Vincenzo Di Marzo

The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase.

The endogenous cannabinoid receptor ligand, anandamide (AEA), is a full agonist of the vanilloid receptor type 1 (VR1) for capsaicin. Here, we demonstrate that the potency and efficacy of AEA at VR1 receptors can be significantly increased by the concomitant activation of protein kinase A (PKA). In human embryonic kidney (HEK) cells over‐expressing human VR1, AEA induces a rise in cytosolic Ca2+ concentration that is mediated by this receptor. The EC50 for this effect was decreased five‐fold in the presence of forskolin (FRSK, 1–5 µm) or the cAMP analogue, 8‐Br‐cAMP (10–100 µm). The effects of 8‐Br‐cAMP and FRSK were blocked by a selective PKA inhibitor. The FRSK (10 nm) also potently enhanced the sensory neurone‐ and VR1‐mediated constriction by AEA of isolated guinea‐pig bronchi, and this effect was abolished by a PKA inhibitor. In rat dorsal root ganglia slices, AEA‐induced release of substance P, an effect mediated by VR1 activation, was enhanced three‐fold by FRSK (10 nm). Thus, the ability of AEA to stimulate sensory VR1, with subsequent neuropeptide release, appears to be regulated by the state of activation of PKA. This observation supports the hypothesis that endogenous AEA might stimulate VR1 under certain pathophysiological conditions.

Temperature-Sensitive Transient Receptor Potential Channels as Ionotropic Cannabinoid Receptors

Since the discovery that the endocannabinoid anandamide could activate the transient receptor potential vanilloid-1 (TRPV1) channel, and that some synthetic TRPV1 agonists could also inhibit anandamide cellular re-uptake, reports of interactions between TRP channels, particularly the temperature-sensitive members of this family, and cannabinoids have intensified. Evidence now exists to suggest that TRPV1 is an ionotropic receptor for some endocannabinoids, and that this as well as other “Thermo-TRPs” can act as transducers for some of the pharmacological actions of phytocannabinoids, including those devoid of significant activity at cannabinoid CB1 and CB2 receptors. Such evidence, and its possible implications in the potential therapeutic applications of endogenous, plant and synthetic cannabimimetic compounds, is reviewed in this chapter.

Neuromodulatory Actions of Endocannabinoids in Pain and Sedation

Endocannabinoids1 are endogenous substances that bind to and activate at least one of the two high affinity membrane receptors discovered for marijuana’s psychoactive principle, (-)-io9-tetrahydrocannabinol (THC). Three types of endocannabinoids have been described so far in both nervous and non-nervous tissues: 1) the anandamides,1 i.e. amides of ethanolamine with polyunsaturated fatty acids with at least twenty carbon atoms and three 1,4-diene double bonds, of which the C20: 4 homologue, arachi-donoylethanolamide (AEA)2,3 has been most thoroughly studied; 2) 2-arachidonoyl glycerol (2-AG)4,5; and 3) the recently described 2-arachidonyl glyceryl ether, or noladin ether,6 whose pharmacological activity as an endocannabinoid has not yet been thoroughly assessed. An entirely saturated AEA congener, palmitoylethanolamide (PEA), was proposed to act as an endocannabinoid at yet-to-be-characterized receptors, but the precise mechanism(s) underlying the THC-like anti-inflammatory and analgesic activity of this compound is(are) still a matter for speculation.7

N-Acyldopamines and N-Acylserotonins: From Synthetic Pharmacological Tools to Endogenous Multitarget Mediators

Abstract The state of the art of our knowledge on two newcomers to the “endocannabinoidome,” the N-acyldopamines (NADs) and N-acylserotonins (NASs), is reviewed here. These two families of bioactive amides of fatty acids (BAFAs) have the peculiarity of having been first investigated as synthetic compounds and pharmacological tools, and then discovered as endogenous mediators. They also share the feature of having been shown to interact with several molecular targets, be them receptors or enzymes, although such interactions often occur at concentrations that are unlikely to be found in tissues, at least under physiological conditions. The available information on the possible metabolic pathways and several mechanisms of actions of NADs and NASs is comprehensively described.