Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors.
OBJECTIVE
Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice.


METHODS
Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10-400 mg kg(-1)). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests.


RESULTS
Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A(1) adenosine-receptor antagonist, DPCPX, but not the selective A(2A) adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg(-1). Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid.


CONCLUSIONS
Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.
Schmidt
A P
AP
Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. aschmidt@ufrgs.br
Böhmer
A E
AE
Antunes
C
C
Schallenberger
C
C
Porciúncula
L O
LO
Elisabetsky
E
E
Lara
D R
DR
Souza
D O
DO
D000241:Adenosine / Q000134:cerebrospinal fluid; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid; D006358:Hot Temperature; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement; D011743:Pyrimidines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014527:Uric Acid / Q000134:cerebrospinal fluid; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000700:Analgesics; D009292:Narcotic Antagonists; D011743:Pyrimidines; D014230:Triazoles; D014970:Xanthines; D014527:Uric Acid; D009270:Naloxone; D018698:Glutamic Acid; D000493:Allopurinol; C051360:1,3-dipropyl-8-cyclopentylxanthine; D014969:Xanthine Oxidase; D000241:Adenosine; D002211:Capsaicin