Inhibition of adenylate cyclase by GTP and its modulation by opiate receptor in rat caudate nucleus

Morphine inhibited the adenylate cyclase activity of the crude synaptosomal fraction of the rat caudate nucleus in the presence of BTP, GDP, Gpp(NH)p or ITP. The purine nucleotides themselves had an inhibitory action on the enzyme. Beta-endorphin and Met-enkephalin also inhibited the enzyme in the presence of GTP. The GTP-dependent in inhibitory action of morphine was blocked by naloxone. Various opiates and opioid peptides inhibited the enzyme by up to approximately 20 per cent in the presence of GTP. The relative potency was in higher order of levorphanol greater than beta-endorphin greater than Met-enkephalin greater than morphine greater than pentazocine. Levorphanol was about 50,000 times as potent as its biologically inactive enantiomer, dextrorphan. Morphine enhanced the inhibitory actions of GTP and GTPase-resistant Gpp(NH)p on the adenylate cyclase activity. These results suggest that GTP plays an important role in the regulation of adenylate cyclase activity in the rat caudate nucleus and that the occupation of opiate receptor by agonists inhibits the enzyme through an actual increase in the inhibitory action of GTP, rather than a suppression of the enzymatic degradation of GTP.