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TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists
Open accessAbstract
Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1 H-indazol-4-yl-N′-[(1 R)-5-piperidin-1-yl-2,3-dihydro-1 H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
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Mezey, É., Tóth, Z. E., Cortright, D. N., Arzubi, M. K., Krause, J. E., Elde, R., Guo, A., Blumberg, P. M., & Szallasi, A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3655 · Cited by 850
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Park, C.-K., Lü, N., Xu, Z.-Z., Liu, T., Serhan, C. N., & Ji, R.-R. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2443-11.2011 · Cited by 241
Metadata
- Authors
- Cui, M., Honore, P., Zhong, C., Gauvin, D., Mikusa, J., Hernandez, G., Chandran, P., Gomtsyan, A., Brown, B., Bayburt, E. K., Marsh, K., Bianchi, B., McDonald, H., Niforatos, W., Neelands, T. R., Moreland, R. B., Decker, M. W., Lee, C.-H., Sullivan, J. P., & Faltynek, C. R.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-09-13
- Volume
- 26
- Issue
- 37
- Pages
- 9385-9393
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2118590048
- Cited by
- 318
- References
- 1
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- The paper
- Cui, M., Honore, P., Zhong, C., Gauvin, D., Mikusa, J., Hernandez, G., Chandran, P., Gomtsyan, A., Brown, B., Bayburt, E. K., Marsh, K., Bianchi, B., McDonald, H., Niforatos, W., Neelands, T. R., Moreland, R. B., Decker, M. W., Lee, C.-H., Sullivan, J. P., & Faltynek, C. R. (2006). TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.1246-06.2006
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
