A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats

Extracellular levels of adenosine (ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors h ave shown antinociceptive activity in a variety of animal models of nocicep tion. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A 134974 (IC50=60 pM), in a rat model of neuro pathic pain (ligations of the L5/L6 spinal nerves) and explored the relativ e contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia ( ED50=5 mu mol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test o f motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 mu mol/kg, i.p.). Administration of A-134974 intratheca lly (i.t.) was more potent (ED50=10 nmol) in relieving tactile allodynia th an delivering the compound by intracerebroventricular (ED50>100 nmol, i.c.v .) or intraplantar (ED50>500 nmol) routes suggesting that spinal sites of a ction are the primary contributors to the anti-allodynic action of A-134974 . The anti-allodynic effects of systemic A-134974 (10 mu mol/kg, i.p.) were antagonized by the non-selective ADO receptor antagonist, theophylline (30 -500 nmol) administered i.t. These data demonstrate that the novel AK inhib itor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be use ful as analgesic agents in a broad spectrum of pain stares. (C) 2001 Elsevi er Science B.V. All rights reserved.