title: TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists.
abstract: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cui
authors.forename: P
authors.initials: P
authors.lastname: Honore
authors.forename: C
authors.initials: C
authors.lastname: Zhong
authors.forename: D
authors.initials: D
authors.lastname: Gauvin
authors.forename: J
authors.initials: J
authors.lastname: Mikusa
authors.forename: G
authors.initials: G
authors.lastname: Hernandez
authors.forename: P
authors.initials: P
authors.lastname: Chandran
authors.forename: A
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: B
authors.initials: B
authors.lastname: Brown
authors.forename: E K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: K
authors.initials: K
authors.lastname: Marsh
authors.forename: B
authors.initials: B
authors.lastname: Bianchi
authors.forename: H
authors.initials: H
authors.lastname: McDonald
authors.forename: W
authors.initials: W
authors.lastname: Niforatos
authors.forename: T R
authors.initials: TR
authors.lastname: Neelands
authors.forename: R B
authors.initials: RB
authors.lastname: Moreland
authors.forename: M W
authors.initials: MW
authors.lastname: Decker
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: C R
authors.initials: CR
authors.lastname: Faltynek
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D018771:Arthralgia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007278:Injections, Spinal; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C514211:1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide; D000700:Analgesics; D007191:Indazoles; D018836:Inflammation Mediators; C514212:N-1H-indazol-4-yl-N'-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea; D011725:Pyridines; D013450:Sulfones; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea; D002211:Capsaicin; D002118:Calcium