ReviewWhen orexins meet cannabinoids: Bidirectional functional interactions
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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.
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2023, Frontiers in NeuroendocrinologyDistinct effects of orexin A on spontaneous and evoked synaptic currents in the rat nucleus tractus solitarius
2022, Journal of Pharmacological SciencesCitation 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.
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2022, NeuropeptidesCitation 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).
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2022, Biomedicine and PharmacotherapyCitation 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.
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2019, Journal of Lipid ResearchCitation 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).