Therapeutic Targeting Of Marijuana Receptors: Type 1, 2 Or Both – That Is The Question

Preparations of Cannabis Sativa L. plants (marijuana) have been used for medicinal and recreational purposes for thousands of years. Today, cannabis is one of the most abused drugs in the UK, and its medicinal use for the management of anxiety and pain caused by a variety of diseases is growing.

Patients smoke and vape marijuana and both natural and synthetic cannabinoids such as Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are present in commercially-available ointments such as oil and cream. The internet and mainstream media are full of anecdotal evidence to support the medicinal benefit of these preparations. However, very little scientific research examined whether the evidence from these reports stands up to scrutiny.

Role of Classic Marijuana receptors in osteoporosis unraveled thanks to a new mouse model

The endogenous cannabinoid (endocannabinoid) system consists of natural ligands, a family of receptors and the molecular machinery for their synthesis, transport, and metabolism. Natural and synthetic cannabinoids exert medicinal benefits as well as increase the risk of psychiatric problems by influencing the action of cannabinoid receptors in the brain and peripheral tissues and organs.

There are two classical cannabinoid receptors; the type 1 receptor (CB1) is highly expressed in the nervous system and is thought to be responsible for regulating appetite, pain perception and motor function. The type 2 receptor (CB2) is highly expressed in peripheral tissues and is responsible for regulation of immune responses. Recently, the orphan receptor GPR55 has been identified as an additional cannabinoid receptor.

Most studies that were conducted to date on the effects of targeting these receptors to treat human diseases used mouse models in which individual CB1 or CB2 receptors have been pharmacologically targeted or genetically inactivated. One key limitation of this approach is that endogenous cannabinoid ligands and natural and synthetic cannabinoids bind both CB1 and CB2, albeit with differing affinities. On the other hand, classical CB1 and CB2 receptors have limited homology and are activated by different chemicals.

Previous research by our laboratories and others using CB1 or CB2 knockout mice or wild-type mice treated with ligands selective for either receptor showed a complex role of these receptors in the regulation of bone metabolism, and revealed discrepancies between the response of osteoclasts (bone resorbing cells – the bad guys) and osteoblasts (bone forming cells – the good guys) to pharmacological and genetic manipulation of CB1 or CB2 individually.

To address these discrepancies we have recently examined whether the role of these receptors in the regulation of bone metabolism was mediated by CB1, 2 or both. To achieve this, we adopted a Mendelian approach by breeding CB1 and CB2 knockout mice to obtain mice that lack both receptors.

Subsequent evaluation of the skeleton of these mice from birth to old age have revealed skeletal phenotypes that contrast with mice with inactivation of either CB1 or CB2 receptors. For example, CB1/2 double knockout mice showed a reduced age-related bone loss and exhibited higher bone mass than wild-type mice. Close histological examinations of the long bones of CB1/2 double knockout mice revealed a significant reduction in the number of both osteoclasts and osteoblasts coupled with an increase in the number of fat cells in the bone marrow.

When combined with previous results that were obtained with single CB1 or CB2 knockout mice and after administration of the selective blockers AM251 (for CB1) and AM630 (for CB2), our current findings suggest that CB1 and CB2 receptors have distinct roles in bone homeostasis and their combined inhibition protects against age-related bone loss primarily by inhibiting bone destruction by osteoclasts.

Whilst it remains to be seen whether targeting both cannabinoid receptors would be of any use in the treatment of osteoporosis in the clinic, this model allowed us to conclude that blockade of individual CB1 or CB2 – but not both – receptors in aging mice may be detrimental. 

Preclinical Models to Assess the Role of Cannabinoids in Cancer Exist – but they can be improved

Metastatic cancer is aggressive and many terminally ill cancer patients are suffering from cancer-related pain. The majority of complications associated with metastatic cancers such as breast and prostate cancer following conventional therapies are a result of the metastatic spread of cells to the skeleton.

Bone damage and bone pain are also serious complications in these patients and in patients with primary bone cancers such as osteosarcoma. Thus, treatments aimed at blocking bone metastasis, reducing bone damage and attenuating bone pain would prove to be beneficial in advanced cancer patients suffering from a cancer-associated bone disease.

The body’s own cannabinoid system plays a key role in the growth and metastasis of cancer cells and synthetic cannabinoids have been known to alleviate pain in mouse models of cancer-induced bone damage.

There are however reports of data from other cancers that conflict with these findings and showed that some cannabinoids exert pro-cancer effects at different doses under certain experimental conditions.  These reports coupled with the adverse psychoactive effects observed in cannabis users and those that have been reported in patients treated with the cannabinoid agent Acomplia® (Rimonabant®) have slowed the progress of the developing cannabis-based pharmaceutical drugs.

A Clear understanding of the role of exogenous and endogenous cannabinoids in cancer and therapeutic exploitation of this knowledge is likely to lead to the development of a cannabinoid-based therapy that could be of value in the treatment of metastatic cancer.

Most cannabinoid-related cancer studies reported in the literature have been carried out using chemicals that often target both CB1 and CB2 as well as multiple other receptors and exert a myriad of off-target pharmacological effects. Our laboratory at the University of Sheffield is currently developing a number of genetically-modified mice in which a combination of key components of the body’s own cannabinoid system was genetically silenced or depleted in the brain and/or peripheral organs. The use of these preclinical models to examine the role of the cannabinoid system in cancer will advance our knowledge about the basic mechanism(s) by which this ancient herb exerts its biological effects.

Such studies are also invaluable because they will enable researchers to establish once and for all if the conflicting medicinal and harmful effects of a number of cannabis preparations reported in scientific journals and media were mediated via their action on the body’s own cannabinoid system. Furthermore, examining the therapeutic effects associated with cannabis preparations – whether natural or synthetic – in such models will pave the path to the development of a safer cannabis-based therapy for the treatment of various human diseases.

This study, Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition was recently published in the journal Aging Cell.