Mechanisms of Human Heat Perception - Involvement of TRPA1, TRPV1 and TRPM3

Early Phase 1

Completed

• Conditions: Pain
• Interventions: Drug: Placebo; Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

• Registration Number: NCT05275751
• Lead Sponsor: Medical University of Vienna

Brief Summary

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.

Detailed 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.

Study Timeline

• Study First Submitted: 2022-02-22
• Study First Submitted QC: 2022-03-02
• Study First Posted: 2022-03-11
• Study Start: 2022-06-13
• Primary Completion: 2022-11-30
• Study Completion: 2022-11-30
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-16
• Last Update Posted: 2023-03-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 51

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.

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Hot injection without TRP-channel inhibition	Placebo	Pain induced by an increasingly hot intradermal injection up to 52°C over 2 minutes.
Hot injection with TRPA1-inhibition	TRPA1-inhibitor	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.
Hot injection with TRPV1-inhibition	TRPV1-inhibitor	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.
Hot injection with TRPM3-inhibition	TRPM3-inhibitor	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.
Hot injection with TRPA1- and TRPV1-inhibition	TRPA1-inhibitor	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.
Hot injection with TRPA1- and TRPV1-inhibition	TRPV1-inhibitor	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.
Hot injection with TRPA1- and TRPM3-inhibition	TRPA1-inhibitor	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.
Hot injection with TRPA1- and TRPM3-inhibition	TRPM3-inhibitor	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.
Hot injection with TRPM3- and TRPV1-inhibition	TRPV1-inhibitor	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.
Hot injection with TRPM3- and TRPV1-inhibition	TRPM3-inhibitor	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.
Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition	TRPA1-inhibitor	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.
Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition	TRPV1-inhibitor	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.
Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition	TRPM3-inhibitor	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.
Hot injection with TRPA1-, TRPM3- and chloride channel inhibition	TRPA1-inhibitor	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.
Hot injection with TRPA1-, TRPM3- and chloride channel inhibition	TRPM3-inhibitor	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.
Hot injection with TRPA1-, TRPM3- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPV1-, TRPM3- and chloride channel inhibition	TRPV1-inhibitor	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.
Hot injection with TRPV1-, TRPM3- and chloride channel inhibition	TRPM3-inhibitor	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.
Hot injection with TRPV1-, TRPM3- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPA1- and chloride channel inhibition	TRPA1-inhibitor	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.
Hot injection with TRPA1- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPV1- and chloride channel inhibition	TRPV1-inhibitor	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.
Hot injection with TRPV1- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition	TRPA1-inhibitor	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.
Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition	TRPV1-inhibitor	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.
Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition	TRPM3-inhibitor	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.
Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPM3- and chloride channel inhibition	TRPM3-inhibitor	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.
Hot injection with TRPM3- and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with TRPV1-, TRPA1, and chloride channel inhibition	TRPA1-inhibitor	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.
Hot injection with TRPV1-, TRPA1, and chloride channel inhibition	TRPV1-inhibitor	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.
Hot injection with TRPV1-, TRPA1, and chloride channel inhibition	Chloride-channel inhibitor	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.
Hot injection with chloride channel inhibition	Chloride-channel inhibitor	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.

Primary Outcome Measures

Name	Time	Method
HPI(50-52) - Heat pain inhibition in the range between 50°C and 52°C	Through study completion, on average 4 days.	'Heat pain inhibition between 50 and 52 °C', abbreviated HPI(50-52). A value of 0% would indicate that for a given injection there was no inhibition between 50 and 52 °C, i.e. that the injection was equal to a heated control injection without substance. In contrast, a value of 100% would indicate that there was complete inhibition and the injection was as indistinguishable from the injection at room temperature.; Of note, pain is rated during the application of the test substances. There are 2 experimental days with injections, separated by a few days, resulting in a time frame of 4 days on average.; The principle of AUC calculations from pain ratings during injections is described in Heber et al. 2020 (PMID: 32107360 DOI: 0.1097/j.pain.0000000000001848)

Secondary Outcome Measures

Name	Time	Method
HPI - Heat pain inhibition	Through study completion, on average 4 days.	'Heat pain inhibition between room temperature and 52 °C', abbreviated HPI. A value of 0% would indicate that for a given injection there was no inhibition, i.e. that the injection was equal to a heated control injection without substance. In contrast, a value of 100% would indicate that there was complete inhibition and the injection was as indistinguishable from the injection at room temperature.; Of note, pain is rated during the application of the test substances. There are 2 experimental days with injections, separated by a few days, resulting in a time frame of 4 days on average.; The principle of AUC calculations from pain ratings during injections is described in Heber et al. 2020 (PMID: 32107360 DOI: 0.1097/j.pain.0000000000001848)

Trial Locations

Locations (1)

Medical University of Vienna; 🇦🇹 Vienna, Austria