Direct evidence for a role of glutamate in the expression of the opioid withdrawal syndrome

• Published in: European journal of pharmacology 1996-01, Vol.295 (2), p.123-129
• Main Authors: Tokuyama, Shogo, Wakabayashi, Hiroyuki, Ho, Ing K.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Butorphanol; Central nervous system; Dizocilpine Maleate - pharmacology; Drug toxicity and drugs side effects treatment; Glutamate; Glutamic Acid - pharmacology; Male; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); MK-801 (dizocilpine); Morphine; Morphine - pharmacology; Naloxone - pharmacology; Narcotics - pharmacology; Opioid dependence; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(95)00645-1

To investigate the role of glutamate in the expression of the withdrawal signs from opioids, rats were intracerebroventricularly (i.c.v.) infused continuously with morphine (a μ-opioid receptor agonist, 26 nmol/μl per h) or butorphanol (a mixed μ/δ/κ-opioid receptor agonist, 26 nmol/μl per h) through osmotic minipumps for 3 days. An i.c.v. injection of glutamate (5 and 50 nmol/5 μl) dose dependently induced withdrawal signs in morphine- or butorphanol-dependent animals. The withdrawal signs precipitated by the glutamate injection were comparable to those precipitated by an opioid receptor antagonist, naloxone (48 nmol/5 μl), except for the expression of some specific behaviors and the duration of withdrawal signs. Glutamate or naloxone challenge failed to precipitate any withdrawal signs in saline controlled animals. On the other hand, the expression of the withdrawal signs precipitated by glutamate or naloxone in opioid-dependent animals was completely blocked by pretreatment with MK-801 a NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cycloheptan-5,10-imine, 0.1 mg/kg, i.p. These unique actions of glutamate in continuously opioid-infused rats suggest that a rapid central release of glutamate may be a key factor in the expression of withdrawal signs from opioids. Furthermore, this effect may be mediated by the NMDA subtype of glutamate receptors.