Anti‐nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A₁ adenosine receptors

Abstract

Background and purpose: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. Experimental approach: 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. Key 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 A1 adenosine-receptor antagonist, DPCPX, but not the selective A2A 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 and implications: 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.

Lower frequency of the low activity adenosine deaminase allelic variant (ADA1*2) in schizophrenic patients

“…3 In animal models of schizophrenia, A1 and A2aR agonists prevent behavioral, as well as neurophysiological (EEG and prepulse inhibition) alterations induced by NMDA antagonists. 16 Moreover, the xanthine oxidase inhibitor allopurinol, which may increase adenosine levels, 17 was effective as add-on treatment of schizophrenia. 18 Taken together, these findings are in line with reduced adenosinergic activity in schizophrenia and also with our results, according to which the low activity ADA genotype in schizophrenic patients is less frequent since this genotype is supposingly associated with higher adenosine levels.…”

Inosine Reduces Pain-Related Behavior in Mice: Involvement of Adenosine A1 and A2A Receptor Subtypes and Protein Kinase C Pathways

“…), and 30 min later they were subjected to the acetic acid test. The doses of the drugs used were based on literature data (Garcia Soriano et al, 2001;Bastia et al, 2002, Schmidt et al, 2009) and previous results from our laboratory.…”

Analgesic activity of allopurinol and febuxostat in experimental animals

“…These effects corroborate with the findings of other workers. 12,13 However febuxostat was not included in their study.…”

“…Similar effects were observed in Acetic acid induced writhing method by some other workers. [12][13][14] Allopurinol and febuxostat possess significant analgesic activity. These drugs may be useful in chronic painful conditions like inflammatory arthritis, sickle cell disease, diabetic neuropathy, fibromyalgia and cancer.…”

“…6 Recently, chronic inhibition of XO-generated ROS by Allopurinol has been suggested to inhibit symptoms of inflammation, painful diabetic neuropathy in rats and to produce acute antinociceptive activity against a variety of noxious stimuli in mice. 7,8 Febuxostat is a newer orally administered nonpurine XO inhibitor that has been recently approved for the treatment of chronic hyperuricemia in patients with gout. 9 Three randomized controlled clinical trials comparing Febuxostat with Allopurinol showed that 40mg/day Febuxostat lowered serum uric acid to similar levels as 300mg/day of Allopurinol.…”