Endocannabinoids are an emerging class of lipid mediators isolated from the brain, peripheral tissues, and reproductive fluids, with biological actions exerted by activating the cannabinoid type-1 and type-2 receptors CNR1 and CNR2 (also known as Cb1 and cB2, respectively) able to bind also the Cannabis constituent D9-tetrahydrocan-nabinol (THC). To date, the best characterized endocannabinoids are arachidonoylethanolamide (AEA or anandamide) and 2-arachidonoyl-glycerol (2-AG). AEA (but not 2-AG), at concentrations higher than those required to activate CNR1, additionally acts at intracellular sites of some ion channels, including the transient receptor potential vanilloid type 1 (TRPV1) generally known to be stimulated by the pungent compound of hot chili pepper, capsaicin.
The effects of AEA and 2-AG on cannabinoid receptors depend on their concentration in the extracellular space, which is controlled by 1) their Ca2+-dependent biosynthesis occurring from membrane precursors and requiring specific enzymes (primarily, N-acylphosphatidylethanol-amine [NAPE]-specific phospholipase-D [PLD] for AEA and sn-1-diacylglycerol lipase [DAGL] for 2-AG); 2) cellular release and uptake, requiring a specific but as yet unidentified transporter (endocannabinoid membrane transporter, EMT); and 3) intracellular degradation, requiring fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MGLL) for 2-AG. The endocannabinoids, their receptors, and the enzymes for their synthesis and degradation constitute the ‘‘endocannabinoid system.’’ This system has recently been characterized in spermatozoa, where it influences important steps controlling their functions. itat on
Endocannabinoids are present in human seminal plasma and in the amphibian cloacal fluid. In vitro studies showed that endocannabinoids inhibit human (ejaculated spermatozoa) and frog (cloacal spermatozoa) sperm motility. In frogs, this effect is dependent on endocannabinoid concentration, mediated by CNR1 (like in humans) and counteracted by spermatozoa dilution or washing. These data suggest that endocannabinoids control the number of motile spermatozoa by keeping them quiescent until release in the aquatic environment (‘‘dilution mechanism’’). However, it is not known yet whether in mammals, where immotile spermatozoa reach the epididymis by passive transport, the acquisition of their potential to become motile in the cauda may also be controlled by loss of endocannabinoid tone. Indeed, it is well known that immotile or sluggish spermatozoa from the caput epididymis are able to attain their full vigor and to move forward (progressive motility) in cauda only when delivered, from cauda, either in physiological solution or in the female reproductive tract. We hypothesized that a decrease of endocannabinoid levels and/or CNR1 receptors might be responsible for potential motility acquisition (‘‘start-up’’) of spermatozoa during their travel from the caput to the cauda of the epididymis.