Sites of action of naloxone in precipitating withdrawal jumping in morphine-dependent mice: investigations by the ED 50 value and CNS content of naloxone

Abstract

The sites of action of naloxone and the possible interaction between supraspinally and spinally administered naloxone in precipitating withdrawal jumping were investigated by comparing the ED50 value and central nervous system (CNS) content of naloxone after three different administration routes in morphine-dependent mice. ED50 values of naloxone for i.c.v., i.t. and s.c. routes were 18.8 nmol, 1.95 nmol and 50.6 nmol/kg, respectively. Jumping occurred most often within 5 min after i.t administered naloxone, but it took more than 10 min to reach the most frequent jumping after s.c. and i.c.v. administered naloxone. After equi-effective doses (ED50) of naloxone were administered i.c.v., i.t. or s.c., the content of naloxone in the brain was 70 times lower after s.c. than that after i.c.v. injection. The concentration of naloxone in the spinal cord was 37 times lower after s.c. than that after i.t. injection. The ED50 values of naloxone and the time courses of jumping suggest that spinal sites appear to be more important than the supraspinal sites and comparisons of naloxone-content suggest that there is a synergistic interaction between supraspinal- and spinal-naloxone after systemic administration.