CHRONIC MORPHINE TREATMENT CAUSES DOWN-REGULATION OF SPINAL ADENOSINE-A1-RECEPTORS IN RATS

Recent studies suggest that the release of adenosine in the spinal cord may be a significant component of the morphine antinociceptive action. We wanted to know whether the spinal adenosine system is involved in morphine tolerance. Animals were rendered tolerant to morphine, and A1 adenosine receptor binding activity was measured. Treating Sprague-Dawley rats with multiple, increasing doses of morphine i.p. for 6 days resulted in an about 10-fold increase in the median antinociceptive dose (AD50) of morphine to elicit an antinociceptive response. On the other hand, this treatment also caused a 4 to 5-fold increase in the AD50 of cyclopentyladenosine (CPA). When A1 adenosine receptor binding was determined by using [H-3]cyclohexyladenosine ([H-3]CHA) a significant decrease in binding (P < 0.05) in the spinal cord but not in the cortex was observed. Scatchard analysis of the [H-3]CHA saturation binding data revealed a decrease in B(max) values (from 185.5 fmol/mg to 110.2 fmol/mg) and no significant change in K(d) values.