PHARMACODYNAMICS OF SUBCUTANEOUSLY ADMINISTERED DIACETYLMORPHINE, 6-ACETYLMORPHINE AND MORPHINE IN MICE

Abstract

Diacetylmorphine (DAM) and 6-acetylmorphine (AM) exhibit virtually identical dose-response and time-action profiles in studies of antinociceptive, excitatory, antidiarrheal and antidiuretic activity after s.c. administration to mice. In antinociceptive and excitatory tests, both drugs are 3-10 times more potent than morphine (M) and reach their peak effect more rapidly than M. Analysis of these data by graded and quantal methods establishes the comparability of the results obtained, while confirming the greater efficiency of graded method. The durations of action of DAM and AM are shorter than that of M, yielding significant differences in potency estimates based upon peak vs. total effect. DAM and AM are only twice as potent as M in the suppression of prostaglandin E2-induced diarrhea and in antidiuretic activity. These pharmacodynamic studies, along with prior dispositional studies, suggest that the ability of DAM and AM to rapidly cross the blood-brain barrier determines their potency and time-action differences from M in centrally mediated bioassays. DAM and AM are only slightly more potent than M in the antidiarrheal and antidiuretic tests. These studies support the concept that the pharmacological effects of DAM are mediated principally by metabolically formed AM.