Cannabinoids and Reproduction : A Lasting and Intriguing History
Giovanna Cacciola, Rosanna Chianese, Teresa Chioccarelli, Vincenza Ciaramella, Silvia Fasano, Riccardo Pierantoni, RosariaMeccariello and Gilda Cobellis
Pharmaceuticals, 2010, 3, 3275-3323.
doi : 10.3390/ph3103275
Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the signal transduction mechanisms, activated by cannabinoid receptors stimulation, will also be discussed. In particular, we will point out the action of cannabinoids and endocannabinoids on the different neuronal networks involved in reproductive axis, and locally, on male and female reproductive tracts, by emphasizing the pivotal role played by this system in the control of fertility.
Keywords : cannabinergic system, male reproduction, female reproduction, hypothalamuspituitary- gonads axis
1. The Cannabinergic System: A Historical Overview
1.1.1 . Cannabinoid receptors
1.1.2 . Exogenous and endogenous ligands
1.1.3 . Endocannabinoids biosynthesis and degradation
2. Interactions of the Cannabinergic System with Different Neuronal Networks in Reproductive Perspective
3. The Cannabinergic System in Male Reproductive Tracts: From Spermatogenesis to Sperm Physiology
3.1.1 . Testis
3.1.2 . Excurrent duct system
4. Effects of the Cannabinergic Sytem on Female Reproduction: From Ovary to Utero-placental Relationship
5. Closing Remarks
1. The Cannabinergic System: A Historical Overview
Cannabis sativa (or marijuana) is one of the oldest psychotropic drugs known to humans. According to archaeological discoveries, its use was already mentioned in the Pen Ts’ao, a Chinese pharmacopeia, around 4,000 BC, where it is reported that “Cannabis is spicy when eaten but has a poison good for the five organs. It helps much your energy, your whole body, stops sweat (because of cold) and leaves the water from the body, urine” . Moreover, the same book reports the first description of the hallucinogenic effects of the plant: “If you eat more, you will see white ghosts walking around and if you eat long enough, you will know how to talk to the Gods”. However, is is hard to precisely date early Cannabis use because the oral traditions only began to be written starting from 2,737 BC. In that year, the Chinese emperor Shen Nung was the first to describe the properties of Cannabis in his compendium of medical herbs . Afterwards, around 1,400 BC, Cannabis, named Bhang, was reported in the Indian holy book Atharvaveda in relation to practices against diseases and demons .
Subsequent fine descriptions of Cannabis can be found in Egyptian, Greek and Latin books. Around 70 AC Dioscorides, a surgeon in the Roman legions under the Emperor Nero, provided in his herbarium De materia medica, (cap CLXV, book III) a precise description of Cannabis and suggested its therapeutical use in case of earache (“Ex eo recente expressus succus convenienter aurium doloribus instillatur”). Additionally, he also described Cannabis sylvestri (also known as Cannabis indica) and indicated its beneficial effect in case of inflammation, oedema and gout (“Cocta autem et imposita radix vim habet inflammations leniendi, oedemata discutiendi et articulorum tophos dissipandi”). Cannabis medical use diffused worldwide even in the New World, to where hemp cultivation was exported by the Spanish Conquistadores to provide ropes and clothes . In Southern Europe, medical interest in Cannabis was awakened by Napoleon’s campaign in Egypt, when the health effects were observed among soldiers .
In 1839, William O’Shaughnessy, a British physician and surgeon working in India, was the first to describe the analgesic, muscle relaxant and anticonvulsant properties of Cannabis. His observations quickly led to the expansion of the medical use of Cannabis. Indeed, it was even prescribed to Queen Victoria for relief of dysmenorrhea , although this seems the only therapeutical benefit described in female reproductive system.
In the USA, in 1854 the United States Dispensatory included Cannabis, which was sold freely in pharmacies of Western countries . However, during the “Noble Experiment” (1920-1933), when sale, manufacture and transportation of alcohol for consumption were banned nationally, the American authorities condemned the use of Cannabis, making it responsible for moral and intellectual deterioration and violence. Thus, in 1937, Marijuana Tax Act made possession or transfer of Cannabis illegal throughout the United States under federal law . Additionally, in 1942, Cannabis was removed from the United States Pharmacopeia, thus losing its therapeutic legitimacy .
Today, the long lasting use of Cannabis accross the centuries is not a warranty of its therapeutical efficacy. For example, mandrake and cantaris, two famous remedies, are completely abandoned nowadays because of their side effects , so caution should be used before accepting any old drug as a therapeutical agent simply based on its lasting therapeutical history. In order to evaluate the safety and efficacy of Cannabis, investigations into the chemestry of Cannabis and identification of its active components can be traced back to the 19th century. At the beginning of this reserch, an alkaloid was considered the active constituent of Cannabis. Only in 1965, Mechoulam and Gaoni determined the correct chemical structure of Δ-9-tetrahydrocannabinol, commonly known as THC, the major psychoactive ingredient of Cannabis . From this starting point, intensive research was carried out to identify the other components of Cannabis, leading to the identification of a total of 483 constituents . Other cannabinoids (CBs) present in Indian hemp include Δ-8-tetrahydrocannabinol (Δ8-THC), cannabinol (CBN), cannabidiol (CBD), cannabicyclol (CBL), cannabichromene (CBC) and cannabigerol (CBG), but they are present in small quantities and have no significant psychotropic effects compared to THC. However, they may have an impact on the product’s overall effect .
In 1987, new potent cannabinoid agonists were developed. This group of CBs consists of ABCtricyclic dibenzopyran derivatives, as 11- hydroxy-Δ8-THC-dimethylheptyl (HU-210) and desacetyl-Lnantradol. These CBs elicited cannabimimetic responses both in vivo and in vitro .
1.1. Cannabinoid receptors