Opiate withdrawal in the neonatal rat: relationship to duration of treatment and naloxone dose

Abstract

Rationale: Treatment of developing rat pups with morphine (MOR) causes the development of physical dependence, but the relationship of the withdrawal syndrome to the duration/intensity of treatment has not been described.

Objectives: The purpose of the present study was to characterize the emergence of various behavioral components of withdrawal in neonatal rats, and to develop a useful measure of overall intensity of withdrawal (OIW).

Methods: Rat pups were treated with morphine (MOR) (20 mg/kg, SC, b.i.d.) for 0-5 days. On postnatal day 10 (P10), animals received saline (SAL) or a challenge dose of MOR (25 mg/kg). Withdrawal was precipitated with naloxone HCl (NAL) (0.1, 0.5 or 2.5 mg/kg) 2 h after the MOR injection, and behaviors were quantitated for 10 min. To investigate the ability of clonidine HCl (CLON) to suppress withdrawal, pups were treated for 0 or 5 days with MOR, given a MOR challenge and either SAL or CLON (0.2 mg/kg), followed by SAL or NAL (2.5 mg/kg, SC). To evaluate endocrine components of withdrawal, growth hormone responses to withdrawal were examined.

Results: The OIW and NAL-induced GH suppression increased with increasing NAL dose and duration of morphine treatment. However, individual behaviors showed differing patterns of expression. Clonidine decreased the severity of tremor and reduced the OIW.

Conclusions: These results demonstrate that the intensity of neonatal opiate withdrawal is related to the duration and intensity of treatment. The profile of observed withdrawal behaviors may reflect the involvement of the noradrenergic system.