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Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.
Eur J Pharmacol. 2010 Sep 01; 641(2-3):114-22.EJ

Abstract

TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

Authors+Show Affiliations

Eli Lilly and Company Ltd., LRL, Indianapolis, IN 46285, USA. Ursu_Daniel@lilly.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Evaluation Study
Journal Article

Language

eng

PubMed ID

20576527

Citation

Ursu, Daniel, et al. "Pungency of TRPV1 Agonists Is Directly Correlated With Kinetics of Receptor Activation and Lipophilicity." European Journal of Pharmacology, vol. 641, no. 2-3, 2010, pp. 114-22.
Ursu D, Knopp K, Beattie RE, et al. Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity. Eur J Pharmacol. 2010;641(2-3):114-22.
Ursu, D., Knopp, K., Beattie, R. E., Liu, B., & Sher, E. (2010). Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity. European Journal of Pharmacology, 641(2-3), 114-22. https://doi.org/10.1016/j.ejphar.2010.05.029
Ursu D, et al. Pungency of TRPV1 Agonists Is Directly Correlated With Kinetics of Receptor Activation and Lipophilicity. Eur J Pharmacol. 2010 Sep 1;641(2-3):114-22. PubMed PMID: 20576527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity. AU - Ursu,Daniel, AU - Knopp,Kelly, AU - Beattie,Ruth E, AU - Liu,Bin, AU - Sher,Emanuele, Y1 - 2010/06/08/ PY - 2009/10/28/received PY - 2010/04/19/revised PY - 2010/05/23/accepted PY - 2010/6/26/entrez PY - 2010/6/26/pubmed PY - 2011/2/1/medline SP - 114 EP - 22 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 641 IS - 2-3 N2 - TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/20576527/Pungency_of_TRPV1_agonists_is_directly_correlated_with_kinetics_of_receptor_activation_and_lipophilicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(10)00479-6 DB - PRIME DP - Unbound Medicine ER -