Mechanisms of Human Heat Perception - Involvement of TRPA1, TRPV1 and TRPM3
Status and phase
Completed
Early Phase 1
Conditions
Pain
Treatments
Drug: TRPV1-inhibitor
Drug: TRPA1-inhibitor
Drug: Chloride-channel inhibitor
Drug: TRPM3-inhibitor
Drug: Placebo
Details and patient eligibility
About
Animal studies suggest that the ion channels TRPV1, TRPA1 and TRPM3 are the relevant heat sensors. This study aims to validate these findings in humans.
Full description
Surprisingly, it is still not fully understood how humans perceive heat pain. There are several heat-sensitive ion channels whose manipulation in animals resulted in a more or less pronounced phenotype. However, complete blockade of heat sensation in animals has only recently been achieved. In triple knockout mice lacking TRPA1, TRPV1 and TRPM3, it was recently shown that only in the absence of all three receptors heat perception is largely abolished. Although the authors were unable to elucidate the underlying mechanism of this redundancy, the redundancy appears to have evolutionary value for protection against burns. In addition, recent evidence suggests that TRPV1 plays a role as a first-line defense against heat injury, i.e., that it encodes noninjurious heat injury in humans.
The goal of this study is to test whether the redundant functions of TRPV1, TRPA1 and TRPM3 observed in mice with respect to heat perception also apply to humans. More broadly, we want to understand which receptors enable humans to perceive heat pain. The study also aims to test if a chloride channel is involved in heat perception.
Design: Cross-over study with a Williams design group, 16 treatments incl. a placebo control.
Enrollment
51 patients
Sex
All
Ages
18 to 70 years old
Volunteers
Accepts Healthy Volunteers
Inclusion criteria
- Age between 18 and 70 years
- Full legal capacity
To ensure an equal number of each sex in the study population, only volunteers of one sex will be included as soon as the number of subjects with the other sex has reached half of the calculated sample size.
Exclusion criteria
- Participant of another study, ongoing or within the last 4 weeks
- Medication intake (except contraception) or drug abuse
- Female subjects: Positive pregnancy test or breastfeeding
- Body temperature above 38°C, diagnostically verified
- Known allergic diseases, in particular asthmatic disorders and skin diseases, known allergic reactions to citrus fruits (but excluding food intolerances).
- Sensory deficit, skin disease or hematoma of unknown origin in physical examination of the test site
- Symptoms of a respiratory tract infection (Covid-19 related criterion)
Trial design
Primary purpose
Basic Science
Allocation
Randomized
Interventional model
Single Group Assignment
Masking
Triple Blind
51 participants in 16 patient groups, including a placebo group
Hot injection without TRP-channel inhibition
Placebo Comparator group
Description:
Pain induced by an increasingly hot intradermal injection up to 52°C over 2 minutes.
Treatment:
Drug: Placebo
Hot injection with TRPA1-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPA1-inhibitor
Hot injection with TRPV1-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPV1-inhibitor
Hot injection with TRPM3-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Hot injection with TRPA1- and TRPV1-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and TRPV1 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPA1-inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPA1- and TRPM3-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and TRPM3 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: TRPA1-inhibitor
Hot injection with TRPM3- and TRPV1-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 and TRPV1 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1, TRPV1 and TRPM3 are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: TRPA1-inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPA1-, TRPM3- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: Chloride-channel inhibitor
Drug: TRPA1-inhibitor
Hot injection with TRPV1-, TRPM3- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: Chloride-channel inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPA1- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPA1 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: Chloride-channel inhibitor
Drug: TRPA1-inhibitor
Hot injection with TRPV1- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: Chloride-channel inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPA1, TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: Chloride-channel inhibitor
Drug: TRPA1-inhibitor
Drug: TRPV1-inhibitor
Hot injection with TRPM3- and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPM3 and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: TRPM3-inhibitor
Drug: Chloride-channel inhibitor
Hot injection with TRPV1-, TRPA1, and chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while TRPV1, TRPA1, and a chloride channel are blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: Chloride-channel inhibitor
Drug: TRPA1-inhibitor
Drug: TRPV1-inhibitor
Hot injection with chloride channel inhibition
Experimental group
Description:
Pain is induced by an increasingly hot intradermal injection up to 52°C over 2 minutes, while a chloride channel is blocked pharmacologically by an antagonist dissolved in the hot fluid (synthetic interstitial fluid). The antagonist(s) have sufficient concentration to reliably block the channel. The total dose is in the range of a microdose trial.
Treatment:
Drug: Chloride-channel inhibitor
Trial contacts and locations
1
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