Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action.
The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) relative contributions of supraspinal, spinal, and peripheral sites to the actions of A-134974. Systemic A-134974 (i.p.) dose dependently reduced hyperalgesia (ED(50) = 1 micromol/kg) and at higher doses, reduced locomotor activity (ED(50) = 16 micromol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50) = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED(50) = 100 nmol, i.c.v.) or intraplantar (ED(50) >300 nmol) routes. In contrast, i.c.v. administration of A-134974 was more effective in reducing locomotor activity than i.t. administration (ED(50) values were 1 and >100 nmol, respectively). Increasing the pretreatment time for i.t.-delivered A-134974 caused a greater reduction in locomotor activity (ED(50) = 10 nmol). This was due to diffusion of A-134974 (i.t.) to supraspinal sites. The antihyperalgesic effects of systemic A-134974 were antagonized by the adenosine receptor antagonist theophylline (THEO, 30-500 nmol) administered i.t., but not i.c.v. In the locomotor assay, i.t.-injected THEO did not antagonize hypomobility caused by systemic or i.t. administration of A-134974. However, i.c.v. infusion of THEO did block the hypomotive actions of i.c.v.-, i.t.-, and i.p.-administered A-134974. These data demonstrate that the novel AK inhibitor A-134974 potently reduces thermal hyperalgesia primarily through interactions with spinal sites, whereas its ability to depress locomotor activity is predominantly mediated by supraspinal sites.
McGaraughty
S
S
Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. Steve.P.McGaraughty@abbott.com
Chu
K L
KL
Wismer
C T
CT
Mikusa
J
J
Zhu
C Z
CZ
Cowart
M
M
Kowaluk
E A
EA
Jarvis
M F
MF
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D002351:Carrageenan; D002490:Central Nervous System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009705:Nucleosides / Q000494:pharmacology*; D017933:Peripheral Nervous System / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects
C422646:A 134974; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D009705:Nucleosides; D002351:Carrageenan; D000248:Adenosine Kinase