Abstract |
Extracellular levels of adenosine ( ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A-134974 (IC(50)=60 pM), in a rat model of neuropathic pain ( ligations of the L5/L6 spinal nerves) and explored the relative contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia (ED(50)=5 micromol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test of motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 micromol/kg, i.p.). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50)=10 nmol) in relieving tactile allodynia than delivering the compound by intracerebroventricular (ED(50)>100 nmol, i.c.v.) or intraplantar (ED(50)>500 nmol) routes suggesting that spinal sites of action are the primary contributors to the anti-allodynic action of A-134974. The anti-allodynic effects of systemic A-134974 (10 micromol/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 inhibitor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be useful as analgesic agents in a broad spectrum of pain states.
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Authors | C Z Zhu, J Mikusa, K L Chu, M Cowart, E A Kowaluk, M F Jarvis, S McGaraughty |
Journal | Brain research
(Brain Res)
Vol. 905
Issue 1-2
Pg. 104-10
(Jun 29 2001)
ISSN: 0006-8993 [Print] Netherlands |
PMID | 11423084
(Publication Type: Journal Article)
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Chemical References |
- A 134974
- Enzyme Inhibitors
- Nucleosides
- Phosphodiesterase Inhibitors
- Theophylline
- Adenosine Kinase
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Topics |
- Adenosine Kinase
(antagonists & inhibitors, metabolism)
- Animals
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Hyperalgesia
(drug therapy, metabolism, physiopathology)
- Male
- Nerve Crush
(adverse effects)
- Nociceptors
(drug effects, metabolism, physiopathology)
- Nucleosides
(pharmacology)
- Pain
(drug therapy, metabolism, physiopathology)
- Pain Measurement
(drug effects)
- Peripheral Nervous System Diseases
(drug therapy, metabolism, physiopathology)
- Phosphodiesterase Inhibitors
(pharmacology)
- Physical Stimulation
(adverse effects)
- Posterior Horn Cells
(drug effects, metabolism)
- Rats
- Rats, Sprague-Dawley
- Theophylline
(pharmacology)
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