Abstract

In the rat and mouse when morphine is coadministered intracerebroventricularly (i.c.v.) in the brain and intrathecally (i.t.) in the spinal cord, a multiplicative (synergistic) interaction occurs for the antinociceptive response. In the male Swiss Cox mouse, with the development of a high degree of systemic tolerance to morphine, this multiplicative interaction decreases (becomes additive), whereas no change occurs in the ED50 for the i.c.v. or i.t. site itself. The purpose of the present study was to extend these findings in one mouse strain to other strains in order to determine how generally applicable such findings are to the phenomenon of tolerance to morphine. Eight different strains of outbred mice were used in the antinociceptive tail-flick test to quantify the multiplicative interaction of simultaneous administration (i.c.v. and i.t.) in relation to the amount of tolerance developed to morphine administered systemically (s.c.). Even though the control ED50 values for s.c. morphine were similar among strains, the amounts of tolerance developed by 3 days of implantation of a morphine pellet were very different (2-18-fold). A relationship was found between the degree of tolerance developed to s.c. morphine and changes in the multiplicative interaction (as reflected by changes in the i.c.v. plus i.t. morphine ED50 values). In control animals, a multiplicative i.c.v.-i.t. interaction was produced in six of the eight strains, whereas an additive interaction was shown in the remaining two strains. With 3 days of morphine pellet implantation, in three strains which developed a large amount of tolerance to s.c. morphine (7-18-fold), the multiplicative interaction decreased to an additive interaction.(ABSTRACT TRUNCATED AT 250 WORDS)