Mechanism of morphine in increasing plasma cyclic GMP level in male mice.

Morphine given systemically or centrally increases the plasma concentration of cyclic GMP in male, ddY strain mice. Normorphine also increased the plasma cyclic GMP level, whereas the same dose of ketocyclazocine and SKF 10,047 had no effect. The effect of morphine on plasma cyclic GMP was mimicked by opioid peptides such as (D-Ala2, Met)-enkephalinamide, FK 33,824 or beta-endorphin. The effect of morphine and opioid peptides on plasma cyclic GMP was antagonized by naloxone, indicating the involvement of the opiate receptor. The increase in plasma cyclic GMP elicited by morphine was abolished by vagotomy and pretreatment with hexamethonium and atropine and was partly inhibited by pretreatment with phentolamine. Adrenalectomy and pretreatment with propranolol, which inhibited the increase in plasma cyclic AMP level elicited by morphine (Muraki et al., 1979), did not alter the cyclic GMP response to morphine. The development of tolerance to the cyclic GMP increase was observed in morphine-tolerant/dependent mice. These results suggest that morphine increases the plasma cyclic GMP level by activating the preganglionic parasympathetic tone via the stimulation of the opiate receptors, thereby increasing the generation of cyclic GMP through the muscarinic receptors on the effector cells.