Mechanisms of Human Heat Perception - Involvement of TRPA1, TRPV1 and TRPM3
Condition: Pain
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): TRPA1-inhibitor; TRPV1-inhibitor; TRPM3-inhibitor; Placebo; Chloride-channel inhibitor
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Pharmacological inhibition of TRPA1 during intradermal injection of hot synthetic interstitial fluid; Pharmacological inhibition of TRPV1 during intradermal injection of hot synthetic interstitial fluid; Pharmacological inhibition of TRPM3 during intradermal injection of hot synthetic interstitial fluid; No pharmacological intervention; Pharmacological inhibition of a chloride channel during intradermal injection of hot synthetic interstitial fluid
Other intervention name(s): Specific antagonist of the TRPA1 channel; Specific antagonist of the TRPV1 channel; Specific antagonist of the TRPM3 channel; No antagonist; Specific inhibitor of a chloride channel
Allocation: Randomized
Intervention model: Single Group Assignment
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
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Psychophysics; Human physiology; Sensory neuron; TRP channels; Heat perception