Precipitation of spinally mediated withdrawal signs by intrathecal administration of naloxone and the mu-receptor antagonist CTP in morphine-dependent mice

Abstract

We evaluated the ability of naloxone and the mu receptor antagonist CTP (D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2) to precipitate withdrawal in morphine-dependent mice after intrathecal (i.t.) administration. The withdrawal syndromes elicited by naloxone and CTP given i.t. were compared to those of CTP or naloxone injected intracerebroventricularly (i.c.v.). When given i.t. or i.c.v., naloxone produced the classical syndrome of events including jumping, wet dog shakes, urination, defecation followed by diarrhea, and weight loss. There was no significant difference in the potency or efficacy of naloxone when it was given i.t. or i.c.v. The profile of withdrawal effects produced by i.t. CTP resembled that caused by i.c.v. CTP; both were different from that of naloxone. The withdrawal signs seen following both i.t. or i.c.v. CTP included wet dog shakes and defecation. Mice treated with i.t. CTP lost significantly less body weight than those treated with i.c.v. CTP. In addition, i.t. and i.c.v. CTP did not stimulate jumping behaviors or diarrhea. In contrast, while i.c.v. CTP resulted in increased incidence of urination, CTP given i.t. did not. These finding indicate that naloxone given spinally acts on mu receptors to precipitate wet dog shaking and defecation, but acts on other non-mu opioid receptors (i.e. delta and/or kappa) to cause jumping, urination, diarrhea and weight loss. The differential effects of CTP given i.c.v. or i.t. suggest that supraspinal mu receptors are more involved in gastrointestinal and urinary bladder function during dependence/withdrawal than their spinal counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)