A Sex-Dependent Cannabinoid CB1 Receptor Role in Circadian Tearing of the Mouse.

Purpose: We have shown that cannabinoid CB1 receptors regulate both salivation and tearing, but for tearing, this regulation is sex dependent with opposing effects by sex. We investigated a potential interplay of circadian and cannabinoid regulation of tearing.

Methods: We measured cannabinoid and circadian regulation of tearing in CD1 strain mice as well as CB1 receptor protein expression using immunohistochemistry.

Results: We now report that CD1 strain mice have a circadian variation in basal tearing, differing by sex in terms of phase and amplitude. The amplitude of circadian variation in females is substantially dampened relative to males. Male CB1 receptor knockout mice do not differ from strain controls, but in female CB1 knockouts, the amplitude is enhanced and resembles that of WT males. This increased tearing is mimicked by the CB1 antagonist SR141716 (4 mg/kg, intraperitoneally [IP]), suggesting that tonic CB1 activation dampens female circadian tearing. Consistent with this, the cannabinoid receptor agonist CP55940 (0.5 mg/kg, IP) decreases tearing during the rest phase but increases tearing during the active phase in females. CB1 protein expression also differs by sex. While both males and females have CB1 receptors in parasympathetic inputs to the lacrimal gland, in female lacrimal glands, CB1 is also detected in myoepithethial cells.

Conclusions: Mice have a sex-dependent circadian cycle of tearing. The endogenous cannabinoid signaling system appears to mediate some circadian effects, albeit in a sex-dependent manner and via distinct cellular targets.