Elsevier

Biochemical Pharmacology

Volume 157, November 2018, Pages 43-50
Biochemical Pharmacology

Review
When orexins meet cannabinoids: Bidirectional functional interactions

https://doi.org/10.1016/j.bcp.2018.08.040Get rights and content

Abstract

A growing body of evidence suggests the existence of biochemical and functional interactions between the endocannabinoid and orexin systems. Cannabinoid and orexin receptors have been shown to form heterodimers in agreement with the overlapping distribution of both receptors in several brain areas, and the activation of common intracellular signaling pathways, such as the MAP kinase cascade. The activation of orexin receptors induces the synthesis of the endocannabinoid 2-arachidonoyl glycerol suggesting that the endocannabinoid system participates in some physiological functions of orexins. Indeed, functional interactions between these two systems have been demonstrated in several behavioral responses including nociception, reward and food intake. The present review is focused on the latest developments in cannabinoid-orexin cross-modulation and the implications of this interesting interaction.

Section snippets

The endocannabinoid and orexin systems

The endocannabinoid system (ECS) consists of two main endogenous ligands: anandamide (AEA) and 2-arachidonoylglycerol (2-AG) called endocannabinoids, the synthetizing enzymes: diacylglycerol lipase-α (DAGL) and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), the degradation enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and two major G protein-coupled receptors (GPCR): the cannabinoid type 1 (CB1R) and type 2 (CB2R) receptors. Other putative

Biochemical interactions between orexins and cannabinoids

A growing body of biochemical and functional evidence suggests that GPCRs, historically considered monomers, form and function as homo- and heterodimers, or even higher-ordered oligomers. These dimers/oligomers often display unique ligand binding, distinct phenotypic trafficking, and specific signaling properties in comparison with their individual monomers [51], [52]. Congruent with an overlapping distribution of CB1R and OX1R in certain brain areas, the first evidence of functional cross-talk

Involvement of endocannabinoids in the effects of orexins on food intake and energy balance

The OX system is a key modulator of both food intake and energy expenditure. Under physiological conditions, hormonal control of food intake is mainly mediated by the action of leptin and ghrelin in the hypothalamus, where they exert opposing effects on the activity of anorexigenic pro-opiomelanocortin (POMC)/cocaine-amphetamine-related transcripts (CART), and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons in the arcuate nucleus. Leptin, produced by adipocytes, indirectly

Involvement of endocannabinoids in the effects of orexins on nociception

OX neurons project to several regions of the CNS involved in the regulation of pain, including the ventrolateral periaqueductal gray (vlPAG) and spinal dorsal horn, where OX receptors are densely distributed [30], [32]. The descending antinociceptive pathway controls pain perception at the spinal level by the activation of PAG neurons leading to the excitation of cells in the rostroventral medulla, that send inhibitory projections to the dorsal horn of the spinal cord via the dorsolateral

Involvement of endocannabinoids in the modulation of the brain reward system by orexins

The OX system regulates the mesocorticolimbic dopaminergic pathway, which is the circuit responsible for the pleasure feelings associated with natural and drug rewards. Numerous studies have demonstrated a role for the OX system in the addictive properties of drugs of abuse [47], [96], consistent with the existence of reciprocal connections between OX-rich nuclei and brain areas involved in reward processing [30], including the VTA and the nucleus accumbens. OXs seem to regulate reward seeking

Involvement of orexins in the pharmacological effects of cannabinoids

As described in the previous sections of this review, the contribution of the ECS in several physiological functions of OX has been clearly established. However, so far few studies have evaluated whether the opposite is also occurring, that is, does the OX system participate in the pharmacological effects of cannabinoids? A relevant aspect of OX-cannabinoid interplay is observed in the addictive properties of cannabinoids. Cannabis is the most frequently used illicit drug worldwide, and the

Concluding remarks

Anatomical, biochemical and behavioral studies support the existence of bidirectional interactions between the ECS and the OX system. There is an increasing amount of data indicating that endocannabinoids exert a crucial modulation of the effects of OXs on food seeking and antinociception through the release of 2-AG in hypothalamic and brain stem areas. Moreover, new data is pointing towards a relevant role of OXs on stress-induced cocaine relapse also via a 2-AG-mediated mechanism in brain

Acknowledgements

This work was supported by Instituto de Salud Carlos III (PI14/00210), the Fundació la Marató de TV3 (231/C/2014) to PR, “Plan Nacional sobre Drogas” (#2014I019) and “Ministerio de Economía y Competitividad” (SAF2017-85299-R) to FB, and the Catalunya Government AGAUR (2017SGR210). We would like to thank Carla Ramón Duaso for her help with reference editing.

Conflict of interest

The authors declare no competing interests.

References (113)

  • T. Holmqvist et al.

    OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms

    J. Biol. Chem.

    (2005)
  • A. Woldan-Tambor et al.

    Activation of orexin/hypocretin type 1 receptors stimulates cAMP synthesis in primary cultures of rat astrocytes

    Pharmacol. Rep.

    (2011)
  • Y. Zhu et al.

    Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins

    J. Pharmacol. Sci.

    (2003)
  • S. Ammoun et al.

    G-protein-coupled OX1 orexin/hcrtr-1 hypocretin receptors induce caspase-dependent and -independent cell death through p38 mitogen-/stress-activated protein kinase

    J. Biol. Chem.

    (2006)
  • J. Tang et al.

    The signalling profile of recombinant human orexin-2 receptor

    Cell. Signal.

    (2008)
  • H.J. Lee et al.

    Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray

    Neuropharmacology

    (2016)
  • G.J. Hervieu et al.

    Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord

    Neuroscience

    (2001)
  • R. Maldonado et al.

    Involvement of the endocannabinoid system in drug addiction

    Trends Neurosci.

    (2006)
  • G. Aston-Jones et al.

    Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction

    Brain Res.

    (2010)
  • A.R. Wilson-Poe et al.

    Distribution of CB1 cannabinoid receptors and their relationship with mu-opioid receptors in the rat periaqueductal gray

    Neuroscience

    (2012)
  • S. Hilairet et al.

    Hypersensitization of the orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716

    J. Biol. Chem.

    (2003)
  • J. Ellis et al.

    Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function

    J. Biol. Chem.

    (2006)
  • R.J. Ward et al.

    Heteromultimerization of cannabinoid CB(1) receptor and orexin OX(1) receptor generates a unique complex in which both protomers are regulated by orexin A

    J. Biol. Chem.

    (2011)
  • R. Imperatore et al.

    Formation of OX-1R/CB1R heteromeric complexes in embryonic mouse hypothalamic cells: Effect on intracellular calcium, 2-arachidonoyl-glycerol biosynthesis and ERK phosphorylation

    Pharmacol. Res.

    (2016)
  • M.H. Jäntti et al.

    Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors

    Biochem. Biophys. Res. Commun.

    (2014)
  • G.M. Leinninger et al.

    Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance

    Cell Metab.

    (2011)
  • A. Yamanaka et al.

    Hypothalamic orexin neurons regulate arousal according to energy balance in mice

    Neuron

    (2003)
  • M.R. Jain et al.

    Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats

    Regul. Pept.

    (2000)
  • H. Yamada et al.

    Inhibition of food intake by central injection of anti-orexin antibody in fasted rats

    Biochem. Biophys. Res. Commun.

    (2000)
  • I. Crespo et al.

    Pretreatment with subeffective doses of Rimonabant attenuates orexigenic actions of orexin A-hypocretin 1

    Neuropharmacology

    (2008)
  • T.M. Becker et al.

    Endocannabinoid-dependent disinhibition of orexinergic neurons: Electrophysiological evidence in leptin-knockout obese mice

    Mol. Metab.

    (2017)
  • H. Funato et al.

    Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity

    Cell Metab.

    (2009)
  • J.A. González et al.

    Inhibitory interplay between orexin neurons and eating

    Curr. Biol.

    (2016)
  • X.-B. Gao et al.

    Feeding behavior: hypocretin/Orexin neurons act between food seeking and eating

    Curr. Biol.

    (2016)
  • S.L. Borgland et al.

    Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine

    Neuron

    (2006)
  • P.M. Zygmunt et al.

    Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

    Nature

    (1999)
  • G.R. Ross et al.

    Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice

    Pharmacology

    (2012)
  • L. De Petrocellis et al.

    The endocannabinoid system: a general view and latest additions

    Br. J. Pharmacol.

    (2004)
  • R.G.A.C. Pertwee et al.

    Ross International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2

    Pharmacol. Rev.

    (2010)
  • B.S. Basavarajappa

    Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity

    Curr. Neuropharmacol.

    (2007)
  • M. Herkenham et al.

    Cannabinoid receptor localization in brain

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

    (1990)
  • M. Herkenham et al.

    Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study

    J. Neurosci.

    (1991)
  • S.C. Azad et al.

    Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala

    Learn. Mem.

    (2008)
  • P. Schweitzer

    Cannabinoids decrease the K(+) M-current in hippocampal CA1 neurons

    J. Neurosci.

    (2000)
  • S. Zhuang et al.

    Behaviorally relevant endocannabinoid action in hippocampus: dependence on temporal summation of multiple inputs

    Behav. Pharmacol.

    (2005)
  • A. Bacci et al.

    Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids

    Nature

    (2004)
  • S. Marinelli et al.

    Self-modulation of neocortical pyramidal neurons by endocannabinoids

    Nat. Neurosci.

    (2009)
  • G. Bénard et al.

    Mitochondrial CB1 receptors regulate neuronal energy metabolism

    Nat. Neurosci.

    (2012)
  • P.L. Prather et al.

    Activation of cannabinoid receptors in rat brain by WIN 55212–2 produces coupling to multiple G protein alpha-subunits with different potencies

    Mol. Pharmacol.

    (2000)
  • R. Diez-Alarcia et al.

    Biased agonism of three different cannabinoid receptor agonists in mouse brain cortex

    Front. Pharmacol.

    (2016)
  • Cited by (22)

    • Distinct effects of orexin A on spontaneous and evoked synaptic currents in the rat nucleus tractus solitarius

      2022, Journal of Pharmacological Sciences
      Citation Excerpt :

      Subsequent application of OX-A reduced the amplitude of the first eEPSCs and increased the PPR (48 ± 7%, p < 0.01 and 0.92 ± 0.16, p < 0.01, respectively) (Fig. 4B and C). A growing body of evidence suggests a functional interaction between the orexin and endocannabinoid systems.25 Therefore, we tested the involvement of endocannabinoids such as 2-arachidonoylglycerol (2-AG) in OX-A effects.

    • Hippocampal orexin-1 and endocannabinoid-1 receptors underlie the kainate-induced occlusion in theta-burst long- term potentiation

      2022, Neuropeptides
      Citation Excerpt :

      Cannabinoids have been shown to play an important role in depressing hippocampal LTP via CB1R signaling (Basavarajappa et al., 2014). Activation of OXR's induces the synthesis of eCBs which may participate in some of the receptor's downstream functions (Berrendero et al., 2018). Lee et al., 2016 demonstrated that activation of OX neurons in the lateral hypothalamus releases the OX into the ventrolateral preaquedactal gray matter (vlPAG) and disinhibits the OX neurons to reduce the pain via an eCB-mediated mechanism (Lee et al., 2016).

    • Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

      2022, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      However, the role played by 2-AG in this response is less evident, and it has been suggested that an optimal level of this endocannabinoid is required for appropriate processing of fear responses [23,24]. Several reports have described the existence of functional interactions between orexins and 2-AG, mainly in the regulation of nociception, reward and food intake [25,26]. However, whether the ECS is part of the neurobiological substrates underlying the modulation that orexins exert on fear remains to be clarified.

    • Intra-periaqueductal gray matter administration of orexin-A exaggerates pulpitis-induced anxiogenic responses and c-fos expression mainly through the interaction with orexin 1 and cannabinoid 1 receptors in rats

      2019, Neuropeptides
      Citation Excerpt :

      It has been demonstrated that most GPCRs exist as dimers or, potentially, as high order oligomers and therefore their ligands with high pharmacological selectivity would be expected to target different types of receptors (Gomes et al., 2016). Anatomical, biochemical and behavioral studies show that there are bidirectional interactions between OX1Rs and CB1 receptors (Berrendero et al., 2018; Flores et al., 2013). For example, it has been reported that orexin-A infusion into the vlPAG induces analgesia via endocannabinoid system in rats (Ho et al., 2011).

    • Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- And ω6-long-chain-PUFA deficiency

      2019, Journal of Lipid Research
      Citation Excerpt :

      In the brains of nd-fads2−/− mice, the two novel endocannabinoids took over the function of AEA and 2-AG in the retrograde action as ligands of presynaptic CB1 on orexinergic neurons in different areas of brain (lateral hypothalamus, hippocampus, arcuate nucleus. The release of inhibitory GABAergic inputs promotes increased appetite and feeding and increased body fat mass, resulting in obesity, and excitatory glutamatergic inputs, suppressing hunger and induce hypophagy (14, 35, 36). PEA, like AEA and 2-AG, is known to attenuate nociception (37, 38).

    View all citing articles on Scopus
    View full text