Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures — A short review

Abstract

In the last 25 years data has grown exponentially dealing with the discovery of the endocannabinoid system consisting of specific cannabinoid receptors, their endogenous ligands, and enzymatic systems of their biosynthesis and degradation. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity which should help in providing a greater understanding of the physiological role of the endocannabinoid system and perhaps also in a broad number of pathologies. This could lead to advances with important therapeutic potential of drugs modulating activity of endocannabinoid system as hypnotics, analgesics, antiemetics, antiasthmatics, antihypertensives, immunomodulatory drugs, antiphlogistics, neuroprotective agents, antiepileptics, agents influencing glaucoma, spasticity and other “movement disorders“, eating disorders, alcohol withdrawal, hepatic fibrosis, bone growth, and atherosclerosis. The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.

Introduction

Cannabinoids are the terpenophenolic constituents of the hemp plant (Cannabis sativa) that has been used for over 4000 years as a recreational drug due to its mind-altering effects. Marijuana, which is made from the dried leaves and tops of the plant, has lower cannabinoid content than hashish, which is a preparation from the dried resin secreted by the plant. The primary psychoactive constituents of cannabis, Δ8-tetrahydrocannabinol (Δ8-THC) and Δ9-THC, were isolated in 1964 (Gaoni and Mechoulam, 1964). Δ9-THC is more prevalent in marijuana and more potent in vivo than Δ8-THC, and thus most of the psychoactivity has been attributed to Δ9-THC (Pertwee, 1988). Δ9-THC is rapidly absorbed and converted in the lungs and liver into a centrally active metabolite, 11-hydroxy-Δ9-THC (Abood and Martin, 1992).

The cannabinoids have been shown to produce a unique syndrome of effects on the behaviour of humans and animals that include disruption of short-term memory, cognitive impairments, a sense of time dilation, mood alterations, enhanced body awareness, a reduced ability to focus attention and to filter out irrelevant information, discoordination, and sleepiness (Block et al., 1992, Chait and Perry, 1994, Court, 1998, Heishman et al., 1997).

Human users as well as laboratory animals exhibit both tolerance and dependence following chronic administration of cannabinoids and withdrawal symptoms (nervousness, tension, restlessness, sleep disturbance and anxiety) upon drug cessation (Lichtman and Martin, 2005). A clear-cut abstinence syndrome has been however rarely reported, presumably because of the long life of cannabinoids, which precludes the emergence of abrupt abstinence symptoms. Cannabinoid pharmacokinetic processes which are dynamic, may change distribution over time, be affected by routes of administration, the frequency and magnitude of drug exposure, diverse from different drug formulations and concentrations, are also dependent on poor or extensive type of metabolism (Huestis, 2007). In mice made tolerant to Δ9-THC, however, administration of the selective cannabinoid CB1 receptor antagonist SR141716A after the last Δ9-THC injection promptly precipitated a profound withdrawal syndrome (Cook et al., 1998). Typical withdrawal behaviour in rats became obvious as expressed in an increase in paw tremors and head shakes that was accompanied by a decrease in such normal behaviour as grooming and scratching.

Cannabis sativa was for a longer time reported as the only abused drug which is not self-administered by laboratory animals. However, recently this animal model of dependence showed that the self-administration of cannabinoid receptor agonists is to some extent comparable to those for cocaine and amphetamines in monkeys (Justinová et al., 2003, Justinová et al., 2004, Justinová et al., 2005a, Justinová et al., 2005b, Tanda et al., 2000) and with the existence of strain and sex differences also in laboratory rodents (Fattore et al., 2001, Fattore et al., 2007). Moreover, neuroplastic changes are present in the dopaminergic brain reward pathway (ventral tegmental area — accumbens nucleus) and caused by repeated intake of cannabis and other drugs of abuse (Castle and Murray, 2004).

Chronic exposure to cannabis may, however, cause long-term impairment. It has been reported that residual neuropsychological effects, as evidenced by greater cognitive impairments, persist even after abstinence (Pope and Yurgelun-Todd, 1996). Chan et al. (1998) have just presented ample evidence for Δ9-THC-induced neurotoxicity. Following treatment of cultured hippocampal neurons or slices with Δ9-THC, they observed shrinkage of neuronal cell bodies and nuclei as well as fragmentation of DNA, indicating neuronal apoptosis.

On the other hand, some effects of cannabinoids may be therapeutically useful, including antiemetic, analgesic, antispasmodic, appetite-stimulating and sleep-inducing effects (Childers and Breivogel, 1998). Antinociceptive effects of cannabinoids have been investigated in various animal models (e.g., Bridges et al., 2001, Calignano et al., 1998, Ibrahim et al., 2003, Malan et al., 2001, Malan et al., 2002, Martin et al., 1998, Pertwee, 1999, Rice et al., 2002, Richardson, 2000, Vaughan and Christie, 2000).