Comparative biology of the endocannabinoid system

Abstract

In this review we discuss data showing that the endogenous cannabinoid system, represented by cannabinoid receptors, endogenous cannabinoid receptor ligands and enzymes for the biosynthesis and degradation of these ligands, is conserved throughout evolution from coelenterates to man. This signaling system has been suggested to play several roles in animals, including the regulation of cell development and growth, nervous functions, reproduction and feeding behavior. In this article, however, we shall describe with more detail the possible function of the endogenous cannabinoid system in the modulation of immune response in organisms from the lower to the higher levels of animal evolution.Keywords: cannabinoids; anandamide; 2-arachidonoylglycerol; immune response; nitric oxide; invertebrates.Over the past years, numerous studies have demonstrated that some signaling molecules and their corresponding receptors, such as the endorphins and the opiate receptors, have been conserved during evolution [1,2]. Moreover, comparative studies on other chemical signals, such as the eicosanoids, i.e. the derivatives of arachidonic acid, have provided new experimental models for the understanding of the physiological role played by these substances in mammals [3]. In this article, we review recent data on the possible occurrence and biological function in several animal phyla of the newly discovered endogenous cannabinoid system', and, in particular, we describe the possible role of this signaling system in animal immunity. A B R I E F D E S C R I P T I O N O F T H E S T R U C T U R E , B I O S Y N T H E S I S , A C T I O N A N D I N A C T I V A T I O N O F E N D O C A N N A B I N O I D S I N M A M M A L SIn the mammalian brain, the`central' receptor for psychotropic cannabinoids, named CB 1 , was cloned and sequenced in 1990 [4]. Evidence for a second subtype of cannabinoid receptor, named CB 2 was provided in 1993. This latter receptor was almost uniquely expressed in immune cells [5]. At almost the same time, endogenous ligands for these receptors, capable of mimicking to some extent the pharmacological actions of marijuana's psychoactive principle D 9 -tetrahydrocannabinol (THC, Fig. 1), have been discovered. The most representative of these substances, named`endocannabinoids' by analogy with the endorphins, are anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG) [6±10]. Although differences between the biological actions of THC or synthetic cannabinoids and their endogenous counterparts have been described, several studies suggest that anandamide and 2-AG act as endogenous agonists of CB 1 and/or CB 2 receptors, thereby mimicking several of the pharmacological and behavioral actions associated with cannabinoids [6±10].Thus, for example, both synthetic cannabinoids and anandamide have neuromodulatory effects [7] through which they influence motor behavior, memory and learning, and sensory, autonomic and neuroendocrine responses. Endocannabinoids also affect reproductive functions and embryo development...

N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein

“…In summary, the present findings support the existence of a membrane-associated CB receptor-like plant NAE-binding protein(s) for NAE 14:0 that mediates NAE biological activities, suggesting the existence of an endocannabinoid-like signaling system that is conserved from primitive organisms to vertebrate mammals (for review, see Salzet et al, 2000) and now to plants.…”

“…) that interact more specifically and potently with CB receptors (Reggio, 1999). Together, the NAEs and their receptors have emerged as active signaling components of an "endocannabinoid" system affecting both neuronal and immune functions in animal systems (Salzet et al, 2000) and have become targets of potential therapeutic applications (De Petrocellis et al, 2000;Straus, 2000).…”

N-Acylethanolamines in human reproductive fluids

“…NAEs and/or cannabinoid receptors have been identified in mammals, fish, invertebrates, microorganisms, and higher plants (Schmid et al, 1990;Chang et al, 1993;Schuel et al, 1994Schuel et al, , 1999Bisogno et al, 1997;Di Tomaso et al, 1996;Chapman, 2000;De Petrocellis et al, 1999;Salzet et al, 2000;Schmid, 2000;Elphick, 2002). Furthermore, cannabinoids affect cyclic nucleotide metabolism in protozoa (Zimmerman et al, 1981).…”

“…Related NAEs such as dihomog-linolenoylethanolamide, 7,10,13,16-docosatetraenoylethanolamide, mead ethanolamide, etc. have been identified as endogenous agonists for cannabinoid receptors (Hanus et al, 1993;Priller et al, 1995;Mechoulam and Hanus, 2000;Schmid, 2000;Piomelli et al, 1998Piomelli et al, , 2000Salzet et al, 2000). 2-Arachidonoylglycerol (2-AG) is also a potent endogenous ligand for cannabinoid receptors (Mechoulam et al, 1995;Stella et al, 1997;Mechoulam and Hanus, 2001;Sugiura et al, 1998;Sugiura and Waku, 2000).…”

Endocannabinoids Link Feeding State and Auditory Perception-Related Gene Expression

“…Endocannabinoids, including anandamide and 2-arachidonoylglycerol (2-AG), are naturally occurring lipids capable of cannabinoid receptor activation (Di Marzo et al, 1998). Endocannabinoids produce diverse physiological effects ranging from peripheral modulation of immune function (Salzet et al, 2000; to persistent changes in memory-related neuronal activity (Gerdeman and Lovinger, 2003). In humans, cannabinoids stimulate appetite and the intake of palatable food (Iversen, 2003), and accumulating evidence supports a relationship between cannabinoid signaling and feeding behavior Hanus et al, 2003;Matias et al, 2003;Matias and Di Marzo, 2004).…”