Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 41; no. 7; pp. 1865 - 1873
• Main Authors: Wills, Kiri L, Petrie, Gavin N, Millett, Geneva, Limebeer, Cheryl L, Rock, Erin M, Niphakis, Micah J, Cravatt, Benjamin F, Parker, Linda A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-06-2016
• Subjects: Addictions; Amygdala - drug effects; Analysis of Variance; Animals; Arachidonic Acids - pharmacology; Cannabinoid Receptor Agonists - pharmacology; Carbamates - pharmacology; Cerebral Cortex - drug effects; Conditioning, Operant - drug effects; Diabetic neuropathy; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug withdrawal; Endocannabinoids - pharmacology; Enzymes; Glycerides - pharmacology; Glycerol; Male; Monoacylglycerol Lipases - antagonists & inhibitors; Morphine; Morphine - toxicity; Naloxone - therapeutic use; Narcotic Antagonists - therapeutic use; Narcotics; Narcotics - toxicity; Neurosciences; Original; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - etiology; Substance Withdrawal Syndrome - psychology; Succinimides - pharmacology; Canada
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.356

Both CB1 receptor antagonism and agonism, in particular by 2-arachidonyl glycerol (2-AG), have been shown to reduce somatic symptoms of morphine withdrawal (MWD). Here we evaluated the effects of both systemic pretreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG) and central administration of both MJN110 and the CB1 antagonist (AM251) on the affective properties of MWD. Acute MWD induced place aversion occurs when naloxone is administered 24 h following a single exposure to a high dose of morphine. Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects of acute MWD by a CB1 receptor-dependent mechanism. Furthermore, in a double dissociation, AM251 infusions into the central amygdala, but MJN110 infusions into the basolateral amygdala, interfered with the naloxone-precipitated MWD induced place aversion. As well, MJN110, but not AM251, infusions into the interoceptive insular cortex (a region known to be activated in acute MWD) also prevented the establishment of the place aversion by a CB1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD.