Receptor and nonreceptor membrane-mediated effects of THC and cannabinoids

A strict chemical nomenclature is first proposed. It is based on the defini tions of cannabinoids, psychoactive (THC) and nonpsychoactive (CBD, CBN, an d THC-11 oic acid), and of identified receptors (AEA and G protein) and the ir physiological ligands (arachidonyl ethanolamine [AEA] and arachidonyl di glycerol [2-AG]). THC is the only natural cannabinoid that interacts with a receptor protein in a stereospecific fashion, a property which is associat ed with its psychoactivity. Other natural, nonpsychoactive cannabinoids, CB N and CBD, vary over a wide range of concentration in marihuana preparation s and antagonize the effects of THC. They also possess biological propertie s, activating membrane enzymes (phosphorylase and acyltransferase) that inc rease arachidonic acid biosynthesis. When THC binds a specific G-protein receptor, a structural change is induce d that modifies an effector mechanism (e.g., decreased adenylate cyclase ac tivity). THC does not interact directly with neurotransmitters or neuromodu lators, but alters their response in a dose-related fashion (e.g., enhancin g the response of a catechol receptor and decreasing the response of an ace tylcholine receptor or modulating the response of opioid [mu and. delta] re ceptors). Also, THC permeates the lipid bilayer and influences the integral membrane proteins through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from AEA-G protein binding. It is proposed that AEA receptor interaction possesses a physiological func tion, which is to regulate the signaling between boundary lipids and the re ceptors or enzymes of the membrane in response to physiological stimuli. Th e boundary lipids surrounding the membrane proteins are the vehicles for th e signals between the AEA receptor and the neurotransmitter receptors and t heir binding sites. The change of configuration of the AEA receptor modulat es the signaling effect of the membrane on its enzymes and. receptors. AEA, a by-product of the membrane phospholipid, is an indirect signal modulator of membrane activity. THC can deregulate the physiological signaling role of the G protein and its boundary lipid bilayer, a fundamental feature of a ll living cells. This deregulation of membrane signaling by THC results in partial and discordant effects.