This slide provides a historical comparison of the earliest use and subsequent development of opioids and cannabinoids. There are a number of similarities in the development of these compounds, namely: Evidence of medicinal use of cannabis in China in 3000 BC and reference to an opium-based elixir as far back as 500 BC, Extraction of morphine from the opium poppy plant and synthesis of morphine analogs in the latter half of the 19 th century, popularization of cannabis use in 1800s, Identification of THC as the main agent in the cannabis plant in 1964, Discovery and identification of opioid receptor and endogenous opioid peptides in the mid 1970 ’s, and discovery, identification and cloning of cannabinoid receptors discovery of endogenous cannabinoids in the 1980’s and 1990’s. References: Mack A & Joy J. Marijuana as Medicine? The Science Beyond the Controversy. National Academy Press, Washington DC , 2001. 2. Notcutt W. Cannabis in the Treatment of Chronic Pain. In Guy G, Whittle B and Robson P. The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press. London, 2004.
This slide compares the mechanism of action of opioids and cannabinoids. Cannabinoid and opioid receptors display similar properties, with both belonging to the G-protein coupled receptor family and both coupled to similar intracellular signalling mechanisms. As regards to opioids, when the opioid is bound to its receptor, the associated G-protein becomes activated and this eventually leads to decreased excitability along the cell membranes of neurons in pain pathways. This action occurs through inhibition of adenylate cyclase and cAMP-dependent protein phosphorylation, leading to changes in activity at sodium, calcium and potassium channels, resulting in analgesia. In addition, the inhibition of the cAMP pathway decreases catecholamine synthesis via reduced phosphorylation of tyrosine hydroxylase. Following chronic administration of opioids, long-term adaptations in intracellular messenger proteins occurs and neurons develop tolerance to these actions, leading to receptor desensitization. As a result, the cAMP pathway may become upregulated, levels of G-proteins may increase and activities of adenylate cyclase, cAMP-dependent protein kinase and tyrosine hydroxylase may increase. In the tolerant state, all of this, together with the presence of opioids is likely needed to produce the required analgesia. With respect to cannabinoids, CB1 and CB2 cannabinoid receptors are the primary targets of endocannabinoids. These G protein-coupled receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. Exogenous cannabinoids such as nabilone act directly on presynaptic CB1 receptors. In contrast, endogenous CB1 ligands act in reverse from classical neurotransmitters by serving as retrograde synaptic messengers: Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron Activation of the postsynaptic neuron leads to the biosynthesis and nonvescicular release of an endocannabinoid The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor The CB1 receptor activates a G-protein, which leads to presynaptic events that result in inhibition of neurotransmitter release Exogenous cannabinoids activate CB1 receptors directly to regulate neurotransmitter release References: Adapted from: Cappendijk S. In: Modulators of Drug Dependence Phenomena, 2010. www.drugtext.org Hanks G et al. Opioid Analgesic Therapy. Oxford Textbook of Palliative Medicine, 3 rd edn, pp 316-341, Oxford University Press, Oxford, 2003 Mackie K. Cannabinoid receptors as therapeutic targets. Ann Rev Pharmacol Toxicol. 2006;46:101-122.
Dr. Mark Ware
Introduction to theEndocannabinoid System Dr Mark A. Ware MD MRCP MSc Alan Edwards Pain Management Unit McGill University Montreal, Quebec, Canada
Learning objectives• Review components and role of endocannabinoid system (ECS)• Summarize pharmacological strategies to harness ECS
Cannabinoids and Opioids: A Historical Perspective Cannabinoids 1988: CB1 receptor identified. 9-THC identified 1990: CB1 receptor cloned as main 1992: Anandamide discovered, CB2First Medicinal psychoactive receptor identifiedevidence of cannabis agent in 1993: CB2 receptor cloned W.B. O’Shaughnessey’smedicinal use declines Cannabis sativa 1998: Endogenous cannabinoid work popularizesuse in China cannabis use plant ligands shown to be analgesic 1900’s 1964 1988 19983000 BC 1800’s 500 BC 1522 1804 1817 1874 1900’s 1970 1975Earliest known Paracelsus 1804: Morphine Morphine analogs 1970s: Discovery of opioid receptors –reference for reference to extracted from opium synthesized: µ (mu), к (kappa), δ (delta)opium-based “laudanum”, poppy plant 1874: Diacetylmorphineelixir opium-based (heroin) 1975: Discovery of endogenous opioid elixir, as a potent 1817: Morphine first 1900s: codeine, peptides - endorphins painkiller marketed in Germany dihydromorphine, as analgesic oxycodone, pethidine, oxymorphone Opioids 1. Mack A & Joy J., 2001. 2. Notcutt W., 2004.