title: Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.
abstract: Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies.
authors.affiliation: Abbott Laboratories, Abbott Park, IL 60064, USA. prisca.honore@abbott.com
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Gricelda
authors.initials: G
authors.lastname: Hernandez
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ghilardi
authors.forename: Molly A
authors.initials: MA
authors.lastname: Sevcik
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Banfor
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Torben
authors.initials: T
authors.lastname: Neelands
authors.forename: Erol
authors.initials: E
authors.lastname: Bayburt
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001859:Bone Neoplasms / Q000150:complications; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D007191:Indazoles / Q000008:administration & dosage*; D007249:Inflammation / Q000150:complications; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009043:Motor Activity / Q000187:drug effects; D010003:Osteoarthritis / Q000150:complications; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: C528492:ABT 102; D000700:Analgesics; D007191:Indazoles; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea; D002118:Calcium