Time-dependent antinociceptive interactions between opioids and nucleoside transport inhibitors

Endogenous purinergic systems are important in spinal mechanisms of antinociception. Antinociception induced by spinal mu opioid receptor-selective agonists, in particular, appears to be mediated in part by opioid-stimulated adenosine release. Nucleoside transport system(s) have been implicated both in adenosine release and in its reuptake at spinal sites. The present investigations were designed to determine the significance of nucleoside transport system(s) inhibition in vivo in antinociception induced by opioids administered intrathecally in mice. Dilazep, but not dipyridamole or s (4-nitrobenzyl)-6-thioinosine, nucleoside transport system(s) inhibitors, induced time- and dose-dependent antinociception in the tail-flick test, putatively via spinal adenosine reuptake inhibition. Each nucleoside transport system(s) inhibitor, at doses that have no significant effects alone, enhanced adenosine-mediated antinociception when coadministered intrathecally. Concurrent treatment of mice with opioid receptor-selective agonists and nucleoside transport system(s) inhibitors had varying effects on antinociception, depending on the timing of the nucleoside transport inhibitor. In general, antinociception induced by mu opioid receptor-selective agonists was inhibited by pretreatment, was not affected after coadministration and was enhanced by post-treatment, with nucleoside transport system(s) inhibitors. In contrast, antinociception induced by delta opioid receptor-selective agonists was enhanced by nucleoside transport system(s) inhibitors in all treatment protocols. These results provide in vivo evidence that alterations in adenosine movements into or out of spinal neurons via the nucleoside transport systems can induce antinociception and enhance or inhibit opioid-mediated antinociception. These data also support the hypothesis that adenosine plays significant but independent roles in antinociception induced by mu and delta opioid receptor-selective agonists.