MECHANISM OF MORPHINE IN INCREASING PLASMA CYCLIC-GMP LEVEL IN MALE-MICE

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Abstract
Morphine given systemically or centrally increases the plasma concentration of cGMP in male, ddY strain mice. Normorphine also increased the plasma cGMP level, whereas the same dose of ketocyclazocine and SKF 10,047 [N-allyl-normetazocine hydrochloride] had no effect. The effect of morphine on plasma cGMP was mimicked by opioid peptides such as (D-Ala2, Met)-enkephalinamide, FK 33,824 [(D-Ala2, 4-MePhe, 5-Met(O)-ol)enkephalin] or .beta.-endorphin. The effect of morphine and opioid peptides on plasma cGMP was antagonized by naloxone, indicating the involvement of the opiate receptor. The increase in plasma cGMP 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 cAMP level elicited by morphine, did not alter the cGMP response to morphine. The development of tolerance to the cGMP increase was observed in morphine-tolerant/dependent mice. Morphine apparently increases the plasma cGMP level by activating the preganglionic parasympathetic tone via the stimulation of the opiate receptors, thereby increasing the generation of cGMP through the muscarinic receptors on the effector cells.