI) -> largely inefficacious, 5-HT/NA reuptake inhibitors (SNRI) and tricyclic antidepressants (TCAs) |
| Fluoxetine | Antidepressant - SSRI -> largely inefficacious |
| Duloxetine | Antidepressant - SNRI -> relief in neuropathic pain -> descending inhibitory pain modulation from locus ceoruleus w/ NA |
| Amitriptyline | Tricyclic antidepressant |
| GABA analogue mechanisms | Decrease cell surface localisation of Ca2+ channel alpha2 delta1 subunit -> decrease in Ca2+ channel current density -> prevent neuropathic pain/reduce nt release |
| Gabapentin/pregabalin | GABA analogue -> epilepsy treatment -> no effect on acute pain |
| Nav inhibitor mechanism/examples | Prevent Na+ influx -> reduce depolarisation -> raise threshold for AP -> lidocaine (Ib - LA -> prevents spontaneous peripheral neuron discharge for neuropathic pain), carbamazepine -> anti-epileptic/treat neuropathic pain via trigeminal neuralgia |
| Cav inhibitor mechanism/examples | Prevent Ca2+ influx -> reduce nt release -> ziconotide -> synthetic analogue administered intrathecally to prevent widespread, deleterious side effects -> expensive and invasive |
| Pain ladder | Step 1 -> non-opioid NSAID + adjuvant, step 2 -> weak opioid (codeine) +- non-opioid/adjuvant, step 3 -> strong opioid (morphine) +- non-opioid/adjuvant |
| Pain ladder dis/advantages | Developed for cancer pain -> works well for post-operative pain but less well for neuropathic pain |
Created by:
vykleung
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