Naltrexone-precipitated morphine withdrawal in infant rat is attenuated byacute administration of NOS inhibitors but not NMDA receptor antagonists

Rationale: There is increasing evidence that the N-methyl-D-aspartate (NMDA ) receptor and the nitric oxide system are involved in opiate dependence in the adult rat, but whether these results in the adult apply to the infant rat is unknown. Objectives: Here we examined the effects of NMDA receptor a ntagonists and nitric oxide synthase (NOS) inhibitors, which reduce the opi ate abstinence syndrome in adult animals, on morphine withdrawal in the inf ant rat. Methods: Neonatal rats were injected with morphine sulfate (10.0 m g/kg) twice daily for 6.5 days. On the 7th day, pups were injected with NOS inhibitors (L-NAME or 7-NI), NMDA receptor antagonists (MK-801 or AP-5), o r vehicle. After 15 min, the pups were injected with naltrexone (1 mg/kg) t o precipitate withdrawal. Behavior for each pup was identified and recorded every 15 s for 10 min before naltrexone injection and 15 min after naltrex one injection. Results: Both L-NAME and 7-NI significantly reduced most wit hdrawal behaviors in the infant rat, a result in line with previous studies in the adult rat. In contrast, AP-5 reduced some withdrawal behaviors but also in creased others (e.g., moving paws). MK-801 was likewise ineffective in reducing most withdrawal behaviors and increased certain withdrawal beh aviors (walking and wall climbing). Conclusions: In the infant rat, the pro duction of nitric oxide is involved in opiate withdrawal whereas the NMDA r eceptor may not yet be functionally active or may play only a minor role.