Inhibition of Salivary Secretion by Activation of Cannabinoid Receptors

Abstract

It is known that marijuana use decreases saliva secretion. Therefore, we hypothesized that cannabinoid receptors (CBs) are located in salivary glands to mediate that effect. In these experiments, we used the submandibular gland (SMG) of male rats, which is one of the major salivary glands. Mammalian tissues contain at least two types of CBs, CB1 and CB2, mainly located in the nervous system and peripheral tissues, respectively. Both receptors are coupled to Gi protein and respond by inhibiting the activity of adenylyl cyclase. We demonstrated that both CB1 and CB2 are present in the SMG, each showing specific localizations. The best-known endocannabinoid is anandamide (AEA), which binds with high affinity to CB1 and CB2. We showed that AEA markedly reduced forskolin-induced increase of cAMP content in vitro. This effect was blocked by AM251 and AM630 (CB1 and CB2 antagonists, respectively), indicating that both receptors are implicated in SMG physiology. In addition, we showed that AEA injected intraglandularly to anesthetized rats inhibited norepinephrine (NE)- and methacholine (MC)-stimulated saliva secretion in vivo and that both AM251 or AM630 prevented the inhibitory action of AEA. Also, the intraglandular injection of AM251 increased saliva secretion induced by lower doses of NE or MC. This increase was synergized after coinjection with AM630. Therefore, we concluded that AEA decreases saliva secretion in the SMG acting through CB1 and CB2 receptors.

Immunohistochemical localization of CB1 receptor in canine salivary glands

“…This study confirms the presence of the CB1 receptor in the major salivary glands of dogs and that CB1 localizes to the cells of striated ducts, as previously demonstrated in rats (Prestifilippo et al 2006;Busch et al 2006). The immunohistochemical positive reaction inside the cells was localized on or near to the apical membrane.…”

“…This finding reflects the characteristics of this receptor that it belongs to the superfamily of G-protein-linked membrane receptors. No reactivity was observed in the acinous cells, which correlated to the immunohistochemical results in the rat studies (Prestifilippo et al 2006).…”

“…They are expressed in the central nervous system (Wenger et al 1999;Pagotto et al 2001), as well as in several neuronal and non-neuronal peripheral tissues (Osei-Hyiaman et al 2005;Cavuoto et al 2007). Recently, the presence of the two receptors has been demonstrated in the major salivary glands of rats by means of immunohistochemical techniques (Busch et al 2004;Prestifilippo et al 2006). In particular, the CB1 receptor has been localized exclusively in the ductal system, while the CB2 receptor in the acini.…”

“…In particular, the CB1 receptor has been localized exclusively in the ductal system, while the CB2 receptor in the acini. These results allowed the "cannabinoid system" to be associated with two fundamental steps of salivary production: secretion of primary saliva from glandular acini and its modifications in the ductal system (Prestifilippo et al 2006).…”

Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus

“…[20][21][22][23] We reported previously that CB1 and CB2 receptors are located in the SMG and that anandamide injected into the SMG decreases the methacholine (MC)-and norepinephrine-stimulated salivary secretion by activating both receptors. 24 In contrast to classical neurotransmitters, endocannabinoids can function as retrograde synaptic messengers. They are released from postsynaptic neurons and travel backwards across synapses, activating CB1 receptors on presynaptic axons and suppressing neurotransmitter release.…”