The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury.
1. Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. 2. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. 4. Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine-mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.
Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT. ucklrsu@ucl.ac.uk
R
R
Suzuki
L C
LC
Stanfa
E A
EA
Kowaluk
M
M
Williams
M F
MF
Jarvis
A H
AH
Dickenson
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006358:Hot Temperature; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013127:Spinal Nerves / Q000601:surgery
D004791:Enzyme Inhibitors; D009025:Morpholines; D011743:Pyrimidines; C416933:ABT 702; D002351:Carrageenan; D000248:Adenosine Kinase