ReviewThe endocannabinoid-CB1 receptor system in pre- and postnatal life
Introduction
Cannabinoid CB1 receptors in the mature organism are widely and densely distributed in neural as well as non-neural tissue including brain, reproductive, immune, digestive systems as well as in peripheral neurons (Fride, 2002c, Maccarrone et al., 2002, Parolaro et al., 2002, Pertwee, 1997, Pinto et al., 2002). CB2 receptors are mainly found in non-neural tissue (Lutz, 2002, Pertwee, 1997) although their presence on peripheral nerves is possible (Ibrahim et al., 2003). In the developing organism, CB1 receptors have been investigated more thoroughly than that of CB2 receptors.
Endogenous ligands for the cannabinoid receptors, denoted as “endocannabinoids”, include thus far anandamide (arachidonyl ethanol amide (Devane et al., 1992)), 2-arachidonoyl glycerol (2-AG (Mechoulam et al., 1995)), noladin (arachidonyl glyceryl ether (Hanus et al., 2001)), the antagonist/partial agonist virodhamine (Porter et al., 2002) and NADA (N-arachidonoyl-dopamine (Walker et al., 2002)). This newly discovered physiological system will be denoted the ‘endocannabinoid CB receptor’ system.
Section snippets
Cannabinoid (CB1 and CB2) receptors
Cannabinoid CB1 and CB2 receptor mRNA has been detected as early as the pre-implantation period in the embryonal mouse (Paria and Dey, 2000) and has also been described around day 11 of gestation (Buckley et al., 1998). Postnatally, a gradual increase in CB1 receptor mRNA (McLaughlin and Abood, 1993) and in the density of CB1 receptors has been measured (Belue et al., 1995, Rodriguez de Fonseca et al., 1993) in whole brain.
Similar developmental patterns of CB1 receptors were found during human
The role of the endocannabinoid CB receptor system in gestation
CB1 and CB2 receptors are already present in the pre-implantation mouse embryo (Paria and Dey, 2000), the CB1 receptor at higher concentrations than those in the brain (Yang et al., 1996). These observations led to the discovery that cannabinoids and endocannabinoids arrest the development of 2-cell embryos into blastocytes. Subsequent studies with CB1 and CB2 receptor antagonists indicated that the cannabinoid-induced embryonal growth arrest is mediated by CB1 and not by CB2 receptors (Paria
Role of cannabinoid receptors in neuronal development
Studies on the expression and functionality of the human CB1 receptor in the developing brain have demonstrated that fetal brain CB1 receptors are functionally active not only in regions which contain cannabinoid CB1 receptors throughout life, such the cerebral cortex and hippocampus, but also in white matter such as the capsula interna and pyramidal tract and in proliferative zones such as the subventricular zone (Mato et al., 2003). These observations are consistent with investigations on the
Neuroprotection in the developing organism
Similarly to the neuroprotective effects of the endocannabinoid CB1 receptor system in adults (Fride and Shohami, 2002), activation of CB1 receptors in postnatal rats (7 days old) with WIN55,212 prevented neuronal loss (in a model of acute asphyxia), both immediate and delayed cell death. However, only delayed neurotoxicity was inhibited by the CB1 receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) (Martinez-Orgado et
Prenatal manipulation of the endocannabinoid CB receptor system and the developing brain
Since the 1960s, a multitude of studies have attempted to assess potential adverse effects of marihuana use during pregnancy, on the offspring. Although description of the teratogenicity of the cannabis plant and its major psychoactive constituent Δ9-tetrahydrocannabinol is beyond the scope of this article, the outcome of such studies has implications for the importance of the endocannabinoid CB receptor system during development. Thus functions which are not affected by prenatal Δ9
Milk suckling and survival during the neonatal period
The involvement of marihuana in feeding and appetite was demonstrated decades ago (Abel, 1971, Fride, 2002b); endocannabinoids appear to fulfill a similar role (Fride, 2002c, Williams and Kirkham, 1999). Endocannabinoids have been detected in bovine as well as human milk, 2-arachidonoyl glycerol (2-AG) in at least 100- to 1000-fold higher concentrations than anandamide (Di Marzo et al., 1998, Fride et al., 2001).
Is it possible that the high levels of CB1 receptor mRNA and 2-AG which have been
Cannabinoids in pediatric medicine
The gradual postnatal increase of anandamide and its CB1 receptors (see Pre- and postnatal development of the endocannabinoid CB receptor system) is accompanied by a gradual maturing response to the psychoactive potential of Δ9-tetrahydrocannabinol and anandamide in postnatal mice between birth and weaning (Fride and Mechoulam, 1996b).
This observation has important implications for cannabinoid therapy in children, since psychoactive side effects may be expected to be minor when treated with
Conclusions
The endocannabinoids and their receptors (CB1, CB2 and the putative CB3 receptor) (Breivogel et al., 2001, Fride et al., 2003b) fulfill a multitude of physiological functions, including immunological, neurological, psychiatric and cardiovascular. Our knowledge of the various roles of the endocannabinoid CB receptor system in developmental processes is still sketchy. However, from the knowledge accumulated until now, it appears that while the endocannabinoid CB receptor system contributes to
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2024, Journal of Nutritional BiochemistryUse of computational toxicology tools to predict in vivo endpoints associated with Mode of Action and the endocannabinoid system: A case study with chlorpyrifos, chlorpyrifos-oxon and <sup>Δ9</sup>Tetrahydrocannabinol
2022, Current Research in ToxicologyCitation Excerpt :The results of the stepwise process of gathering in vivo and in vitro data, selecting ToxCast/Tox21 data relevant to the known MOA/eCBS pathways, determining the most predictive HTTK model and interspecies extrapolation method and refining the predictions based on age by use of HTTK-Pop Data are summarized in Table 5. ToxCast/Tox21 results indicated a weak link between CPF and CPFO and GABA, dopamine, opioid and mitochondrial targets that are known to be affected by CPF treatment and associated with the eCBS (Berghuis, 2005, Berghuis et al., 2007, Fernández-Ruiz et al., 2019, Navarro et al., 1996, Fernández-Ruiz et al., 2004, Bénard et al., 2012, Djeungoue-Petga and Hebert-Chatelain, 2017, Fride, 2004, Wang et al., 2006). However, the ToxCast/Tox21 results alone would not have supported an association.
Oxygenation of endocannabinoids by mammalian lipoxygenase isoforms
2021, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :They bind to specific G-protein-coupled cell surface receptors, which are abundantly expressed in the central and peripheral nervous system of vertebrates [3,4]. Endocannabinoids have been implicated in a large number of physiological and cognitive processes, which include fertility regulation and sexual behavior [5], pregnancy [6,7], pre- and postnatal development [8], regulation of the immune system [9], pain sensation [10], food intake [11], and mood and memory [1,2]. Two primary cannabinoid receptors (CB1, CB2) have been identified, but a number of G-protein-coupled orphan receptors (GPR18, GPR55, GPR119) may also contribute to endocannabinoid signaling [4,12].
Adolescent cannabinoid exposure interacts with other risk factors in schizophrenia: A review of the evidence from animal models
2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The endocannabinoid system is a retrograde ligand messaging system involving cannabinoid receptors, namely type 1 and 2 (CB1r/CB2r), naturally occurring endogenous ligands such as anandamide and 2-arachidonoylglycerol, and enzymes responsible for the synthesis and degradation of these ligands. This system is involved in various functions such as neurodevelopment, appetite, mood and memory (extensively reviewed in Akirav, 2011; Díaz-Alonso et al., 2012; Fride, 2004; Rodríguez de Fonseca et al., 2005). Cannabis (Cannabis sativa) contains a multitude of cannabinoids which act via the endocannabinoid system in central and/or peripheral tissues.