Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

Abstract

Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.

Keywords: auditory; cannabinoids; hearing; neuroimmune; tinnitus.

Figure 1

EC and their effects. (A): Principal EC targets in neural and immune systems, and in the cochlea. (a) In most brain areas, 2-AG (purple) is synthetized by DAGL-α in neuronal dendrites and somata and catabolized by MAGL in presynaptic terminals, where CB1R (red) are also present. 2-AG is produced postsynaptically in a Ca²⁺-dependent way upon activation of metabotropic receptors (blue) and inactivated presynaptically near its target (1). For AEA (yellow), on the other hand, the biosynthetic enzyme NAPE-PLD is both pre- and postsynaptic, and the catabolic enzyme FAAH-1 is predominantly postsynaptic (1). Astrocytes are also involved in synaptic effects through an EC modulation of gliotransmission, and in addition EC effects on astrocyte mitochondria contribute to neuronal metabolism regulation. (b) In the cochlea, CB2R (green) are found in the organ of Corti (OC), basal cells of the stria vascularis (SV) and spiral ganglion (SG), whereas TRPV1 channels (blue) are found in the organ of Corti and marginal cells of the stria vascularis. (c) During neuroinflammation, several changes are seen in the EC system. The overall EC production increases. Activated microglia increases AEA production (yellow trapezoid) and CB2R expression (green). Astrocytes become activated and BBB is affected (both effects are counteracted by EC responses). (d) Cell activation may change CB2R expression as in macrophages (purple) (2) or CB2R subcellular localization as in B lymphocytes (blue) (3). (e) Anti-inflammatory EC responses in immune cells include the block of Th1 responses due to direct effects on T cells (green) and indirect effects on dendritic cells (yellow), apoptosis induction on several cell types, and the inhibition of proinflammatory cytokines and factors. (B): Principal EC receptors and their main intracellular pathways. Both 2-AG (purple trapezoid) and AEA (yellow trapezoid) act on CB1R and CB2R, which are class A GPCRs (4) coupled to Gi/o G-proteins (5, 6), reducing cAMP concentration (7). β-Arrestin binding (light red arrowheads) induces CBR internalization and switches receptor coupling, especially for CB1, also activating MAP kinase pathways (–10) linked to nuclear effects (large light blue arrow). MAPK pathways are also activated through Gi βγ action (dotted line), both by CB1R and by CB2R (11). Functional CBRs have been also found in intracellular compartments such as the outer mitochondrial membrane (12), where they modulate cell energetic balance (13), and ROS production (14) or endoplasmic reticulum, where they may induce Gq-related Ca2+ release from intracellular stores (3). Moreover, ECs or related lipids activate nuclear PPARs (15). TRPV1 channels are often colocalized with CB1R and/or CB2R and activated by cytoplasmic ECs (16), increasing cytosolic Ca2+. Finally, orphan receptors may activate other pathways, e.g., GPR55 is linked to Gq-PLC and therefore contributes to cytosolic Ca2+ increase. Most cells only express a subset of these pathways. (C): Metabolism of 2-AG and anandamide (AEA). 2-AG (purple) is produced from DAG by DAG lipases (DAGLα and β). Biosynthesis of AEA (yellow) is more complex and may involve hydrolysis of NAPE membrane phospholipids by NAPE-PLD (which directly generates AEA) or sequential action of several enzymes (not shown), followed by a lyso-PLD (17). Although lipophilic, ECs have membrane transport mechanisms (EMT, light gray) (18). EC binding sites on CB1 (red) and CB2 (green) are extracellular, whereas on TRP channels (blue) the site is intracellular. Degradation of AEA is mainly due to FAAH, whereas 2-AG is primarily degraded by MAGL, and less by ABHD6 and ABHD12 (19). Created with Biorender.

Figure 2

Tinnitus-related EC targets are present in the cochlea and central auditory system but also in CNS circuits altered in tinnitus; moreover, ECs may target phenomena which are known to be associated with tinnitus risk (e.g., anxiety) even though precise cellular mechanisms are uncertain. In panel “Tinnitus network,” numbers indicate as follows: 1: parahippocampal cortex; 2: ventromedial prefrontal cortex; 3: cingulate cortex; 4: amygdala; 5: dorsolateral prefrontal cortex; 6: insula (from 273). In panel “Auditory CNS” numbers indicate as follow: 1: cochlear nuclei; 2: auditory pons and midbrain; 3: medial geniculate body; 4: auditory cortex. In panel “Cochlea,” numbers indicate as follows: 1: spiral ganglion; 2: organ of Corti; 3: stria vascularis; 4: cochlear macrophages. Created with Biorender.