6.0 Pharmacology of Pain Flashcards
(41 cards)
Define pain:
Unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Define nociception:
The neural processes of encoding noxious stimuli
What are the nociceptive fibres?
Aδ (thin myelin)<br></br>C (no myelin)
Where are cell bodies of nociceptors found?
1) Dorsal root ganglia<br></br>2) Trigeminal ganglia (head and neck)
What is the structure of the nociceptive fibre axon terminals?
Free endings (do not have specialised endings)
What are the steps for nociceptive transmission from nociceptive receptor to post-synaptic neuron:
1) Many ion channel can be activated in peripheral nerve → receptor potential<br></br>2) If receptor potential is great enough → <b>Voltage-gated sodium channels (NaVs) open</b><br></br>3) Action potential propagates along the presynaptic nerve towards the spinal cord<br></br>4) AP opens <b>voltage gated calcium channels (CaVs)</b> in end terminals<br></br>5) Influx of Ca²⁺ → neurotransmitter release onto post-synaptic neuron in spinal cord
What are the ion channels that are stimulated by the following noxious stimuli:<br></br><br></br>1) Noxious heat<br></br>2) Noxious cold<br></br>3) Protons<br></br>4) ATP<br></br>5) Mechanical stimuli
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At what temperature do heat sensitive nociceptive neurons activate? <br></br><br></br>(What temperature is pain reported?)
42°C
Define sensitisation:
A characteristic of nociceptors. When a stimulus is large enough to cause damage, subsequent stimuli generate a larger response. Can cause hyperalgesia or allodynia
Define hyperalgesia:
Stimuli that usually cause pain, now cause more pain
Define allodynia:
Previously innocuous stimuli now cause pain
What are examples of external stimuli and internal factors that nociceptors can <b>directly</b> respond to:
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Give examples of agents that are purely sensitising agents:<br></br><br></br>(i.e. they do not directly excite nociceptive nerve terminals, only enhance response to excitatory agents)
1) Prostaglandins<br></br>2) Nerve growth factor (NGF)
Give examples of agents that both excite and sensitize nociceptiors:
1) Bradykinin<br></br>2) ATP<br></br>3) H⁺
What agents, released from nerves, induce neurogenic inflammation?
<b>1) Calcitonin gene-related peptide (CGRP)</b><br></br>Indirect effect<br></br><br></br><b>2) Substance P (SP)</b><br></br>Direct effect (cause mast cell degranulation)
What is the mechanism by which PGE2 sensitises nociceptors?
1) PGE₂ binds to EP₄ receptor (upregulated in inflammation)<br></br>2) Gs coupled → ↑ cAMP → + PKA → phosphorylation of sodium channels<br></br>3) This phosphorylation means that the sodium channel has a lower threshold for AP firing
Define neuropathic pain:
Peripheral nerve damage can cause pain that outlasts initial nerve injury (sometime permanent). <br></br><br></br>Following changes in periphery, it is likely that nociceptive processing at the spinal cord and higher centres are likely involved in disease progression.<br></br><br></br>Examples:<br></br>1) Phantom limb<br></br>2) Diabetic neuropathy<br></br>3) Trigeminal neuopathy<br></br>4) Post-herpetic neuropathy
Mechanism of action of most NSAIDs:
1) Enter COX via hydrophobic channel<br></br>2) H-bond with Arg 120<br></br>3) This prevents arachidonic acid to enter catalytic site<br></br><br></br>Reversible
Mechanism of action of Aspirin:
1) Enters active site<br></br>2) Acetylates Serine 530<br></br>3) This prevents arachidonic acid to enter catalytic site<br></br><br></br>Irreversible
Mechanism for COX-2 selectivity:
COX-2 has a larger hydrophobic channel thus, COX-2 selective drugs have a large sulphur side group.<br></br><br></br>This prevents them from entering the hydrophobic channel of COX-1
What activates COX-2 to increase its expression during inflammation?
TNFα
Effect of NSAIDs on periphery:
<b>NSAIDs work mainly via peripheral action:</b><br></br>COX inhibition ⟶ ↓ PGE₂ ⟶ ↓ nociceptor sensitisation and less pain <br></br>(nociceptor excitability is returned to the resting, normal state)<br></br><br></br>Some PGs are also vasodilators (PGE₂ and PGI₂) ∴ NSAIDs can also help in headache (by ↓ vasodilation of cerebral vasculature)
Effect of NSAIDs centrally:
<b>NSAIDs work mainly via peripheral action</b><br></br><b>Smaller effect centrally</b><br></br><br></br>PGs are thought to facilitate nociceptor neurotransmission
What is the lifespan of a platelet?
10 days<br></br><br></br>(Effect of aspirin on platelets = 10 days)
Etoricoxib
Tend to end in -coxib
1) GI bleeding
2) Bronchospasm
3) Renal insufficiency
4) Stroke/MI (because of disruption of consitutive COX-2 in CVS tissue)
2) Endomorphin
3) Dynorphin
4) Enkephalin
2) κ
3) δ
4) ORL₁
All receptors are Gi/Go protein coupled
2) Free hydroxyl group on one ring
3) Nitrogen atom linked by 2 carbon atoms to another benzene ring
βγ subunit interacts with:
1) GIRKS (inward rectifying K⁺ channels)
→ hyperpolarisation → less chance of AP
2) Voltage gated calcium channels → ↓ opening
3) Adenylate cyclase (AC) → ↓ activity
1) Periphery
2) Spinal cord
3) Supraspinally
• Inhibition of AC counteracts sensitising activity of PGs
Spinal cord
• Dorsal horn opioids act:
1) Presynaptically on nociceptors ⟶ ↓ neurotransmitter release
2) Postsynaptically on nociceptors ⟶ ↓ dorsal horn neuron excitability
Supraspinally
• Opioids have roles in a number of brain areas including PAG region
• Opioids may evoke the activation of endogenous inhibitory systems
2) Nausea/vomiting
3) Constipation
4) Tolerance and dependence
(inhibits respiratory rhythm + central chemoreceptors)
2) δ
2) κ
3) δ
Mechanism = unclear
Though to ↓ surface localisation of α₂δ₁ subunit of the voltage gated calcium channels.
This reduces neurotransmitter release
Pregabalin = better pharmacokinetics
Needs to be administered intrathecally
