Pain
Conditions
Keywords
Psychophysics, Human physiology, Sensory neuron, TRP channels, Heat perception
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.
Interventions
DRUGTRPA1-inhibitor
Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid
DRUGTRPV1-inhibitor
Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid
DRUGTRPM3-inhibitor
Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid
DRUGPlacebo
No pharmacological intervention
DRUGChloride-channel inhibitor
Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid
Sponsors
Medical University of Vienna
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
Factorial: There are 4 treatments (TRPV1-, TRPA1-, TRPM3- and chloride channel inhibition). These will be applied in all possible combinations (16). Each healthy volunteer will receive 8 of these 16 combinations in a sequence defined by a Williams square (Hinkelmann, K., and Kempthorne, O. (2005). Design and Analysis of Experiments Vol. 2 - Advanced Experimental Design (Wiley)) Randomized: Volunteers will be randomly assigned to a pre-specified sequence. Placebo-controlled: One of the 16 combinations includes none of the three treatments, i.e., can be regarded as placebo control. Adaptive: Due to the complex study design, a priori assumptions about the distribution and correlation of data could not be made reliably. Therefore, after 16 volunteers, the responsible bio-statistician will simulate how much more patients are necessary to detect the a priori defined effect size with the until then observed data
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
Austria
Outcome results
None listed