Characterization of the effects of adenosine kinase inhibitors on acute thermal nociception in mice.
Adenosine (ADO) is an inhibitory neuromodulator that can increase the nociceptive threshold in animals exposed to a variety of noxious stimuli. Inhibition of the ADO-metabolizing enzyme, ADO kinase (AK), provides a means of locally enhancing extracellular ADO concentrations. In the present study, the AK inhibitors 5'-amino,5'-deoxy-ADO (NH2dADO), 5-iodotubercidin (5-IT), and 5'-deoxy,5-iodotubercidin (5'd-5IT) were examined for their analgesic efficacy in the hot-plate model of acute somatic nociception. Control and drug-treated adult male mice were placed on a 55 degrees C hot plate and the latency to the 10th jump was recorded via a computer driven infrared-beam photosensor. All three AK inhibitors were found to significantly increase jump latencies in a dose-dependent fashion. 5'd-5IT was the most potent AK inhibitor (approx. ED50 value = 1 micromol/kg, IP), followed by 5-IT (ED50 value = 10 micromol/kg, IP), and NH2dADO (ED50 value = 100 micromol/kg, IP). 5'd-5IT was found to be more potent and equally efficacious to morphine (ED50 value = 5.2 micromol/kg, IP) in this assay. In a model of persistent chemical pain, the phenyl-p-quinone-induced abdominal constriction assay, 5'd-5IT (ED50 value = 1.5 micromol/kg, SC) and morphine (ED50 value = 3.0 micromol/kg, SC) dose dependently reduced nociception. Pretreatment of mice with either the nonselective ADO receptor antagonist, theophylline (56 micromol/kg, IP), but not the peripherally acting antagonist, 8-(p-sulfophenyl)-theophylline (8-PST, 200 micromol/kg, IP) significantly attenuated the antinociceptive effects of 5'd-5IT in the hot-plate assay. Furthermore, the antinociceptive effects of 5'd-5IT were completely blocked by an ADO A1 receptor selective antagonist, DPCPX, while an ADO A2A receptor selective antagonist, ZM 241385, showed markedly less antagonist activity. The analgesic effects of 5'd-5IT were not blocked by the opioid receptor antagonist naloxone; however, 5'd-5IT could produce additive analgesic effects with morphine when both compounds were administered in combination. The apparent efficacy of 2.5 micromol/kg, IP, of 5'd-5IT was not significantly altered following the repeated administration of this dose twice daily for 4 days. The present data provide evidence for an antinociceptive action of AK inhibitors in the hot-plate test, which, at least for 5'd-5IT, is mediated by an enhancement of ADO's actions at the ADO A1 receptor subtype, is nonopioid in nature, and which does not exhibit tolerance following repeated administration.
Kowaluk
E A
EA
Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Kohlhaas
K L
KL
Bannon
A
A
Gunther
K
K
Lynch
J J
JJ
Jarvis
M F
MF
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017288:Pain Threshold / Q000187:drug effects*
D004791:Enzyme Inhibitors; D000248:Adenosine Kinase