47 © Springer Nature Switzerland AG 2021 S. N. Narouze (ed.), Cannabinoids and Pain, https://doi.org/10.1007/978-3-030-69186-8_7 Cannabinoid Receptor 1 (CB1) Glenn R. Rech and Samer N. Narouze CB1 Receptors The CB1 receptor was discovered after the iso- lation of Δ-9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana [1]. CB1 is encoded by the gene CNR1, located on chromosome 6, and consists of 472 amino acids in humans (Fig. 7.1). CB1 along with CB2 belongs to the superfamily of G protein-coupled receptors (GPCRs). These receptors are charac- terized by a conserved structure consisting of an extracellular N-terminal domain, seven trans- membrane domains, and a C-terminal intracel- lular tail (Fig. 7.2). When CB1 receptors are activated, adenylyl cyclase is inhibited, mitogen- associated protein kinase is activated, and cal- cium and potassium ion channels are regulated by signaling through G i/o proteins [2]. CB1 was frst discovered in the brain. Later, by using autoradiography, in situ hybridization, and immunohistochemistry, CB1 was proven to be the most widely expressed receptor protein from the GPCR family in the brain [3]. Ligand bind- ing sites for CB1 are distributed widely in the brain at various levels depending on the regions and the neuron types within a given region. High levels are observed in the innermost layers of the olfactory bulb, hippocampus, lateral part of the striatum, target nuclei of the striatum (i.e., globus pallidus, entopeduncular nucleus, sub- stantia nigra pars reticulata), and cerebellar molecular layer. The thalamus, other nuclei in the brain stem, and spinal ventral horn are low in ligand binding. Generally low levels of ligand binding in the lower brain stem areas that con- trol cardiovascular and respiratory functions may explain why high doses of cannabinoids are not lethal [4]. The CB1 receptors are also expressed in the peripheral nervous system. In the peripheral ner- vous system, the CB1 receptors are mostly expressed in the sympathetic nerve terminals. Agonists binding to the CB1 receptors are associ- ated with the cardiovascular system: promote pro- infammatory effects [5]. Likewise agonist binding to the CB1 receptors expressed within the gastrointestinal tract may contribute to obesity. CB1 receptors are also found in the liver, muscles, bones, reproductive system, and skin [5]. CB1 Receptor Physiology, Pathology, and Pharmacology Like many GPCRs, the CB1 receptors are pri- marily located in the cell membrane where they are activated by their ligands. However consider- able observations have reported predominant intracellular localization of CB1 receptors in G. R. Rech (*) Western Reserve Hospital, Cuyahoga Falls, OH, USA S. N. Narouze Western Reserve Hospital, Center For Pain Medicine, Cuyahoga Falls, OH, USA e-mail: narouzs@hotmail.com 7