Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of …

S McGaraughty, KL Chu, CT Wismer, J Mikusa… - … of Pharmacology and …, 2001 - ASPET
S McGaraughty, KL Chu, CT Wismer, J Mikusa, CZ Zhu, M Cowart, EA Kowaluk, MF Jarvis
Journal of Pharmacology and Experimental Therapeutics, 2001ASPET
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 (ip) dose dependently reduced hyperalgesia (ED50= 1 μmol/kg) and at
higher doses, reduced locomotor activity (ED50= 16 μmol/kg). Administration of A-134974 …
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.
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