Thermosensation Flashcards
What are thermoreceptors?
are neurons that are specialised to respond to small changes in temperature although sensitivity is not uniform across the body
What are some characteristics of cold thermoreceptors?
typically C and Ad fibres that respond to innocuous cold (15-30C) and noxious cold <15
What is the AP firing pattern for cold thermoreceptors?
they continuously fire at comfortable skin temperatures and increase firing rate at lower temperatures and stop at higher temperatures
Do thermoreceptors demonstrate adaptation?
they demonstrate adaptation cooling initially and then slowing decreasing the firing frequency in rapid and slow phases of adaptation
What substance might be used to mimic a cooling sensation?
menthol
Approximately how many DRG and trigeminal ganglion cells respond to both cold and menthol?
7% of DRG and 13-16% of TG respond with an increase in Ca
What is the main mechanism of depolarisation in cold receptors?
the opening of cation selective channels mediating an inward current
What two other mechanisms may contribute to the depolarisation of thermoreceptors in the DRG?
the closure of background K conductance channels such as TREK1
the inhibition of the Na/K-ATPase (minor effect)
Which TRP channel responds to menthol in a concentration dependent manner?
TRPM8
Which TRP channel responds to capsaicin?
TRPV1 - a cation selective channel causing neuronal depolarisation and excitation
Where might TRPV1 be found int he PNS?
on a subset of primary sensory neurons which act as nociceptors
What are some of the effects of acute activation by capsaicin?
causes the release of neurotransmitters and pro-inflammatory mediators at central and peripheral terminals
gives the subjective sensation of burning pain and increased sensitivity to other stimuli
What are some of the effects of chronic activation by capsaicin?
causes pharmacological desensitisation and functional desensitisation as the response of the nociceptor is reduced - probably underlying the analgesic effects of capsaicin
withdrawal of epidermal nerve fibres and nociceptor injury and degeneration
What is the structure of TRPV1?
it is a 95kDa, 6TM domain with IC N and C terminus and ankyrin repeats on the N terminus - Transient Receptor Potential Vannilloid
What is a feature of the agonists for TRPV1?
they all have a vanillyl group - capsaicin, rrsiniferatoxin and jellyfish and spider venom
What are some antagonists of the TRPV1?
ABT - high affinity, competitive and clinical candidate
capsazepine - competitive, med affinity, not selective
AMG - competitive, high affinity, discontinued as clinical candidate
How are TRPV1 channels activated and how is this countered?
activated by mildly noxious heat >43 although response is blocked by capsazepine and ruthenium red - single channel current block - can be seen from isolated membrane patches
What is the effect of pH on activation of TRPV1?
An acidic pH lowers the temperature at which the TRPV1 channel will activate and therefore activates in severe local acidosis
How are TRPV1 KO mice created?
removal of TM 2-4 or TM5, P loop and TM 6
What are some features of TRPV1 KO mice?
viable, fertile and generally indistinguishable but have disturbed bladder function
What are some of the hypoalgesic features of the KO mice?
increased tail latency at >48, increased hot plate latency at >50 and hyperalgesia to mechanical but not thermal stimuli
What are the inflammatory mediators at TRPV1?
PGE2 - thermal hyperalgesia gone in (-/-)
NGF - thermal hyperalgesia gone in (-/-)
Bradykinin - thermal hyperalgesia gone in (-/-)
PAR 2 receptor suppressed
Why was AMG 517 discontinued in clincal trials?
induced high hyperthermia which did not respond to paracetamol
What are antagonists of TRPV1 useful in?
reducing inflammatory pain
neuropathic pain, post-operative pain, cancer pain and osteoarthritis
What antagonists have so far been used and been successful?
ABT, SB and MK
What are some features of ABT?
causes mild hyperthermia which attenuates with daily use and increases heat pain tolerance and reduces painfulness of supra threshold oral and cutaneous heat
