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

Abstract

Both CB 1 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 CB 1 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 CB 1 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 CB 1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD.

Endocannabinoid regulation of homeostatic feeding and stress‐induced alterations in food intake in male rats

“…To date, there are no reports assessing i.c.v. administration of MJN110, although several studies have demonstrated CB 1 receptor‐dependent effects of localized injection (2 μg) into distinct brain regions (Limebeer et al ., ; Sticht et al ., ; Wills et al ., ). As the current study assessed i.c.v.…”

The Insula: A Brain Stimulation Target for the Treatment of Addiction

“…The anxiety-like behavior observed during protracted withdrawal is alleviated by lesions of the medial IC. The cannabinoid system has also been implicated, with the inhibition of monoacylglycerol lipase (causing elevation of the endocannabinoid 2-arachidonyl glycerol; 2-AG) in the pGIC preventing the acquisition of CPA from morphine withdrawal, which was reversed by the blockade of cannabinoid-1 receptors (Wills et al, 2016).…”

Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature

“…Contrary to somatic withdrawal, the cannabinoid agonist, Δ 9 THC, and the FAAH enzyme inhibitors, PF3845 and URB-597, tested were unable to modify the establishment of a naloxone-precipitated CPA ( Wills et al, 2014 ; Gamage et al, 2015 ). However, while activation of the cannabinoid system via exogenous cannabinoid administration or endogenous elevation of AEA proved to have little efficacy, inhibition of MAGL activity and concomitant elevation of 2-AG showed mixed ( Wills et al, 2014 , 2016 ; Gamage et al, 2015 ) but more promising results. Given that these discrepant findings were obtained by different laboratories using different procedures, compounds (JZL-184 vs. MJN110), and species (mice vs. rats), more research into the potential of MAGL inhibition in reducing affective opioid withdrawal will be required in order to elucidate its role.…”

“…Although the deleterious reputation of cannabinoid antagonists/inverse agonists may limit their therapeutic potential ( Bergman et al, 2008 ), blockade of the endocannabinoid system may be effective for reducing affective opioid withdrawal. Indeed, acute CB 1 R antagonism (with both AM251, and the neutral CB 1 antagonists, AM4113, and AM6527) was effective in preventing the establishment of a naloxone-precipitated CPA ( Wills et al, 2014 , 2016 ). This is in contrast to the ability of acute CB 1 antagonism to reliably reduce somatic withdrawal, but could be attributed to the fact that the CPA paradigm may provide a more sensitive measure of opioid withdrawal ( Azar et al, 2003 ).…”

“…Although the above studies do not make any direct comparisons between the BLA and CeA on cannabinoid–opioid interactions, a recent experiment suggests a functional double dissociation between these regions in the ability of the cannabinoid system to modulate affective opioid withdrawal. Indeed, cannabinoid agonism (via inhibition of MAGL activity with MJN110) within the BLA, while cannabinoid antagonism (AM251) within the CeA, is able to interfere with the establishment of a naloxone-precipitated CPA in acutely morphine dependent rats ( Wills et al, 2016 ). Though the mechanisms mediating the dissociation between these regions were not investigated, this finding suggests potential differences in cannabinoid–opioid modulation within different sub-regions of the amygdala.…”