Related Experiment Videos
Attenuation of thermal nociception and hyperalgesia by VR1 blockers
Carolina García-Martinez1, Marc Humet, Rosa Planells-Cases
1Centro de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain.
Abstract:
Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] and DD191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain.
Insights
New nonpeptidic VR1 antagonists, DD161515 and DD191515, effectively block the vanilloid receptor 1 (VR1) channel. These compounds reduce thermal and chemical pain perception and neurogenic inflammation in vivo.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- The vanilloid receptor subunit 1 (VR1) is crucial for sensing noxious chemical and thermal stimuli.
- VR1 antagonists are valuable tools for pain research and potential analgesics.
Purpose of the Study:
- To identify novel, nonpeptidic channel blockers of VR1 using a combinatorial approach.
- To evaluate the efficacy of identified compounds in attenuating pain and inflammation.
Main Methods:
- Screening of a library of N-alkylglycine trimers to identify VR1 antagonists.
- Testing the identified compounds (DD161515 and DD191515) in mouse models of thermal nociception, capsaicin-induced pain, and nitrogen mustard-induced hyperalgesia.
Main Results:
- Two nonpeptidic compounds, DD161515 and DD191515, were identified as selective VR1 channel blockers with micromolar efficacy.
- Intraperitoneal administration of these compounds significantly reduced thermal nociception and eliminated capsaicin-evoked pain and neurogenic inflammation.
- The compounds did not affect responses to mechanical stimuli, suggesting modulation of sensory nerve fiber excitability.
Conclusions:
- Blockade of VR1 activity effectively attenuates chemical and thermal nociception and hyperalgesia.
- These trialkylglycine-based, noncompetitive VR1 antagonists show potential for development into analgesics for inflammatory pain.