Spinal NMDA receptor - nitric oxide mediation of the expression of morphine withdrawal symptoms in the rat

Jerry J. Buccafusco, Alvin V Terry, Laura Shuster

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Previous studies in this laboratory have demonstrated that cholinergic receptors within the spinal cord play an important role in the expression of naloxone-precipitated withdrawal symptoms in the morphine-dependent rat. Related cardiovascular studies in non-dependent animals have demonstrated that this spinal cholinergic system is linked to a glutamatergic, NMDA pressor pathway which also involves the participation of a nitric oxide (NO) generating system. The purpose of this study was to determine whether spinal NMDA receptors and/or NO are involved in the expression of morphine withdrawal symptoms. Rats bearing previously implanted intrathecal (IT) catheters were dependent on morphine following chronic i.a. infusion of increasing doses over 5 days. Naloxone (0.5 mg/kg) was administered via the i.a. line to precipitate withdrawal; and both cardiovascular and behavioral symptoms were recorded over 60 min. Pretreatment 20 min before naloxone with IT injection of either of the NMDA receptor antagonists, MK-801 or AP-7 (100-200 nmol), produced a significant reduction in the expression of both the cardiovascular and behavioral symptoms of up to about 60%. IT pretreatment with the NO synthase inhibitorl-NAME - a methyl ester derivative ofl-arginine, also produced a dose-dependent,l-arginine reversible inhibition of the cardiovascular (mainly the pressor) component of withdrawal, but had no significant effect on the expression of behavioral signs. In contrast, IT pretreatment withl-NOARG andl-NMMA, non-ester analogs ofl-arginine, significantly inhibited the expression of the behavioral signs of withdrawal but did not alter the pressor component. A combined pretreatment withl-NAME andl-NOARG resulted in suppression of both pressor and behavioral components of withdrawal. The anti-withdrawal actions of either class of NO synthase inhibitor could not be attributed to blockade of local muscarinic receptors. These findings are consistent with a role for both spinal NMDA receptors and a NO generating system in the expression of both the behavioral and autonomic components of naloxone-precipitated withdrawal. They also suggest that different structural analogs ofl-arginine have different profiles of activity in this regard - opening the possibility that different isozymes of NO synthase located within the same spinal region mediate different physiological or behavioral functions.

Original languageEnglish (US)
Pages (from-to)189-199
Number of pages11
JournalBrain Research
Volume679
Issue number2
DOIs
StatePublished - May 15 1995

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Substance Withdrawal Syndrome
Naloxone
N-Methyl-D-Aspartate Receptors
Morphine
Arginine
Nitric Oxide
Nitric Oxide Synthase
Behavioral Symptoms
Nitroarginine
Spinal Injections
Dizocilpine Maleate
Cholinergic Receptors
Muscarinic Receptors
N-Methylaspartate
Cholinergic Agents
Isoenzymes
Spinal Cord
Esters
Catheters

Keywords

  • Behavior
  • Blood pressure
  • Heart rate
  • Morphine withdrawal
  • NMDA receptor
  • Naloxone
  • Nitric oxide
  • Spinal cord

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Developmental Biology
  • Clinical Neurology

Cite this

Spinal NMDA receptor - nitric oxide mediation of the expression of morphine withdrawal symptoms in the rat. / Buccafusco, Jerry J.; Terry, Alvin V; Shuster, Laura.

In: Brain Research, Vol. 679, No. 2, 15.05.1995, p. 189-199.

Research output: Contribution to journalArticle

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