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

• Published in: Neurochemistry international 2001-08, Vol.39 (2), p.103-109
• Main Authors: Tokuyama, Shogo, Zhu, Hong, Oh, Seikwan, Ho, Ing K., Yamamoto, Toshinori
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Biological and medical sciences; Butorphanol; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Extracellular Space - metabolism; Glutamate; Glutamic Acid - administration & dosage; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Locus coeruleus (LC); Locus Coeruleus - metabolism; Male; Medical sciences; Microdialysis; MK-801; Morphine; N-Methyl- d-aspartate (NMDA); N-Methylaspartate - administration & dosage; N-Methylaspartate - pharmacology; Naloxone - administration & dosage; Naloxone - pharmacology; Narcotics - adverse effects; Neuropharmacology; Pharmacology. Drug treatments; Physical dependence; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - physiology; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - physiopathology
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/S0197-0186(01)00019-5

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.