Pharmacology of Pain Flashcards
Give the definitions of pain vs nociception
how do they relate
Pain: An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
Nociception: The neural process of encoding noxious stimuli.
activation of a nociceptor can be considered sufficient, but not necessary, for the experience of pain.
What are the 2 types of nociceptor fibre
Nociceptors are either thinly myelinated Aδ-fibres or unmyelinated C-fibres
Describe the stoma and axon terminals of nociceptors
cell bodies are located in the dorsal root ganglia (DRG; trigeminal ganglia, TG, for the head) and their axon terminals do not have specialised endings, rather so-called free-endings
What are the 3 steps for the transmission of pain information along a nociceptor
(1). If receptor potential depolarisation is great enough, NaVs are activated (2); action potential propagation to the presynaptic terminals in the spinal cord results in the opening of voltage-gated calcium channels (CaVs) and Ca2+ influx results in the release of neurotransmitters on to postsynaptic terminals in the spinal cord (3)
For each of the following noxious stimuli, state which ion channels are activated: Temperature Protons ATP mechanical stimuli
- Heat = TRPV1, TRPM3, anoctamin-1, and TRPA1, and cold = TRPM8, TRPA1 (yes, senses both)
- Protons = ASICs, TRPV1, TASKS
- ATP = P2X3
- Mechanical stimuli = Piezo1/2, TRPV4?, ASICs?
How do you measure nociceptor activation
Nociceptor cell bodies can be isolated from DRG/TG, cultured and patch-clamp electrophysiology recordings made
True or false
sensitization does not occur in nociceptors
false
Sensitisation is a property characteristic of nociceptors: when a stimulus is great enough to cause tissue damage, the response to subsequent stimuli increases. Stimuli that usually cause pain now result in more pain (hyperalgesia) and previously innocuous stimuli now cause pain (allodynia).
Give an everyday example of allodynia
taking a shower when sunburned – hot water that would usually cause no pain now does!
How are allodynia and hyperalgesia reflected electrically in nociceptors
decreased response threshold (allodynia) and greater response (hyperalgesia) when compared to response before sensitisation
What are the 3 types of external stimuli that are capable of exciting a nociceptor
thermal, mechanical, or chemical.
Give 3 examples of internal stimuli that excite nociceptors
ATP (released from damaged cells), bradykinin (formed by kallikrein cleaving kininogen) and acid (released by anaerobic metabolism during anoxia or metabolic overload).
What are sensitising agents
do not directly excite the nociceptive nerve terminals, but instead enhance responses to excitatory agents. This class includes prostaglandins and nerve growth factor (NGF).
Some agents both excite and sensitize nociceptors, examples include bradykinin, ATP and H+.
What do nociceptor nerve terminals release when stimulated
what does this lead to
eg as calcitonin gene-related peptide (CGRP) and substance P (SP), peptides that cause vasodilatation and an increase in the permeability of blood vessels; these effects are both direct and indirect through SP inducing mast-cell degranulation.
The inflammation caused by the release of CGRP and SP from nerve terminals causes a redness (“flare”) surrounding the site of injury and is referred to as neurogenic inflammation.
What 2 reactions does COX catalyse
AA is first cyclised and oxygenated forming the endoperoxide PGG2; the hydroperoxyl in PGG2 is then reduced to form PGH2. PGE synthase produces PGE2 from PGH2, which acts to sensitise nociceptors
How does PGE2 bring about nociceptor sensitisation
give the cascade and how it is modified
There are 4 EP receptors and EP4 appears particularly important in inflammatory pain because its expression is upregulated. EP4 is Gs-coupled resulting in increased adenylate cyclase activity, cAMP production and thus activation of PKA and other signalling pathways.
One pathway for sensitisation involves PKA phosphorylation of the NaV isoform NaV1.8, which reduces its activation threshold meaning that a smaller depolarisation is able to evoke action potential firing
What is neuropathic pain
Peripheral nerve damage can result in pain that often outlasts the initial nerve injury, sometimes indefinitely
Following initiation in the periphery, changes in nociceptive processing at spinal and higher centres are likely involved in disease
give 5 examples of neuropathic pain
progression
- Phantom limb pain – sensation of pain in an amputated limb, long after its removal
- Infectious diseases (e.g. HIV, leprosy and hepatitis)
- Diabetic neuropathy
- Trigeminal neuralgia
- Post-herpetic neuralgia
How do NSAIDs work usually
by entering a hydrophobic channel on COX and forming hydrogen bonds with an Arg120, which prevents the entrance of fatty acids, like arachidonic acid, into the catalytic domain and preventing PG production
How does aspirin differ from other NSAIDs
; it enters the active site and acetylates a serine at position 530, which irreversibly inactivates COX, an action that explains certain long-lasting actions of aspirin
How can some drugs be COX2 selective
The bulky side group of COX-2 enables some drugs with large, sulphur-containing side groups to selectively act upon COX-2, but not COX-1.
Where are the different COX enzymes expressed
COX-1 is constitutive and expressed in many tissues, whereas COX-2 is induced in inflammatory cells when they are activated by, for example, cytokines such as TNF-α during inflammation (some tissues do have constitutive COX-2 activity )
Why does NSAIDs’ inhibition of COX enzymes result in pain reduction
results in decreased PGE2 synthesis and thus less nociceptor sensitisation and less pain; nociceptor excitability is returned to the resting, normal state. Because certain PGs are powerful vasodilators (PGE2 and PGI2), pain relief in headache may also result from decreased vasodilation of the cerebral vasculature.
For which conditions are NSAIDs most effective
inflammatory conditions when COX-2 is upregulated, e.g. arthritis, muscular pain, toothache, bursitis and dysmenorrhoea (period pain).
Describe the cardiovascular protective action of aspirin
inhibition platelet derived thromboxane – acetylated COX can be replaced by newly synthesised protein in cells, but thromboxane production by platelets is switched off for their lifetime (approx. 10 days).
