It has been long established that compounds produced by the Cannabis sativa plant cause a range of psychological effects. The isolation of delta-9-tetrahydrocannabinol (D9THC) as the main psychoactive constituent (Gaoni and Mechoulam, 1964) led to many studies investigating its in vivo effects. However, it was not until 1990, when the first cannabinoid receptor was cloned (Matsuda et al., 1990), followed by the cloning of cannabinoid receptor 2 in 1993 (Munro et al., 1993) that research into the function of cannabinoids escalated.
Anandamide was the first endogenous cannabinoid to be isolated and described (Devane et al., 1992) but a period of almost 10 years remained until evidence emerged of its physiological relevance. In 2001 the endo-cannabinoids were identified as the signal messengers responsible for the phenomenon of retrograde signaling, providing a physiological rationale for their presence in the central nervous system (CNS) (Ohno-Shosaku et al., 2001; Wilson and Nicoll, 2001). Shortly after the discovery of anandamide, a second, now well-studied endocannabinoid, 2-arachidonoylglycerol (2-AG) was identified (Mechoulam et al., 1995).
The cannabinoid receptors belong to a family of G protein-coupled receptors (GPCRs) which exhibit a canonical seven transmembrane structure and the ability to couple to G proteins intracellularly. Anandamide exerts its actions by binding and activating cannabinoid receptors and other targets. Currently only two cannabinoid receptors have been cloned and extensively investigated; CB1 and CB2 receptors (cannabinoid receptors 1 and 2, respectively). However, it should not be overlooked that there is substantial evidence for additional receptors and targets through which anandamide may act. This chapter will encompass the current knowledge of the signaling pathways activated by the action of anandamide on known and putative receptors.
Upon its discovery anandamide was shown to inhibit the cyclic adeno-sine monophosphate (cAMP) generating enzyme adenylate cyclase (Vogel et al., 1993) and N-type calcium currents (Mackie et al., 1993) in CB1 receptor expressing cell lines, consistent with the effects of synthetic- and plant-derived cannabinoids. Rapid hydrolysis of anandamide can lead to an under estimation of the potency of the ligand and complications of active breakdown products exerting cellular effects. This can be circumvented by employing the use of a metabolically stable analog of anandamide (metha-nandamide) or inhibiting fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide hydrolysis (Abadji et al., 1994; Pertwee, 1997).
To date there is a lack of signal transduction information pertaining to anandamide actions in vivo, largely due to experimental difficulties working with this lipophilic and rapidly hydrolyzed molecule as well as the multiple targets it is able to interact with to elicit responses.
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