Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.
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.
Honore
Prisca
P
Abbott Laboratories, Abbott Park, IL 60064, USA. prisca.honore@abbott.com
Chandran
Prasant
P
Hernandez
Gricelda
G
Gauvin
Donna M
DM
Mikusa
Joseph P
JP
Zhong
Chengmin
C
Joshi
Shailen K
SK
Ghilardi
Joseph R
JR
Sevcik
Molly A
MA
Fryer
Ryan M
RM
Segreti
Jason A
JA
Banfor
Patricia N
PN
Marsh
Kennan
K
Neelands
Torben
T
Bayburt
Erol
E
Daanen
Jerome F
JF
Gomtsyan
Arthur
A
Lee
Chih-Hung
CH
Kort
Michael E
ME
Reilly
Regina M
RM
Surowy
Carol S
CS
Kym
Philip R
PR
Mantyh
Patrick W
PW
Sullivan
James P
JP
Jarvis
Michael F
MF
Faltynek
Connie R
CR
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*
C528492:ABT 102; D000700:Analgesics; D007191:Indazoles; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea; D002118:Calcium