Should peripheral CB₁ cannabinoid receptors be selectively targeted for therapeutic gain?

Endocannabinoids, endogenous lipid ligands of cannabinoid receptors, mediate a variety of effects similar to those of marijuana. Cannabinoid CB₁ receptors are highly abundant in the brain and mediate psychotropic effects, which limits their value as a potential therapeutic target. There is growing evidence for CB₁ receptors in peripheral tissues that modulate a variety of functions, including pain sensitivity and obesity-related hormonal and metabolic abnormalities. In this review we propose that selective targeting of peripheral CB₁ receptors has potential therapeutic value because it would help to minimize addictive, psychoactive effects in the case of CB₁ agonists used as analgesics, or depression and anxiety in the case of CB₁ antagonists used in the management of cardiometabolic risk factors associated with the metabolic syndrome.

Introduction

The age-old use of cannabis has acquainted humankind with the potent effects of this plant on mood and sensory perception. However, as reflected in its empirical use for medicinal purposes over the centuries, cannabis can cause many other effects, such as alleviating pain and nausea, increasing appetite or suppressing disturbed gastrointestinal motility and secretions, all of which have become a source of growing interest due to their potential therapeutic exploitation. The discovery of specific cell membrane receptors for Δ⁹-tetrahydrocannabinol (THC), the psychoactive ingredient of cannabis, was followed by the isolation and identification of endogenous ligands, called endocannabinoids (reviewed in Ref. [1]). Endocannabinoids are lipid mediators generated in the cell membrane from phospholipid precursors via multiple, parallel biosynthetic pathways (Figure 1) [2]. The two main endocannabinoids are arachidonoyl ethanolamine or anandamide, selectively degraded by fatty acid amide hydrolase (FAAH), and 2-arachidonoylglycerol (2-AG), selectively degraded by monoglyceride lipase (MGL) (Figure 1). They interact with the same receptors that recognize the psychoactive ingredient of marijuana (cannabis) and can produce similar biological effects. To date, two G-protein-coupled cannabinoid receptors have been identified: CB₁, expressed at very high levels in the brain but also present at lower yet functionally relevant levels in many peripheral tissues, and CB₂, expressed predominantly although not exclusively in cells of the immune and hematopoietic systems [1]. Selective pharmacological inhibitors of cannabinoid receptors and mouse strains deficient in these receptors have been key tools in uncovering a growing list of biological functions that are under tonic control by endocannabinoids. Not surprisingly, this has focused attention on the endocannabinoid system as a potential target for pharmacotherapy [1]. To date, the primary focus has been on the CB₁ receptor as a druggable target, because of its well-documented role in the control of pain, nausea, mood and anxiety, appetite, and drug and alcohol reward. All of these effects involve activation of CB₁ receptors in the central nervous system, and therein lies the dilemma. The medicinal use of cannabis has provided ample evidence for its efficacy in relieving not only pain and nausea but also anxiety. However, the psychoactive properties of cannabis and its potent synthetic analogs preclude their general use as therapeutics. Although CB₁ receptors responsible for the addictive nature of cannabis and those implicated in analgesia, antinausea or anxiolytic effects might be located at distinct sites in the brain [3], they are pharmacologically indistinguishable. The same conundrum is faced when CB₁ receptor blockade is considered for therapeutic purposes. The role of CB₁ receptors in the central neural control of appetite [4] and evidence for the tonic activity of the endocannabinoid/CB₁ receptor system in obesity 5, 6 provide a rationale for the use of CB₁ antagonists as antiobesity agents. However, an increased incidence of anxiety and depression in obese patients treated with the first such CB₁ antagonist, rimonabant [7], limits the usefulness of such compounds, because these side effects most likely represent a ‘class’ effect due to blockade of CB₁ receptors in the CNS. A potential resolution of this dilemma might be suggested by recently emerging evidence for the existence and functional relevance of a peripheral endocannabinoid/CB₁ receptor system 5, 6, 8, 9, 10, 11. We briefly review such evidence and its potential therapeutic significance, with a focus on inflammatory pain and the metabolic syndrome as examples of conditions that could benefit from the availability of peripherally restricted CB₁ agonists or antagonists, respectively.