Naltrexone-precipitated morphine withdrawal in infant rat is attenuated by acute administration of NOS inhibitors but not NMDA receptor antagonists.
BACKGROUND
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.


OBJECTIVE
Here we examined the effects of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors, which reduce the opiate abstinence syndrome in adult animals, on morphine withdrawal in the infant rat.


METHODS
Neonatal rats were injected with morphine sulfate (10.0 mg/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), or vehicle. After 15 min, the pups were injected with naltrexone (1 mg/kg) to precipitate withdrawal. Behavior for each pup was identified and recorded every 15 s for 10 min before naltrexone injection and 15 min after naltrexone injection.


RESULTS
Both L-NAME and 7-NI significantly reduced most withdrawal 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 increased others (e.g., moving paws). MK-801 was likewise ineffective in reducing most withdrawal behaviors and increased certain withdrawal behaviors (walking and wall climbing).


CONCLUSIONS
In the infant rat, the production of nitric oxide is involved in opiate withdrawal whereas the NMDA receptor may not yet be functionally active or may play only a minor role.
Department of Psychology, Hunter College, City University of New York, NY 10021, USA.
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000375:Aging / Q000523:psychology; D000818:Animals; D000831:Animals, Newborn; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007231:Infant, Newborn; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000009:adverse effects*; D009357:Neonatal Abstinence Syndrome / Q000523:psychology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D009292:Narcotic Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D009271:Naltrexone; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester