Cz. Zhu et al., A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats, BRAIN RES, 905(1-2), 2001, pp. 104-110
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.