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Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid
J S Kreeger1, Yukhananov RYu, A A Larson
1Department of Veterinary PathoBiology, University of Minnesota, St. Paul.
Abstract:
N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.
Insights
Increased N-methyl-D-aspartate (NMDA) receptor activity in the spinal cord correlates with opioid withdrawal but does not directly cause it. This finding suggests NMDA receptors are involved in opioid dependence but not the primary mediators of withdrawal symptoms.
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- N-methyl-D-aspartate (NMDA) receptors are implicated in opioid tolerance and dependence.
- Increased NMDA activity in the spinal cord, revealed by naloxone in morphine-pretreated mice, may contribute to opioid withdrawal.
Purpose of the Study:
- To investigate if heightened NMDA receptor activity in the spinal cord is a direct cause of opioid withdrawal.
- To explore the role of NMDA receptors in the mechanisms underlying opioid dependence and withdrawal.
Main Methods:
- Utilized a mouse model involving morphine pretreatment and subsequent administration of NMDA, naloxone, dizocilpine (MK-801), and CPP.
- Assessed behavioral responses to intrathecal NMDA injections and naloxone-induced withdrawal jumping.
- Examined the effects of NMDA receptor antagonists (MK-801 and CPP) on these behaviors.
Main Results:
- Morphine pretreatment inhibited NMDA-induced behaviors, while co-administration with naloxone enhanced them.
- Dizocilpine (MK-801), a phencyclidine (PCP) ligand, prevented morphine's excitatory effects on NMDA-induced behaviors and inhibited naloxone-induced withdrawal jumping.
- CPP, a competitive NMDA antagonist, did not affect morphine-induced changes in NMDA behaviors or inhibit withdrawal jumping.
Conclusions:
- Opioid withdrawal from acute dependence is associated with, but not directly mediated by, increased NMDA receptor activity.
- The findings suggest a complex interaction between NMDA receptors and opioid withdrawal, with MK-801 showing potential in modulating withdrawal symptoms.