Antinociception produced by interactions between intrathecally administered adenosine agonists and norepinephrine.

It is well-established that intrathecal injection of noradrenergic agonists produces dose-dependent antinociception in rats. Recently, the antinociceptive actions of norepinephrine in the central nervous system have been shown to be modulated by adenosine and adenosine analogs. This study examined whether there is an interaction between norepinephrine and adenosine analogs in the regulation of nociceptive transmission in the rat spinal cord using the tail flick and hot plate tests. The results indicate that dose-dependent antinociception was produced by intrathecal injection of norepinephrine (4.8-195 nmol), the A1/A2 adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA; 0.97-4.9 nmol), and the A1 adenosine agonist R-phenylisopropyladenosine (R-PIA; 0.78-26 nmol). Furthermore, subeffective doses of NECA and norepinephrine interacted synergistically to produce potent antinociception. In contrast, no synergistic interaction was observed between norepinephrine and doses of R-PIA as high as 26 nmol. The antinociception produced by coadministration of norepinephrine and NECA appears to be mediated by adenosine receptors, since it was attenuated by pretreatment with theophylline, a non-selective adenosine antagonist. The synergistic interaction between NECA and norepinephrine did not appear to result from alterations in cardiovascular tone because blood pressure values were not significantly altered by drug administration. These results suggest that purinergic and noradrenergic systems interact synergistically to modify nociceptive transmission in the spinal cord. The purinergic component of this interaction may be mediated, in part, by adenosine A2 receptors.