Chronic Morphine Modulates the Contents of the Endocannabinoid, 2-Arachidonoyl Glycerol, in Rat Brain

Viganò, Daniela; Cascio, Maria Grazia; Rubino, Tiziana; Fezza, Filomena; Vaccani, Angelo; Marzo, Vincenzo Di; Parolaro, Daniela

doi:10.1038/sj.npp.1300117

Cited by 83 publications

(66 citation statements)

References 40 publications

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“…In our studies, induction of withdrawal in morphine-dependent mice did not alter AEA or 2-AG levels in brain areas associated with opiate withdrawal, including LC, PAG, and amygdala, although 2-AG levels have been reported to be increased in other brain regions of rats treated repeatedly with morphine (Viganò et al, 2003). Likewise, long-term heroin self-administration in rats does not produce overt CB 1 receptor functional changes in LC, PAG, amygdala, and other brain structures (Sim-Selley et al, 2000).…”

Section: Discussioncontrasting

confidence: 51%

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

Ramesh

Ross²,

Schlosburg³

et al. 2011

J Pharmacol Exp Ther

108

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⌬9 -Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB 1 and CB 2 cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophe-]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB 1 receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxoneprecipitated jumps and paw flutters through the activation of CB 1 receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxoneprecipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxoneinduced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

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Section: Discussioncontrasting

confidence: 51%

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

Ramesh

Ross²,

Schlosburg³

et al. 2011

J Pharmacol Exp Ther

108

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“…Because this endocannabinoid lipid has been implicated in a diversity of brain functions, targeting MGL may offer a rational approach for pharmacological intervention in neuroprotection, drug addiction, and feeding (Panikashvili et al, 2001;Yamaguchi et al, 2001;Kirkham et al, 2002;Hanus et al, 2003;Vigano et al, 2003). …”

Section: Discussionmentioning

confidence: 99%

RNA Interference Suggests a Primary Role for Monoacylglycerol Lipase in the Degradation of the Endocannabinoid 2-Arachidonoylglycerol

Dinh¹,

Kathuria²,

Piomelli³

2004

Mol Pharmacol

216

149

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The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is produced by neurons and other cells in a stimulus-dependent manner and undergoes rapid biological inactivation through transport into cells and catalytic hydrolysis. The enzymatic pathways responsible for 2-AG degradation are only partially understood. We have shown previously that overexpression of monoacylglycerol lipase (MGL), a cytosolic serine hydrolase that cleaves 1-and 2-monoacylglycerols to fatty acid and glycerol, reduces stimulus-dependent 2-AG accumulation in primary cultures of rat brain neurons. We report here that RNA interference-mediated silencing of MGL expression greatly enhances 2-AG accumulation in HeLa cells. After stimulation with the calcium ionophore ionomycin, 2-AG levels in MGL-silenced cells were comparable with those found in cells in which 2-AG degradation had been blocked using methyl arachidonyl fluorophosphonate, a nonselective inhibitor of 2-AG hydrolysis. The results indicate that MGL plays an important role in the degradation of endogenous 2-AG in intact HeLa cells. Furthermore, immunodepletion experiments show that MGL accounts for at least 50% of the total 2-AG-hydrolyzing activity in soluble fractions of rat brain, suggesting that this enzyme also contributes to 2-AG deactivation in the central nervous system.

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“…For example, the endocannabinoid system seems to be involved in molecular mechanisms of ethanol and morphine. Chronic ethanol or morphine exposure to cultures of cerebellar granule cells produces accumulation of 2-arachidonylglycerol and arachidonylethanolamide (AEA) [99,100,101]. The synthesis of these endocannabinoids increases proportionally to the duration of the ethanol exposure and is prevented by CB 1 antagonist [100].…”

Section: Cannabis Sativamentioning

confidence: 99%

Why Should We Keep the Cerebellum in Mind When Thinking About Addiction?

Miquel¹,

Toledo²,

Hernández³

et al. 2009

CDAR

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Marta Miquel; Rebeca Toledo; Luis I Garcia ; Genaro A Coria-Avila¸ Jorge Manzo. Why should we keep the cerebellum in mind when thinking about addiction?Increasing evidence has involved the cerebellum in functions beyond the sphere of motor control. In the present article, we review evidence that involves the cerebellum in addictive behaviour. We aimed on molecular and cellular targets in the cerebellum where addictive drugs can act and induce mechanisms of neuroplasticity that may contribute to the development of an addictive pattern of behaviour. Also, we analyzed the behavioural consequences of repetitive drug administration that result from activitydependent changes in the efficacy of cerebellar synapses.Revised research involves the cerebellum in drug-induced long-term memory, druginduced sensitization and the perseverative behavioural phenotype. Results agree to relevant participation of the cerebellum in the functional systems underlying drug addiction. The molecular and cellular actions of addictive drugs in the cerebellum involve long-term adaptative changes in receptors, neurotransmitters and intracellular signalling transduction pathways that may lead to the re-organization of cerebellar microzones and in turn to functional networks where the cerebellum is an important nodal structure. We propose that drug induced activity-dependent synaptic changes in the cerebellum are crucial to the transition from a pattern of recreational drug taking to the compulsive behavioural phenotype. Functional and structural modifications produced by drugs in the cerebellum may enhance the susceptibility of fronto-cerebellar circuitry to be changed by repeated drug exposure. As a part of this functional reorganization, drug-induced cerebellar hyper-responsiveness appears to be central to reducing the influence of executive control of the prefrontal cortex on behaviour and aiding the transition to an automatic mode of control.Key words: cerebellum, drug addiction, alcohol, morphine, cocaine, amphetamine, endocannabinoids, sensitization, conditioned emotional memories, cerebellar plasticity 3 THE CEREBELLUM: MORE THAN WHAT WE THOUGHTVery recently, Masao Ito [1] and Narender Ramnani [2] published two excellent and exhaustive reviews on the cerebellum and its functions. Both are highly recommended papers to get a broad perspective on past and current research in this topic. Surely the lesson to be learned from both articles is that later developments in cerebellar research situate functions of the cerebellum beyond motor control. The assumption that the cerebellum controls movement came from medical observations in the mid 19 th and the beginning of the 20 th century [1, 3]. Neurologists observed that lesions in this structure resulted in difficulties in coordinating movement, and experimental physiologists showed that after removing the cerebellum a lack of motor coordination was produced. In the sixties, a specialized role for the cerebellum in the learning of motor patterns was proposed, initially in conventional mo...

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Chronic Morphine Modulates the Contents of the Endocannabinoid, 2-Arachidonoyl Glycerol, in Rat Brain

Cited by 83 publications

References 40 publications

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

RNA Interference Suggests a Primary Role for Monoacylglycerol Lipase in the Degradation of the Endocannabinoid 2-Arachidonoylglycerol

Why Should We Keep the Cerebellum in Mind When Thinking About Addiction?

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