Vol. 296, Issue 2, 501-509, February 2001

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

Steve McGaraughty, Katharine L. Chu, Carol T. Wismer, Joe Mikusa, Chang Z. Zhu, Marlon Cowart, Elizabeth A. Kowaluk and Michael F. Jarvis

Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois

The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC₅₀ = 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 (ED₅₀ = 1 µmol/kg) and at higher doses, reduced locomotor activity (ED₅₀ = 16 µmol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED₅₀ = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED₅₀ = 100 nmol, i.c.v.) or intraplantar (ED₅₀ >300 nmol) routes. In contrast, i.c.v. administration of A-134974 was more effective in reducing locomotor activity than i.t. administration (ED₅₀ values were 1 and >100 nmol, respectively). Increasing the pretreatment time for i.t.-delivered A-134974 caused a greater reduction in locomotor activity (ED₅₀ = 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.