TIME-DEPENDENT ANTINOCICEPTIVE INTERACTIONS BETWEEN OPIOIDS AND NUCLEOSIDE TRANSPORT INHIBITORS

Endogenous purinergic systems are important in spinal mechanisms of an tinociception. Antinociception induced by spinal mu opioid receptor-se lective agonists, in particular, appears to be mediated in part by opi oid-stimulated adenosine release. Nucleoside transport system(s) have been implicated both in adenosine release and in its reuptake at spina l sites. The present investigations were designed to determine the sig nificance of nucleoside transport system(s) inhibition in vivo in anti nociception induced by opioids administered intrathecally in mice. Dil azep, but not dipyridamole or s (4-nitrobenzyl)-6-thioinosine, nucleos ide transport system(s) inhibitors, induced time- and dose-dependent a ntinociception in the tail-flick test, putatively via spinal adenosine reuptake inhibition. Each nucleoside transport system(s) inhibitor, a t doses that have no significant effects alone, enhanced adenosine-med iated antinociception when coadministered intrathecally. Concurrent tr eatment 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 ge neral, antinociception induced by mu opioid receptor-selective agonist s was inhibited by pretreatment, was not affected after coadministrati on and was enhanced by post-treatment, with nucleoside transport syste m(s) inhibitors. in contrast, antinociception induced by delta opioid receptor-selective agonists was enhanced by nucleoside transport syste m(s) inhibitors in all treatment protocols. These results provide in v ivo evidence that alterations in adenosine movements into or out of sp inal neurons via the nucleoside transport systems can induce antinocic eption and enhance or inhibit opioid-mediated antinociception. These d ata also support the hypothesis that adenosine plays significant but i ndependent roles in antinociception induced by mu and delta opioid rec eptor-selective agonists.