Abstract: Salivation is easily taken for granted, but without normal salivation, simple essential tasks such as chewing and swallowing become difficult, with consequences for quality of life, nutrition and oral health. Many important drug classes cause dry mouth as a side effect, contributing substantially to patient non-compliance. Available treatments are mostly palliative. Cannabis user complaints of dry mouth prompted a study that showed that basal salivation is likely regulated by cannabinoid CB1 receptors on neurons that innervate the submandibular gland. But what about stimulated salivation? The adjoining parotid gland releases saliva in response to olfactory or other cues and contributes a large portion of the net salivation in humans. We investigated cannabinoid regulation of stimulated salivation using functional and protein-expression studies in mice. In developing a model of stimulated salivary responses to food-related odorants in mice, we noted sex-dependent responses to food-related cues. Only male mice learned to salivate in response to the odor of peanut butter while only female mice responded to a chocolate hazelnut spread. Both males and females responded to sugar or marmite. Testing peanut butter, we found that the cannabinoid receptor agonist CP55940 (0.5 mg/kg, IP) lowered baseline salivation, as shown previously, but also prevented the odorant-induced increase in salivation. CB1 receptors are expressed in axons innervating the parotid gland, paralleling our findings in the submandibular gland. Notably, we also found that CB1 deletion impaired some responses (those to peanut butter and chocolate hazelnut spread) but not others (sugar or marmite). In mice, the CB1 antagonist SR141716 (4 mg/kg, IP) prevented a previously learned salivary response to peanut butter. We find that CB1 receptors are expressed in a subset of glomeruli in coronal sections of olfactory bulb that may serve as a site of action for scent-specific effects of CB1 receptors. We additionally observe CB1 expression in accessory olfactory bulb. In summary, we find a novel sex-dependence in responses to a subset of food-related odorant cues and that cannabinoid receptors regulate some of these responses. We propose that CB1 receptors act at the parotid gland to inhibit stimulated salivation but also in the olfactory system, where functional CB1 receptors are required for salivary responses to specific appetitive odors.
(© 2024. The Author(s).)
References: Andreis, K. et al. Cannabinoid CB1 receptors regulate salivation. Sci. Rep. 12, 14182 (2022). (PMID: 10.1038/s41598-022-17987-2359860669391487)
Proctor, G. B. & Carpenter, G. H. Salivary secretion: Mechanism and neural regulation. Monogr. Oral Sci. 24, 14–29 (2014). (PMID: 10.1159/00035878124862591)
Chauncey, H. H. & Shannon, I. L. Parotid gland secretion rate as method for measuring response to gustatory stimuli in humans. Proc. Soc. Exp. Biol. Med. 103, 459–463 (1960). (PMID: 10.3181/00379727-103-2555713809490)
Olofsson, J. K., Ekstrom, I., Larsson, M. & Nordin, S. Olfaction and aging: A review of the current state of research and future directions. Iperception. 12, 20416695211020331 (2021). (PMID: 342493278239976)
Nagle, B., Tomassone, B. M., Digregorio, J. & Piraino, A. The influence of delta9-tetrahydrocannabinol on pilocarpine-induced parotid secretions of the rat. Eur. J. Pharmacol. 40, 337–343 (1976). (PMID: 10.1016/0014-2999(76)90071-6991940)
Busch, L., Sterin-Borda, L. & Borda, E. Expression and biological effects of CB1 cannabinoid receptor in rat parotid gland. Biochem. Pharmacol. 68, 1767–1774 (2004). (PMID: 10.1016/j.bcp.2004.06.02915450942)
Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 283, 401–404 (1999). (PMID: 10.1126/science.283.5400.4019888857)
Hu, S. S. et al. Architecture of cannabinoid signaling in mouse retina. J. Comp. Neurol. 518, 3848–3866 (2010). (PMID: 10.1002/cne.22429206530382982216)
Sain, N. M., Liang, A., Kane, S. A. & Urban, M. O. Antinociceptive effects of the non-selective cannabinoid receptor agonist CP 55,940 are absent in CB1(-/-) and not CB2(-/-) mice in models of acute and persistent pain. Neuropharmacology. 57, 235–241 (2009). (PMID: 10.1016/j.neuropharm.2009.06.00419538975)
Thayer, A. et al. THC regulates tearing via Cannabinoid CB1 receptors. Invest. Ophthalmol. Vis. Sci. 61, 48 (2020). (PMID: 10.1167/iovs.61.10.48328525447452851)
Heinbockel, T. & Straiker, A. Cannabinoids regulate sensory processing in early olfactory and visual neural circuits. Front. Neural Circuits. 15, 662349 (2021). (PMID: 10.3389/fncir.2021.662349343055368294086)
Wang, Z. J. et al. Cannabinoid receptor-mediated modulation of inhibitory inputs to mitral cells in the main olfactory bulb. J. Neurophysiol. 122, 749–759 (2019). (PMID: 10.1152/jn.00100.2018312153026734407)
Mori, K., Takahashi, Y. K., Igarashi, K. M. & Yamaguchi, M. Maps of odorant molecular features in the mammalian olfactory bulb. Physiol. Rev. 86, 409–433 (2006). (PMID: 10.1152/physrev.00021.200516601265)
Gabellec M, Panzanelli P, Sassoe-Pognetto M, Lledo, P-M. Synapse-specific localization of vesicular glutamate transporters in the rat olfactory bulb. Eur J Neurosci. 25(5):1373–83 (2007). (PMID: 10.1111/j.1460-9568.2007.05400.x17425564)
Cota, D. et al. Endogenous cannabinoid system as a modulator of food intake. Int. J. Obes. Relat. Metab. Disord. 27, 289–301 (2003). (PMID: 10.1038/sj.ijo.080225012629555)
Standring, S. E. A. Gray’s Anatomy - The Anatomical Basis of Clinical Practice. Vol. 41 (Elsevier, 2016).
Soria-Gomez, E. et al. The endocannabinoid system controls food intake via olfactory processes. Nat. Neurosci. 17, 407–415 (2014). (PMID: 10.1038/nn.364724509429)
Terral, G. et al. CB1 CB1 receptors in the anterior piriform cortex control odor preference memory. Curr. Biol. 29, 2455–2464e2455 (2019). (PMID: 10.1016/j.cub.2019.06.04131327715)
Takahashi, Y. K., Kurosaki, M., Hirono, S. & Mori, K. Topographic representation of odorant molecular features in the rat olfactory bulb. J. Neurophysiol. 92, 2413–2427 (2004). (PMID: 10.1152/jn.00236.200415152015)
Halpern, M. The organization and function of the vomeronasal system. Annu. Rev. Neurosci. 10, 325–362 (1987). (PMID: 10.1146/annurev.ne.10.030187.0015453032065)
Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. U S A. 87, 1932–1936 (1990). (PMID: 10.1073/pnas.87.5.1932230895453598)
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