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

Human Heat Sensation - a Single-group, Randomized, Placebo-controlled, Adaptive, Full-factorial Crossover Trial

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.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Placebo; Drug: TRPA1-inhibitor; Drug: TRPV1-inhibitor; Drug: TRPM3-inhibitor; Drug: Chloride-channel inhibitor

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 Type: Interventional
• Enrollment (Actual): 51
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Stefan Heber, PD MD PhD; Phone Number: 31425 +43140160; Email: stefan.heber@meduniwien.ac.at
• Study Contact Backup: Name: Michael JM Fischer, Professor MD; Phone Number: 31410 +43140160; Email: michael.jm.fischer@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

16

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Hot injection without TRP-channel inhibition; Pain induced by an increasingly hot intradermal injection up to 52°C over 2 minutes.	Drug: Placebo; No pharmacological intervention; Other Names: No antagonist
Experimental: Hot injection with TRPA1-inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel
Experimental: Hot injection with TRPV1-inhibition; 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.	Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel
Experimental: Hot injection with TRPM3-inhibition; 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.	Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel
Experimental: Hot injection with TRPA1- and TRPV1-inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel
Experimental: Hot injection with TRPA1- and TRPM3-inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel
Experimental: Hot injection with TRPM3- and TRPV1-inhibition; 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.	Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel
Experimental: Hot injection with TRPA1-, TRPV1 and TRPM3-inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel
Experimental: Hot injection with TRPA1-, TRPM3- and chloride channel inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPV1-, TRPM3- and chloride channel inhibition; 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.	Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPA1- and chloride channel inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPV1- and chloride channel inhibition; 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.	Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPV1-, TRPA1, TRPM3- and chloride channel inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPM3- and chloride channel inhibition; 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.	Drug: TRPM3-inhibitor; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPM3 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with TRPV1-, TRPA1, and chloride channel inhibition; 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.	Drug: TRPA1-inhibitor; Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPA1 channel; Drug: TRPV1-inhibitor; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific antagonist of the TRPV1 channel; Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel
Experimental: Hot injection with chloride channel inhibition; 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.	Drug: Chloride-channel inhibitor; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid; Other Names: Specific inhibitor of a chloride channel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HPI(50-52) - Heat pain inhibition in the range between 50°C and 52°C	'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)	Through study completion, on average 4 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HPI - Heat pain inhibition	'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)	Through study completion, on average 4 days.

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Study Chair: Michael JM Fischer, Professor MD, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2022
• Primary Completion (Actual): November 30, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: February 22, 2022
• First Submitted That Met QC Criteria: March 2, 2022
• First Posted (Actual): March 11, 2022

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Psychophysics; Human physiology; Sensory neuron; TRP channels; Heat perception
• Other Study ID Numbers: EK Nr: 1152/2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All raw data will be shared with other researches upon reasonable request
• IPD Sharing Time Frame: As soon as the study is published.
• IPD Sharing Access Criteria: Access will be granted to other researchers as well as clinicians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No