Effects of forskolin and phosphodiesterase inhibitors on spinal antinociception by morphine.

The effect of intrathecal pretreatment with forskolin and the phosphodiesterase inhibitors Ro 20-1724, rolipram and 3-isobutyl-1-methylxanthine (IBMX) on the antinociceptive action of morphine administered intrathecally was examined using the rat tail-flick test to determine whether inhibition of adenylate cyclase contributed to spinal antinociception. Intrathecal pretreatment with forskolin (10 micrograms), Ro 20-1724 (15 micrograms) and IBMX (10 micrograms) inhibited the action of morphine in the tail-flick test. However, pretreatment with Ro 20-1724 (30 micrograms), rolipram (10 and 30 micrograms) and IBMX (30 micrograms) increased the action of morphine. These agents were devoid of intrinsic antinociceptive activity. Inhibition of spinal antinociception by morphine with agents which increase cyclic AMP levels in biochemical experiments is consistent with the hypothesis that some opiate actions are due to inhibition of adenylate cyclase. However, in view of the consistent increase in the effect of morphine with phosphodiesterase inhibitors at higher doses, this hypothesis may be insufficient to account for opiate interactions with the adenylate cyclase system in the spinal cord. Some effects on spinal antinociception also may be due to additional pharmacological actions of the agents used.