Spinal adenosine modulates descending antinociceptive pathways stimulated by morphine

Adenosine-mediated analgesia and interactions between opioids and adenosine in the brain have been observed by several researchers. Our investigations were designed to examine opioid-adenosine interactions at spinal sites and possible modulation of opioid-stimulated descending antinociceptive pathways by adenosine in the spinal cord. Methylxanthines administered intrathecally (i.t.) were used as adenosine receptor antagonists to determine possible interactions between opioids and endogenous adenosine. Theophylline administered i.t. dose-dependently antagonized analgesia induced by morphine administered i.t. or i.c.v. as measured by tail-flick and hot-plate assays. Analgesia induced by i.t. injections of 2-chloroadenosine, an adenosine agonist, was also antagonized by theophylline. However, doses of naloxone (i.t.) that antagonized analgesia induced by i.t. injections of morphine had no effect on 2-chloroadenosine (i.t.)-induced analgesia. These data support morphine-stimulated release of adenosine in the spinal cord. Antagonism of morphine (i.c.v.)-induced analgesia by theophylline was mimicked by caffeine and isobutylmethylxanthine. The results could not be explained as a consequence of effects on phosphodiesterease enzymes, drug-induced hyperalgesia or spinal redistribution of i.c.v. administered morphine. Therefore, our studies suggest that endogenous adenosine in the spinal cord is involved in analgesia mediated by opioid-stimulated descending antinociceptive pathways.