A cyclic somatostatin analog that precipitates withdrawal in morphine-dependent mice

We evaluated the ability of the mu selective, peptidic, opioid antagonist CTP to precipitate withdrawal in morphine-dependent mice after intracerebroventricular (i.c.v.) and subcutaneous (s.c.) administration. The withdrawal syndrome evoked by i.c.v. CTP was different in some respects from that observed after i.c.v. naloxone. Naloxone, given i.c.v., produced shakes and tremors, defecation, diarrhea, wet dog shakes, jumping and weight loss. In contrast, the prominent signs following i.c.v. CTP were grooming, tremors and shakes, defecation, wet dog shakes and weight loss. CTP treated mice exhibited a greatly reduced incidence of jumping behaviors and diarrhea. While s.c. naloxone evoked similar effects to i.c.v. naloxone, CTP given s.c. stimulated defecation and modest weight loss only. The differences in the profile of withdrawal signs between naloxone and CTP may be related to their differences in receptor selectivity or possibly to their respective alkaloidal and peptidic natures. The relative lack of behavioral effects seen after s.c. CTP probably reflects the inability of CTP to pass through the blood brain barrier, and indicates that although the majority of withdrawal signs are mediated by centrally located opioid receptors, the gastrointestinal tract can be withdrawn independently of the central nervous system.