Antagonism of enkephalin action on acetylcholine release by methylxanthines: lack of a purine link.

Theophylline (Theo) and caffeine antagonized the inhibitory effect of methionine (Met)-enkephalin, leucine (Leu)-enkephalin and morphine on the twitch height of the field stimulated myenteric plexus longitudinal muscle (MPLM) preparation of the guinea-pig ileum. Antagonism by Theo was observed only in tissues stimulated submaximally, but that by caffeine was observed in tissues stimulated submaximally and supramaximally. Injection of Theo (20, 40 mg kg-1) or caffeine (40 mg kg-1) reversed or blocked the inhibitory effects of Leu-enkephalin (50 micrograms i.c.v.) and a systemically active enkephalin FK 33,824 (0.5 mg kg-1) on the release of acetylcholine (ACh) from the rat cortex in vivo. Injections of morphine (2.5, 5.0 mg kg-1 i.v.) did not modify the in vivo release of radiolabelled purines from the cerebral cortex prelabelled with [3H]-adenosine (2.8 X 10(-7) M). Application of K+ (60 mM) to the cortex readily stimulated this release. Injection of morphine (5.0 mg kg-1 i.v.) increased the spontaneous release of radiolabelled purines from the cortex prelabelled with a higher concentration of [3H]-adenosine (10(-4) M) in six out of eleven experiments. Under similar conditions neither Leu-enkephalin (50 micrograms i.c.v.) nor FK 33,824 (0.5 mg kg-1 i.v.) stimulated purine release. It is concluded that methylxanthines can antagonize the inhibitory action of opioids on the peripheral and central release of ACh. However, this antagonism does not reflect an intermediary purine step in the action of opioids on the release of ACh.