Further evidence for a role of NMDA receptors in the locus coeruleus in the expression of withdrawal syndrome from opioids

Shogo Tokuyama, Hong Zhu, Seikwan Oh, Ing K. Ho, Toshinori Yamamoto

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41 Scopus citations

Abstract

To examine a role of N-methyl-D-aspartate (NMDA) receptors in the locus coeruleus (LC) in the expression of the withdrawal signs from opioids, rats were continuously infused with morphine (a μ-opioid agonist, 26 nmol/μl per h) or butorphanol (a μ/δ/κ-mixed opioid agonist, 26 nmol/μl per h) intracerebroventricularly (i.c.v.) through osmotic minipumps for 3 days. An LC injection of NMDA (0.1 and 1 nmol/5 μl) induced withdrawal signs in opioid-dependent animals. However, it did not precipitate any abnormal behaviors in saline-treated control rats. The expression of the withdrawal signs precipitated by NMDA (1 nmol/5 μl), glutamate (10 nmol/5 μl), or naloxone (an opioid antagonist, 24 nmol/5 μl) was completely blocked by pretreatment with a NMDA antagonist, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), 0.1 mg/kg, i.p. In animals that had been infused with opioids in the same manner, naloxone (48 nmol/5 μl, i.c.v.) precipitated withdrawal signs and increased extracellular glutamate levels in the LC of opioid-dependent rats measured by in vivo microdialysis method. Pretreatment with MK-801, however, did not affect the increases of glutamate levels in the LC. These results further demonstrate that the expression of opioid withdrawal induced by an expeditious release of glutamate in the LC region of opioid-dependent animals might be mainly mediated by the postsynaptic NMDA receptors.

Original languageEnglish
Pages (from-to)103-109
Number of pages7
JournalNeurochemistry International
Volume39
Issue number2
DOIs
StatePublished - 2001

Keywords

  • Butorphanol
  • Glutamate
  • Locus coeruleus (LC)
  • Microdialysis
  • MK-801
  • Morphine
  • N-Methyl-D-aspartate (NMDA)
  • Physical dependence

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