TRPV1 in Nociception Flashcards
What are TRP receptors?
Sensory function
TRPV1, TRPM3 and TRPA 1 - involved with heat nociception and thermal fibre algesia
What are the major families within the TRP superfamily?
TRPC - canonical TRPM - melastatin TRPV - vanilloid (major focus; esp TRPV1) TRPA - ankryrin TRPML - mucolipin TRPP - polycycstin
What does capsacin activate?
TRPV1 with an integral cation selective channel
What is the effect of capsaicin on a DRG neuron?
Inward current response of sodium and calcium ions
Neuronal depolarization
Excitation
Inward current response evoked by capsaicin applied to an adult rate DRG neuron
Highly permeable to calcium, which increases prolonged activation
As the channel is activated for longer periods of time, the permeability to calcium increases
In the PNS; TRPV1 is mainly located upon a subset of primary sensory neurons (C-fibres and A-delta) that act as nociceptors
Expressed on vagal sensory afferents and urinary bladder
Describe the structure of TRPV1
Rat TRPV1;
838 Amino Acid Protein (subunit is roughly double that of a nAChR)
Each subunit of TRPV1 is around 95 kDa
Displays intracellular N and C termini, predicted TM domains and a P-loop sequence
N terminal has ankyrin repeats (important to allow for TRPV1 to attach to cytoskeleton)
Re-entrant loop (5th and 6th TM) forming a pore region
Assembles as a tetramer of identical subunits
What are the acute effects of capsaicin upon nociceptors
Acute activation; membrane depolarization and neuronal excitation
Release of transmitters and pro-inflammatory peptides (e.g. sub P and CGRP) mediators and central and peripheral terminals
Subjective sensation of warming, itching, stinging or burning pain (algesic action)
Increased sensitivity to other stimuli (heat, acidosis) around site of application
What are the long term effects of capsaicin upon nociceptors
Pharmacological desensitization (i.e. loss of responsiveness to capsaicin)
Nociceptor defunctionalisation (e.g. functional desensitization - response of the nociceptor to other inputs is also reduced; underlies the analgesic effect (occurs within hours of treatment with high doses and may persist for several weeks)
Withdrawal of epidermal nerve fibres; nociceptor injury/ degeneration
Skin biopsies show a reversible loss of TRPV1 immunoreactivity
How does defunctionalisation of nociceptors occur?
Rapid effects; inactivation of voltage activated Na+ channels and pharmacological desensitization of TRPV1
Long term;
Buffering of intracellular calcium exceeded because of; excessive calcium influx via TRPV1, release of calcium from intracellular organelles via TRPV1 (TRPV1 receptors present on ER), mitochondrial dysfunction
This consequently results in protease activation and breakdown of the cytoskeleton. Loss of terminals of nociceptive terminals - reduced immunoreactivity in response to prolonged capsaicin application
What agonists are present for TRPV1?
Capsaicin (found in chilli peppers)
Spider venom (vanilotoxin)
Resiniferatoxin (ultra-potent agonist)
Jellyfish venom (positive modulator)
All contain a vanillyl moiety
Describe the role of spider venom with its action on TRPV1
Double Knot Toxin (DkTx)
Bivalent, high avidity, activating interaction
Irreversible activator of TRPV1
2 Heads to the molecule tethered by a flexible chain.
Each head is capable of binding to separate TRPV1 subunits
Antibody like mode of activation
Describe some additional activators of TRPV1
Piperine; pungent component of black pepper
Gingerol and zingerone; ginger
Eugenol; clove
Ethanol; activates TRPV1 (burning sensation)
Endogenous endovanilloids; anandamide (endocannabanoid) , arachidonic acid metabolites, linoleic acid metabolites
