Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

Flores, África; Maldonado, Rafaël; Berrendero, Fernando

doi:10.3389/fnins.2013.00256

Cited by 57 publications

(44 citation statements)

References 196 publications

(242 reference statements)

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“…Findings are emerging suggesting the existence of a crosstalk between the orexinergic and the endocannabinoid systems (Flores et al ., ). Anatomical studies show an overlapping distribution of CB 1 and orexin receptors in several brain areas (Marcus et al ., ; Mackie, ), and the existence of heterodimers between CB 1 and OX 1 receptors has also been demonstrated (Jäntti et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol

Flores

Julià-Hernández

Maldonado

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEAnatomical, biochemical and pharmacological evidence suggest the existence of a crosstalk between the orexinergic and endocannabinoid systems. While the orexin receptor 1 (OX 1 receptor) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ 9 -tetrahydrocannabinol (THC) remains unexplored. EXPERIMENTAL APPROACHWe assessed the possible role of orexins in THC-induced hypolocomotion, hypothermia, antinociception, anxiolytic-and anxiogenic-like effects and memory impairment. Selective OX 1 and OX 2 receptor antagonists and OX 1 knockout (KO) mice as well as prepro-orexin (PPO) KO mice were used as pharmacological and genetic approaches. CB 1 receptor levels in control and PPO KO mice were evaluated by immunoblot analysis. The expression of c-Fos after THC treatment was analysed in several brain areas in wild-type mice and in mice lacking the PPO gene. KEY RESULTSThe hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX 2 receptor signalling. OX 1 receptors did not seem to be involved in these THC responses. No differences in CB 1 receptor levels were found between wild-type and PPO KO mice. THC-induced increase in c-Fos expression was reduced in the central amygdala, medial preoptic area and lateral septum in these mutant mice. CONCLUSIONS AND IMPLICATIONSOur results provide new findings to further clarify the interaction between orexins and cannabinoids. OX 1 and OX 2 receptors are differently implicated in the pharmacological effects of cannabinoids.Abbreviations DI, discrimination index; KO, knockout; MPE, maximum possible effect; PPO, prepro-orexin; THC, Δ -Tetrahydrocannabinol (THC), the main psychoactive constituent of Cannabis sativa, produces a wide spectrum of central and peripheral actions, including antinociception, hypothermia, immunomodulation, hypolocomotion, catalepsy, memory disruption, rewarding effects and emotional responses (Pertwee, 2008). The CNS responses to THC are mainly mediated by the cannabinoid receptor 1 (CB 1 receptor), which is a member of the family of GPCRs (Pertwee et al., 2010). Thus, the antinociceptive, hypolocomotor and hypothermic effects of THC, as well as the somatic signs of THC withdrawal, were not observed in CB 1 knockout (KO) mice (Ledent et al., 1999). The discovery of CB 2 receptors in neurons of the CNS (Van Sickle et al., 2005) suggests that these receptors could also contribute to some central pharmacological effects of THC. Several heterologous systems, different from the endocannabinoid system, also participate in the behavioural responses induced by THC. Thus, dopamine (Sami et al., 2015), endogenous opioids (Robledo et al., 2008), monoamines (Viñals et al., 2015), GABA (Radhakrishnan et al., 2015), glutamate (Castaldo et al., 2010), ACh (Goonawardena et al., 2010), adenosine (Justinová et al., 2014) and several neuropeptides (Verty et al., 2004) have been shown to be involved in cannabinoid pharmacolo...

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Section: Introductionmentioning

confidence: 97%

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol

Flores

Julià-Hernández

Maldonado

et al. 2016

British J Pharmacology

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“…The major physiological effect of endocannabinoids is analgesia [1, 2], but 2-AG is also implicated in food intake [3], as well as in anxiety, stress and fear responses, and movement disorders [4–6]. In addition, 2-AG levels are altered under ischemia and stroke [7–10], traumatic brain injury [11], obesity [12], Parkinson’s disease [13], and multiple sclerosis [14], indicating a possible role for 2-AG under these conditions.…”

Section: Introductionmentioning

confidence: 99%

Brain 2‐Arachidonoylglycerol Levels Are Dramatically and Rapidly Increased Under Acute Ischemia‐Injury Which Is Prevented by Microwave Irradiation

Brose

Golovko

2016

Lipids

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The involvement of brain 2-arachidonoylglycerol (2-AG) in a number of critical physiological and pathophysiological regulatory mechanisms highlights the importance for an accurate brain 2-AG determination. In the present study, we validated head-focused microwave irradiation (MW) as a method to prevent postmortem brain 2-AG alterations before analysis. We have compared MW to freezing to prevent 2-AG induction and estimated exogenous and endogenous 2-AG stability upon exposure to MW. Using MW, we have measured, for the first time, true 2-AG brain levels under basal conditions, 30 sec after brain removal from the cranium, and upon exposure to 5 min of brain global ischemia. Our data indicate that brain 2-AG levels are instantaneously and dramatically increased ~ 60 fold upon brain removal from the cranium. Upon 5 min of brain global ischemia 2-AG levels are also, but less dramatically, increased 3.5 fold. Our data indicate that brain tissue fixation with MW is a required technique to measure both true basal 2-AG levels and 2-AG alterations under different experimental conditions including global ischemia, and 2-AG is stable upon exposure to MW.

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“…merging anatomical, biochemical, and pharmacological evidence supports a functional interaction between endocannabinoids and orexin-A (OX-A) (also known as hypocretin-1) in the hypothalamic regulation of appetite, energy expenditure, and metabolism (1). In hypothalamic neurons, the endocannabinoid 2-arachidonylglycerol (2-AG) is under the negative control of leptin (2) and acts through the cannabinoid receptor type 1 (CB 1 R) to promote appetite by activating several intracellular pathways, including mitogen-activated protein kinases of the extracellularsignal-regulated kinase (ERK) family (3).…”

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confidence: 99%

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

Morello

Imperatore

Palomba

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocytestimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB 1 R) on the plasma membrane. OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana's psychotropic and appetite-inducing component Δ 9 -tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB 1 R. We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB 1 R-induced and extracellularsignal-regulated kinase 1/2 activation-and STAT3 inhibitionmediated suppression of Pomc gene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/ob and high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice. Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease. These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.hypocretin-1 | cannabinoid type 1 receptor | 2-arachidonoylglycerol | α-melanocyte-stimulating hormone | hypothalamus E merging anatomical, biochemical, and pharmacological evidence supports a functional interaction between endocannabinoids and orexin-A (OX-A) (also known as hypocretin-1) in the hypothalamic regulation of appetite, energy expenditure, and metabolism (1). In hypothalamic neurons, the endocannabinoid 2-arachidonylglycerol (2-AG) is under the negative control of leptin (2) and acts through the cannabinoid receptor type 1 (CB 1 R) to promote appetite by activating several intracellular pathways, including mitogen-activated protein kinases of the extracellularsignal-regulated kinase (ERK) family (3). OX-A is an orexigenic neuropeptide expressed by neurons of the lateral hypothalamus (LH), which acts through the OX-A receptor type 1 (OX-1R) (4). Activation of OX-1R by OX-A signaling has been found to affect CB 1 R function by stimulating 2-AG biosynthesis via the phospholipase C/diacylglycerol lipase α (PLC/DAGL) pathway (5) and by enhancing ERK1/2 phosphorylation and activity in cells expressing both OX-1R and CB 1 R (6, 7). Proopiomelanocortin (POMC)-containing neurons represent t...

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Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

Cited by 57 publications

References 196 publications

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol

Brain 2‐Arachidonoylglycerol Levels Are Dramatically and Rapidly Increased Under Acute Ischemia‐Injury Which Is Prevented by Microwave Irradiation

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

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Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

Cited by 57 publications

References 196 publications

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ9‐tetrahydrocannabinol

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ9‐tetrahydrocannabinol

Brain 2‐Arachidonoylglycerol Levels Are Dramatically and Rapidly Increased Under Acute Ischemia‐Injury Which Is Prevented by Microwave Irradiation

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

Contact Info

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Resources

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Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ⁹‐tetrahydrocannabinol