The psychoactive actions of the cannabinoids, and the distribution of the cannabinoid receptor in the central nervous system, suggest that cannabinoids mimic endogenous compounds(s) that modulate neural signals for mood, memory, movement and pain. Indeed, the recent identification and purification of an endogenous ligand, anandamide, for the cannabinoid receptor confirms this hypothesis. In addition, cannabinoids hold tantalizing promise as therapeutic agents for a range of illnesses. Anandamide (arachidonyl ethanolamide) may well be the first of a series of related compounds that serve as neuromodulators. Our understanding of how these compounds influence neuronal excitability is at an early stage, making further investigation important. This study will use patch clamp recording to identify ion channels modulated by cannabinoids and then will examine in detail the signal transduction pathway between them and the cannabinoid receptor. Emphasis will be placed both on direct guanine-nucleotide protein (G protein) modulation of ion channels as well as indirect actions as might follow from decreases in cAMP levels. In order to understand their role in normal cell physiology, the potency of cannabinoid agonists for different modulatory events will be determined. Site-directed mutagenesis will be used to define the regions of the cannabinoid receptor that mediate the interactions between the receptor and their associated G proteins(s). The results of these studies will increase our understanding of the signal transduction pathways of a novel and widespread neuromodulatory system. An understanding of these pathways is especially important in the therapeutic application of the cannabinoids, as it has been very difficult to separate the desired actions of cannabinoids (for example, analgesia) from their undesired side-effects (for example, dysphoria). Thus, knowledge of these pathways will allow a more rational assessment of the therapeutic potential of the cannabinoids, suggest new therapeutic targets for this class of drug and will offer insights into cellular consequences of their non-medicinal or recreational use.
