Thermosensation

Question 1

What are thermoreceptors?

Answer 1

are neurons that are specialised to respond to small changes in temperature although sensitivity is not uniform across the body

Question 2

What are some characteristics of cold thermoreceptors?

Answer 2

typically C and Ad fibres that respond to innocuous cold (15-30C) and noxious cold <15

Question 3

What is the AP firing pattern for cold thermoreceptors?

Answer 3

they continuously fire at comfortable skin temperatures and increase firing rate at lower temperatures and stop at higher temperatures

Question 4

Do thermoreceptors demonstrate adaptation?

Answer 4

they demonstrate adaptation cooling initially and then slowing decreasing the firing frequency in rapid and slow phases of adaptation

Question 5

What substance might be used to mimic a cooling sensation?

Answer 5

menthol

Question 6

Approximately how many DRG and trigeminal ganglion cells respond to both cold and menthol?

Answer 6

7% of DRG and 13-16% of TG respond with an increase in Ca

Question 7

What is the main mechanism of depolarisation in cold receptors?

Answer 7

the opening of cation selective channels mediating an inward current

Question 8

What two other mechanisms may contribute to the depolarisation of thermoreceptors in the DRG?

Answer 8

the closure of background K conductance channels such as TREK1
the inhibition of the Na/K-ATPase (minor effect)

Question 9

Which TRP channel responds to menthol in a concentration dependent manner?

Answer 9

TRPM8

Question 10

Which TRP channel responds to capsaicin?

Answer 10

TRPV1 - a cation selective channel causing neuronal depolarisation and excitation

Question 11

Where might TRPV1 be found int he PNS?

Answer 11

on a subset of primary sensory neurons which act as nociceptors

Question 12

What are some of the effects of acute activation by capsaicin?

Answer 12

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

Question 13

What are some of the effects of chronic activation by capsaicin?

Answer 13

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

Question 14

What is the structure of TRPV1?

Answer 14

it is a 95kDa, 6TM domain with IC N and C terminus and ankyrin repeats on the N terminus - Transient Receptor Potential Vannilloid

Question 15

What is a feature of the agonists for TRPV1?

Answer 15

they all have a vanillyl group - capsaicin, rrsiniferatoxin and jellyfish and spider venom

Question 16

What are some antagonists of the TRPV1?

Answer 16

ABT - high affinity, competitive and clinical candidate
capsazepine - competitive, med affinity, not selective
AMG - competitive, high affinity, discontinued as clinical candidate

Question 17

How are TRPV1 channels activated and how is this countered?

Answer 17

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

Question 18

What is the effect of pH on activation of TRPV1?

Answer 18

An acidic pH lowers the temperature at which the TRPV1 channel will activate and therefore activates in severe local acidosis

Question 19

How are TRPV1 KO mice created?

Answer 19

removal of TM 2-4 or TM5, P loop and TM 6

Question 20

What are some features of TRPV1 KO mice?

Answer 20

viable, fertile and generally indistinguishable but have disturbed bladder function

Question 21

What are some of the hypoalgesic features of the KO mice?

Answer 21

increased tail latency at >48, increased hot plate latency at >50 and hyperalgesia to mechanical but not thermal stimuli

Question 22

What are the inflammatory mediators at TRPV1?

Answer 22

PGE2 - thermal hyperalgesia gone in (-/-)
NGF - thermal hyperalgesia gone in (-/-)
Bradykinin - thermal hyperalgesia gone in (-/-)
PAR 2 receptor suppressed

Question 23

Why was AMG 517 discontinued in clincal trials?

Answer 23

induced high hyperthermia which did not respond to paracetamol

Question 24

What are antagonists of TRPV1 useful in?

Answer 24

reducing inflammatory pain

neuropathic pain, post-operative pain, cancer pain and osteoarthritis

Question 25

What antagonists have so far been used and been successful?

Answer 25

ABT, SB and MK

Question 26

What are some features of ABT?

Answer 26

causes mild hyperthermia which attenuates with daily use and increases heat pain tolerance and reduces painfulness of supra threshold oral and cutaneous heat