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THC Regulates Tearing via Cannabinoid CB1 Receptors

Authors
  • Thayer, Amanda1, 2
  • Murataeva, Natalia1, 2
  • Delcroix, Vanessa3
  • Wager-Miller, Jim1, 2
  • Makarenkova, Helen P.3
  • Straiker, Alex1, 2, 4
  • 1 The Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, United States
  • 2 Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States
  • 3 Scripps Research Institute, Department of Molecular Medicine, La Jolla, California, United States
  • 4 Program in Neuroscience, Indiana University, Bloomington, Indiana, United States
Type
Published Article
Journal
Investigative Opthalmology & Visual Science
Publisher
Association for Research in Vision and Ophthalmology (ARVO)
Publication Date
Aug 27, 2020
Volume
61
Issue
10
Identifiers
DOI: 10.1167/iovs.61.10.48
PMID: 32852544
PMCID: PMC7452851
Source
PubMed Central
Keywords
License
Unknown

Abstract

Purpose Aqueous deficiency dry eye (ADDE) is a chronic condition affecting millions, with symptoms ranging from a dry itchiness to blurred vision and accompanied by an increased risk of eye infections. ADDE typically arises from disorders of the lacrimal gland that produces tears necessary for eye lubrication. Cannabis users frequently report dry eye, but the basis for this is unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of tearing. Methods We examined expression of cannabinoid CB1 receptors in the lacrimal gland using immunohistochemistry, Western blotting, and PCR and tested tetrahydrocannabinol (THC) regulation of tearing in wild-type and CB1-null mice. Results We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the lacrimal gland. Little if any staining is seen in lacrimal gland epithelial cells (acinar and ductal) or myoepithelial cells (MECs). Activation of CB1 receptors by THC or the cannabinoid agonist CP55940 reduces tearing in male mice. In female mice, THC has no effect, but CP55940 increases tearing. In both sexes, the effect of CP55940 is absent in CB1 knockout mice. CB1 mRNA and protein levels are approximately four- to fivefold higher in males than females. In male knockouts, THC increases tearing, suggesting that THC also acts through different receptors. Conclusions Our results suggest a novel, albeit sex-dependent, physiologic basis for the dry eye symptoms experienced by cannabis users: activation of neuronal CB1 receptors in the lacrimal gland reduces tearing.

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