1. ¹Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA
2. ²Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

Correspondence: Dr RA Ross, School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: r.ross@abdn.ac.uk

Received 30 October 2007; Revised 8 November 2007; Accepted 8 November 2007.

Abstract

Over the years CB₂ cannabinoid receptors have received much less attention than CB₁ receptors, the latter mediating most of the psychoactive effects of cannabis. Primarily this was due to difficulties in assigning a physiological function to CB₂ receptors. In recent years this situation has changed, and CB₂ receptors have been implicated in processes as diverse as analgesia, hepatic fibrosis, bone growth, and atherosclerosis. This special issue of the British Journal of Pharmacology addresses these and other topics in CB₂ receptor research by compiling a series of reviews and primary research papers stemming from a meeting 'CB2₂ cannabinoid receptors: New vistas' that was held in Banff, Canada, from May 31 to June 3, 2007.

The meeting 'CB₂ cannabinoid receptors: new vistas' was held in Banff, Canada, from 31 May to 3 June 2007 and was organized by a team led by Keith Sharkey of the University of Calgary. The motivation for this meeting was the growing appreciation that cannabinoid 2 (CB₂) receptors appear to be involved in many biological processes, several of which may be potential therapeutic targets. However, the very diversity of systems involving CB₂ receptors has limited the interactions between scientists studying CB₂ receptor-mediated responses. This meeting was designed to bring together scientists studying CB₂ receptors from diverse perspectives, including those interested in the chemistry of CB₂ ligands, the role of CB₂ receptors in normal biological processes and the involvement of CB₂ receptors in pathological processes.

To meet this goal, the meeting was comprised of six sessions: 'Structural and molecular determinants of CB₂ receptors and CB₂ receptor signaling', 'CB₂ receptors in osteoporosis', 'CB₂ receptors and immune modulation', 'CB₂ receptors and the modulation of pain', 'Talks from submitted abstracts' and 'The role of CB₂ receptors in reproductive, cardiovascular, liver, and gastrointestinal systems'. In addition, there were more than two dozen poster presentations. This themed issue of the British Journal of Pharmacology is comprised of contributed reviews from many of the speakers at the meeting as well as several original research papers involving aspects of CB₂ receptor biology.

The CB₂ receptor was the second cannabinoid receptor cloned, the first being CB₁. As their names might suggest, CB₁ and CB₂ are closely related. As such there is considerable overlap in the specificity of CB₁ and CB₂ ligands, an issue accentuated by the lipophilicity of most of these ligands. A theme that emerged from several of the talks was that great care must be taken in assigning a biological response to being CB₂ receptor-mediated. Many of the ligands that are thought to be 'CB₂ receptor-specific' have varying degrees of activity at other receptors, and this must be considered in interpreting experimental responses. Some of the highlights that emerged from the meeting were as follows:

1. The need for more specific CB₂ receptor agonists and, to a lesser degree, antagonists.
2. To unequivocally establish the role of the CB₂ receptor in a process, it is prudent to use both pharmacological and mouse genetic tools.
3. Agonist trafficking at the CB₂ receptor must be considered when interpreting the results from different agonists (for example, AM1241 ((2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]-methanone), 2AG (2-arachidonoyl glycerol) and JWH133, (6aR, 10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran.
4. There are significant differences in ligand efficacy between rodent and human CB₂ receptors. This has important implications for drug development.

In this special issue, various potential therapeutic targets of CB₂ receptors are explored and reviewed by experts in this field. Emerging targets for ligands directed to the CB₂ receptor include pain (Hohmann and Guindon, 2008; McDougall et al., 2008; Rimmerman et al., 2008), (neuro)inflammation (Romero et al., 2008), hepatic fibrosis (Loterszajn et al., 2008), gastrointestinal motility and inflammation (Sharkey et al., 2008), atherosclerosis (Mach and Montecucco, 2008), immune function (Cabral et al., 2008; Dittel, 2008; Stella and Miller, 2008) demyelinating disease (Arevalo-Martin et al., 2008), ischaemia (Pacher and Hasko, 2008; Pacher et al., 2008), bone disease (Bab and Zimmer, 2008) and disorders of reproduction (Maccarrone, 2008). Although the toolbox of ligands directed towards the CB₂ receptor is rapidly expanding, the pharmacology of these ligands is complex (Fox et al., 2008; Huffman and Poso, 2008; Lunn et al., 2008; Meyer and Yao, 2008; Pertwee, 2008).

This special issue highlights the diverse physiological role of the CB₂ receptor and its involvement in the pathophysiology of a variety of disease states. Clearly, more research is required to illuminate further the nature of CB₂ receptor agonist and antagonist action in these various conditions. The development of conditional CB₂ receptor knockout mice (Buckley, 2008) and of ligands with greater selectivity will serve to further clarify the role of the CB₂ receptor in the many physiological and pathophysiological processes in which it appears to be implicated.