Review
The endocannabinoid-CB1 receptor system in pre- and postnatal life

https://doi.org/10.1016/j.ejphar.2004.07.033Get rights and content

Abstract

Recent research suggests that the endogenous cannabinoids (“endocannabinoids”) and their cannabinoid receptors have a major influence during pre- and postnatal development. First, high levels of the endocannaboid anandamide and cannabinoid receptors are present in the preimplantation embryo and in the uterus, while a temporary reduction of anandamide levels is essential for embryonal implantation. In women accordingly, an inverse association has been reported between fatty acid amide hydrolase (the anandamide degrading enzyme) in human lymphocytes and miscarriage. Second, CB1 receptors display a transient presence in white matter areas of the pre- and postnatal nervous system, suggesting a role for CB1 receptors in brain development. Third, endocannabinoids have been detected in maternal milk and activation of CB1 receptors appears to be critical for milk sucking by newborn mice, apparently activating oral–motor musculature. Fourth, anandamide has neuroprotectant properties in the developing postnatal brain. Finally, prenatal exposure to the active constituent of marihuana (Δ9-tetrahydrocannabinol) or to anandamide affects prefrontal cortical functions, memory and motor and addictive behaviors, suggesting a role for the endocannabinoid CB1 receptor system in the brain structures which control these functions. Further observations suggest that children may be less prone to psychoactive side effects of Δ9-tetrahydrocannabinol or endocannabinoids than adults. The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.

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

References (77)

  • P.A. Fried et al.

    Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (1998)
  • P.A. Fried et al.

    Growth and pubertal milestones during adolescence in offspring prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (2001)
  • P.A. Fried et al.

    Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana

    Neurotoxicol. Teratol.

    (2003)
  • D.E. Hutchings et al.

    Prenatal cocaine: maternal toxicity, fetal effects and locomotor activity in rat offspring

    Neurotoxicol. Teratol.

    (1989)
  • D.E. Hutchings et al.

    Prenatal delta-9-tetrahydrocannabinol in the rat: effects on postweaning growth

    Neurotoxicol. Teratol.

    (1991)
  • C.D. Jolley

    Failure to thrive

    Curr. Probl. Pediatr. Adolesc. Health Care

    (2003)
  • B. Lutz

    Molecular biology of cannabinoid receptors

    Prostaglandins, Leukot. Essent. Fat. Acids

    (2002)
  • M. Maccarrone et al.

    Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage

    Lancet

    (2000)
  • M. Maccarrone et al.

    Endocannabinoids, hormone–cytokine networks and human fertility

    Prostaglandins, Leukot. Essent. Fat. Acids

    (2002)
  • I.S. McGregor et al.

    Cannabinoid modulation of rat pup ultrasonic vocalizations

    Eur. J. Pharmacol.

    (1996)
  • C.R. McLaughlin et al.

    Developmental expression of cannabinoid receptor mRNA

    Brain Res. Dev. Brain Res.

    (1993)
  • R. Mechoulam et al.

    Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

    Biochem. Pharmacol.

    (1995)
  • M. Navarro et al.

    Motor behavior and nigrostriatal dopaminergic activity in adult rats perinatally exposed to cannabinoids

    Pharmacol. Biochem. Behav.

    (1994)
  • B.C. Paria et al.

    Ligand–receptor signaling with endocannabinoids in preimplantation embryo development and implantation

    Chem. Phys. Lipids

    (2000)
  • D. Parolaro et al.

    Endocannabinoids in the immune system and cancer

    Prostaglandins, Leukot. Essent. Fat. Acids

    (2002)
  • R.G. Pertwee

    Pharmacology of cannabinoid CB1 and CB2 receptors

    Pharmacol. Ther.

    (1997)
  • L. Pinto et al.

    Endocannabinoids and the gut

    Prostaglandins Leukot. Essent. Fatty Acids

    (2002)
  • J.M. Stern et al.

    Thermal control of mother–young contact revisited: hyperthermic rats nurse normally

    Physiol. Behav.

    (2002)
  • G. Vela et al.

    Maternal exposure to delta9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central mu opioid receptors in adult offspring female rats

    Brain Res.

    (1998)
  • D. Viggiano et al.

    Prenatal elevation of endocannabinoids corrects the unbalance between dopamine systems and reduces activity in the Naples High Excitability rats

    Neurosci. Biobehav. Rev.

    (2003)
  • J.M. Walker et al.

    Endocannabinoids and related fatty acid derivatives in pain modulation

    Chem. Phys. Lipids

    (2002)
  • X. Wang et al.

    Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain

    Neuroscience

    (2003)
  • T. Wenger et al.

    The effects of prenatally administered endogenous cannabinoid on rat offspring

    Pharmacol. Biochem. Behav.

    (1997)
  • T. Wenger et al.

    The hypothalamic levels of the endocannabinoid, anandamide, peak immediately before the onset of puberty in female rats

    Life Sci.

    (2002)
  • E.L. Abel

    Effects of marihuana on the solution of anagrams, memory and appetite

    Nature

    (1971)
  • F. Berrendero et al.

    Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period

    Synapse

    (1999)
  • M.S. Blumberg et al.

    Do infant rats cry?

    Psychol. Rev.

    (2001)
  • I. Branchi et al.

    Ultrasonic vocalizations by infant laboratory mice: a preliminary spectrographic characterization under different conditions

    Dev. Psychobiol.

    (1998)
  • Cited by (73)

    • Use 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 Toxicology
      Citation 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 Lipids
      Citation 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 Reviews
      Citation 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.

    View all citing articles on Scopus
    View full text