The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons.
Previous research has demonstrated that mGlu2/3 agonists can decrease many behavioral signs and the activation of locus coeruleus (LC) neurons observed during morphine withdrawal. However, it is not known if mGlu2/3 receptors are activated during morphine withdrawal by endogenous glutamate. Therefore, we investigated the effect of a novel metabotropic glutamate 2, 3 (mGlu2/3) receptor antagonist (LY341495) on naltrexone-precipitated behavioral signs of morphine withdrawal and withdrawal-induced activation of LC neurons. Three levels of severity of morphine withdrawal (mild, moderate, and strong) were operationally defined by varying the exposure to morphine. Pretreatment with LY341495 (1 mg/kg, s.c.) had no affect on behavioral signs at the mild level of withdrawal, but significantly increased behavioral signs at the moderate level of withdrawal. At the strong level of withdrawal, 3 and 10 mg/kg, but not 1 mg/kg, LY341495 significantly increased the behavioral signs of withdrawal. In in vivo recordings from anesthetized rats, pretreatment with 1 mg/kg LY341495 did not affect the morphine-withdrawal-induced activation of LC neurons at the mild level of withdrawal. At the moderate level of withdrawal, 1 and 10 mg/kg LY341495 did not affect morphine-withdrawal-induced activation of LC neurons. At the strong level of withdrawal, both 1 and 10 mg/kg LY341495 significantly increased morphine-withdrawal-induced activation of LC neurons. These results indicate that endogenous activation of mGlu2/3 receptors during morphine withdrawal acts to reduce the severity of morphine withdrawal and demonstrates that mGlu2/3 receptors are activated under a physiologically relevant, pathological condition.
Neuroscience Division, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA. rasmussen_kurt@lilly.com
Kurt
K
Rasmussen
Mei-Ann
MA
Hsu
Jim
J
Vandergriff
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009021:Morphine Dependence / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014966:Xanthenes / Q000494:pharmacology*
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3