Don't Sweat It: Cannabinoid <scp>CB1</scp> Receptors Reduce Sweating in a Mouse Model

ABSTRACT Numerous exocrine glands play key physiological roles in the body that include tearing, salivation, and lactation, as well as the control of body temperature via sweating. Malfunction of sweat glands can be deeply problematic or—in the case of anhidrosis—life‐threatening. The prevalence of sweating disorders is high, affecting millions. The few available therapies are generally of limited effectiveness. Several lines of evidence point to regulation of sweating by the cannabinoid signaling system, an arrangement that would mirror cannabinoid regulation of tearing and salivation. Mice sweat in their paws via glands that closely resemble human eccrine sweat glands, including regulation by muscarinic signaling and by temperature. We applied a galvanic skin response‐based assay to investigate cannabinoid regulation of sweating in awake, unanesthetized mice. The muscarinic agonist pilocarpine increased conductance while the antagonist glycopyrrolate reduced conductance, validating the model as a measure of sweating. The cannabinoid receptor agonist CP55940 substantially reduced conductance in wild‐type and CB2 but not CB1 receptor knockout mice. The phytocannabinoid tetrahydrocannabinol (THC) also reduced conductance, while the non‐psychoactive cannabidiol (CBD) did not. Using immunohistochemistry, we detected CB1 receptors in periglandular cholinergic axons, the anandamide‐synthesizing enzyme NAPE‐PLD in myoepithelial cells, and the anandamide metabolizing enzyme FAAH in acinar cells. This indicates that a local CB1/anandamide‐based circuit is present in mouse walking pads. In summary, we employed a novel galvanic skin response‐based assay to determine that cannabinoid CB1 receptors reduce sweating in a mouse model. This may point to a previously unappreciated effect on sweating in cannabis users.