Summary of Symposium
The symposium on "Cannabinoids: Chemistry & Biology" was held August 16&17 at Bldg 31, NIH . This conference had 9 scientific sessions and a session on group discussion at the end of the symposium. The first speaker, Dr. Michael Walker, reported on the isolation, identification, tissue distribution and biosynthesis of a novel endogenous arachidonic acid-derived compound, N-arachidonylglycine from bovine brain extract. Additionally, two more amino acids, N-arachidonyl-gamma-aminobutyric acid and N-arachidonylalanine were also identified. N-arachidonylglycine appears to suppress tonic inflammatory pain and is likely to dampen pain. Dr. Mechoulam spoke on the role of endocannabinoids on neuroprotection and he presented evidence on the role of 2-AG as a neuroprotective agent using the CHI model. Dr. Razdan delivered a talk on the synthesis of new probes for the cannabinoid receptors and he presented data on O-1812, O-1860 which are highly selective CB-1 ligands and O-2095, which is 21,000 more selective for the vanilloid receptor over CB-1 receptor. Dr. Makriyannis talked about the four-cannabimimetic membrane-bound proteins, CB-1 and 2 receptors, anandamide amidase and the anandamide transporter as excellent targets for development of novel medications for pain, immunosuppression, peripheral vascular disease, appetite regulation and mental illness.
Drs. Kunos and Martin presented evidence for the existence of a, yet undiscovered cannabinoid receptor, that is different form CB-1 and 2, and speculated that there may be additional receptors and endogenous ligands. Dr. Gifford reported on the evaluation of AM2233, a novel aminoalkylindole CB-2 agonist and it was found to have a greater potency than WIN55212-2 in vitro assays but with a similar potency in the mouse locomotor assay. It was proposed that its behavioral effects might have been mediated, in part, via an action on another receptor type in addition to the CB-1 receptor. Dr. Gatley gave an overview on the radioligands for the PET imaging of the CB-1 cannabinoid receptors and gave an account of results obtained with AM281 and AM22333. AM 2233 represents the first agonist CB1 receptor ligand with potential as an in vivo imaging agent for these receptors.
Dr. Piomelli discussed the mechanisms for the biosynthesis of the endocanabinoids and related enzymology and how these events could be regulated by some of the synthetic ligands. Dr. Schmid pointed that future work should not only emphasize possible mechanisms for the selective formation, transport and inactivation of the known cannabinoids, as compared with their congeners, but also attempt to identify the mechanisms and conditions that cause the upregulation and control of cellular endocannabinoid levels. Dr.Cravatt presented data to demonstrate that FAAH is the primary regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone essential for normal pain transmission. He further indicated that FAAH might represent a pharmaceutical target for the treatment of pain and neuropsychiatric disorders. Most of his studies were conducted on FAAH knock-out mice. Dr. Peter Blumberg of NCI, presented a nice overview of the VR1 receptor, structure-activity relationships of VR1 ligands and how multiple factors contribute to the complex pharmacology of VR1. He also presented data to demonstrate the role of species differences in VR1 activity. Dr. Arpad Szallasi discussed the biological activity of a number of VR1 ligands, especially arvanil, a chimeric ligand that combines the structural features of anandamide and vanilloids, a potent analgesic agent. Based on additional pharmacological studies, he hypothesized additional, as yet unrecognized, endocannabinoid and/or vanilloid sites.
Dr. Freund of the Hungarian Academy of Sciences, presented findings that are consistent with a CB1 cannabinoid receptor-dependent modulation of GABAergic postsynaptic currents, and speculated that a novel cannabinoid-sensitive receptor must be responsible for the inhibition of glutamatergic neurotransmission. Dr. Mackie presented evidence to show that CB1 receptors exist in a dimerized state in both rodent and human brain and that the dimerization state of CB1 receptors appears to have functional consequences. This talk was followed by Dr. Mukhopadhyay's talk on CB1 cannabinoid receptor-G protein interaction and it was suggested that agonists could be developed that can bind to the cannabinoid receptor at the common hydrophobic interaction site but induce conformational changes that would promote selective activation G protein subtypes. Dr. Rachel Wilson presented studies that indicate that endocannabinoids are retrograde messengers, that is, molecules released by neurons to modulate the strength of their presynaptic inputs and that cannabinoid-sensitive synapses are unusual in that they use N- but not P/Q 2+ channels for neurotransmitter release. This talk was followed by one complete session devoted to some of the intramural research at NIDA that is currently being carried out. The speakers were Drs. Hoffer, Gorelick, Gardner and Huestis. Talks were presented on a number of important areas including an update on neurological basis for the addictive potential of cannabinoids and blockade of effects of smoked marijuana by SR141716A.
A separate session was organized on cannabinoids and analgesic effects. Dr. Malan presented a talk on the pain-relieving effects of CB2 ligands and his studies show that CB2 receptor activation produces antinociception to thermal stimuli and that this effect is mediated peripherally at the site of application of the thermal stimulus. Using the CB2 receptor-selective agonist, AM1241, the investigator's group showed that CB2 receptor activation blocks inflammatory hyperalgesia and allodynia and hyperalgesia produced by peripheral nerve injury. These results suggest that the CB2 receptor agonists may have value clinically, since these would be predicted to relieve pain and inflammation without the central nervous system side effects. Dr. Hohman presented a talk on the understanding cannabinoid analgesic mechanisms and one of her investigations centered on the environmental factors that activate the endocannabinoid analgesic mechanisms. Her data provided evidence that manipulation of endocannabinoids and peripheral cannabinoid analgesic mechanisms represent novel targets for therapeutic interventions. Later, Dr. Porreca spoke on mechanisms of cannabinoid antinociceptive tolerance. Dr. Porreca presented evidence to show that, like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain that results in increased expression of spinal dynorphin and that the actions of dynorphin are pronociceptive. Manipulations that block cannabinoid-induced pain also block the behavioral manifestations of cannabinoid antinociceptive tolerance.
Dr. Pollock from DNBR, NIDA presented a talk the utilization of microarray technology to understand the genetics of drug abuse and this talk was followed by a presentation by Dr. Deadwyler on the microarray analysis of gene expression changes during acute and chronic cannabinoid exposure in rats. The results indicated that exposure to delta-9 THC resulted in genetic changes and 49 genes were altered, some permanently and some transiently and time course of the genetic alterations was also discussed.
Dr. Kaminski and Dr. Roth presented talks on the immune effects of cannabinoids. Dr. Kaminski pointed about the three important avenues of research concerning the immune system: 1) elucidating the role of cannabinoid receptors in immune modulation by cannabinoids 2) characterizing the physiologic role of cannabinoid receptors in immune competence via endogenous ligands and 3) identifying the signal transduction pathways that are regulated by cannabinoids, dependently and independently of cannabinoid receptors. A major focus of the talk was the signal transduction pathway critical for the T cell function modulated by cannabinoids. This talk followed by Dr. Roth's talk on immune function in marijuana smokers and it was suggested that suppression of cell-mediated immunity by delta-9 THC may place marijuana smokers at risk for infection or cancer.
In the session on the effects of cannabinoids on the reproductive system, Dr. Dey gave an update on the recent work on the effects of cannabinoids on embryo implantation. The results suggested that tight regulation of endocannabinoids is important in synchronizing embryo development with uterine receptivity for implantation. Dr.Schuel discussed the effects of AEA and cannabinoids on the reproductive system, as they may be involved in the regulation of early embryonic development and implantation, sperm capacitation, fertilization and early embryonic development.
The final session was a discussion session to identify the gaps and critical areas of future research and a number of speakers and the audience participated. It was agreed that the cannabinoid research is a critical area of research and research in this area should be expanded.