Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8

Medical University of Vienna

Status and phase: Completed; Early Phase 1

Conditions: Pain

Treatments: Drug: PF-05089771; Drug: A967079; Drug: Lidocain; Drug: PF-06305591; Other: Room temperature; Drug: PF-05105679; Other: Cold temperature

Study type: Interventional

Funder types: Other

Identifiers

NCT05935280

EK Nr: 1164/2023

Details and patient eligibility

About

Animal studies suggest that the transient receptor potential ion channels TRPM8 and TRPA1 are cold sensors and that sodium channels Nav1.8 and Nav1.7 are essential for detecting pain induced by cold temperatures. This study aims to validate these findings in humans.

Full description

It is essential for human survival to be able to perceive potentially harmful cold. The perception of slight cooling in animals depends on the ion channel TRPM8, but this may represent a largely separate mechanism from painful cold. In mice, TRPM8 and TRPA1 appear to be involved, but also the sodium channels Nav1.7 and Nav1.8, through their temperature-dependent function. These receptors might be redundant, so that failure of individual receptors only leads to no or only a partial reduction in the detection of cold.

Since results obtained in animals do not always translate to humans, the investigators want to clarify whether TRPM8, TRPA1, Nav1.7 and Nav1.8 are involved in the perception of cold pain in humans.

In order to induce cold pain experimentally, an increasingly cooled solution (down to 3°C) is injected into the skin, and the inhibitors for the mentioned targets are added individually and in combination.

Enrollment: 36 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
• Sensory deficit, skin disease or hematoma of unknown origin in physical examination of the test site

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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36 participants in 9 patient groups, including a placebo group

Room temperature injection

Placebo Comparator group

Description:

Pain induced by intradermal injection of fluid with room temperature.

Treatment:

Other: Room temperature

Cold temperature injection 1

Placebo Comparator group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C.

Treatment:

Other: Cold temperature

Cold temperature injection with lidocain

Active Comparator group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker).

Treatment:

Other: Cold temperature

Drug: Lidocain

Cold temperature injection 2

Placebo Comparator group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C.

Treatment:

Other: Cold temperature

Cold temperature injection with PF-05105679

Experimental group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist).

Treatment:

Other: Cold temperature

Drug: PF-05105679

Cold temperature injection with A-967079

Experimental group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist).

Treatment:

Other: Cold temperature

Drug: A967079

Cold temperature injection with PF-05089771

Experimental group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05089771 (specific Nav1.7 antagonist).

Treatment:

Other: Cold temperature

Drug: PF-05089771

Cold temperature injection with PF-06305591

Experimental group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-06305591 (specific Nav1.8 antagonist).

Treatment:

Other: Cold temperature

Drug: PF-06305591

Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591

Experimental group

Description:

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (TRPM8)-, A-967079 (TRPA1)-, PF-05089771 (Nav1.7)-, PF-06305591 (Nav1.8)- antagonist.

Treatment:

Other: Cold temperature

Drug: PF-05105679

Drug: PF-06305591

Drug: A967079

Drug: PF-05089771