The effect of intradermal microdosing of a transient receptor potential cation channel subfamily V member 1 antagonist on heat evoked pain and thermal thresholds in normal and ultraviolet‐C exposed skin in healthy volunteers
| Autor: | Anna K Sundgren, Lars Ståhle, Erik Sjögren, Magnus M. Halldin, Hans Quiding, Bror Jonzon |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Pain Threshold Hot Temperature Injections Intradermal Erythema Ultraviolet Rays Analgesic TRPV1 Administration Oral TRPV Cation Channels Stimulation Pharmacology Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Double-Blind Method Oral administration medicine Animals Humans Thermosensing 030212 general & internal medicine Pain Measurement Inflammation Analgesics business.industry Antagonist Pain Perception Laser Doppler velocimetry Healthy Volunteers Anesthesiology and Pain Medicine chemistry Capsaicin medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | European Journal of Pain. 23:1767-1779 |
| ISSN: | 1532-2149 1090-3801 |
| Popis: | Background Three TRPV1 (Transient Receptor Potential Vanilloid Receptor 1) antagonists were developed for testing in situ in human skin (Sjogren et al., 2016; Sjogren et al., 2018; Sjogren et al., 2018). The first human study using these compounds and capsaicin, was performed to determine the required local antagonist concentrations needed for target engagement (Proof of Mechanism, PoM) (Sjogren et al., 2018). In this paper, the aim was to address a TRPV1 antagonist's ability to inhibit a more complex pain signal and to define translational endpoints that could be used in further drug development, when progressing orally bioavailable TRPV1 antagonists as novel analgesic medications. Method This was a single centre, placebo-controlled, clinical proof of principle (PoP) study in 25 healthy volunteers. The subjects were exposed to UV irradiation, causing a local tissue inflammation. Three different doses of AZ12048189 were administered to assess pain perception through quantitative sensory testing (QST) and erythema using Laser Doppler scanning. Results AZ12048189 increased the warmth detection threshold (WDT) and the heat pain threshold (HPT) and decreased the intensity of supra threshold heat pain (STHP). AZ12048189 did not, however, have any significant effects as assessed using mechanical stimulation or Laser Doppler. Conclusions This study validated translational tools to confirm target engagement for TRPV1 antagonists; WDT, HPT and STHP have utility in this respect, after oral administration of a TRPV1 antagonist. This study also proved that TRPV1 antagonists can inhibit a more complex, non-capsaicin dependent thermally induced pain signal. |
| Databáze: | OpenAIRE |
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