RT Journal Article SR Electronic T1 TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9385 OP 9393 DO 10.1523/JNEUROSCI.1246-06.2006 VO 26 IS 37 A1 M. Cui A1 P. Honore A1 C. Zhong A1 D. Gauvin A1 J. Mikusa A1 G. Hernandez A1 P. Chandran A1 A. Gomtsyan A1 B. Brown A1 E. K. Bayburt A1 K. Marsh A1 B. Bianchi A1 H. McDonald A1 W. Niforatos A1 T. R. Neelands A1 R. B. Moreland A1 M. W. Decker A1 C.-H. Lee A1 J. P. Sullivan A1 C. R. Faltynek YR 2006 UL http://www.jneurosci.org/content/26/37/9385.abstract AB 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-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-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.