Work

The Cannabinoid CB1 Receptor Inverse Agonist/Antagonist SR141716A Activates the Adenylate Cyclase/PKA Signaling Pathway Among Other Intracellular Emetic Signals to Evoke Vomiting in Least Shrews (Cryptotis parva)

Year: 2025

Type: article

Abstract: Intracellular emetic signals involved in the cannabinoid CB1 receptor inverse agonist/antagonist SR141716A were investigated. SR141716A (20 mg/kg, i.p.)-evoked vomiting occurred via both the central and peripheral mechanisms. This was accompanied by robust emesis-associated increases in the following: (i) c-fos- and phospho-glycogen synthase kinase-3α/β (p-GSK-3αβ)-expression in the shrew’s dorsal vagal complex (DVC), (ii) phospho-extracellular signal-regulated kinase1/2 (p-ERK1/2) expression in both the DVC and jejunal enteric nervous system, and (iii) time-dependent upregulation of cAMP levels and phosphorylation of protein kinase A (PKA), protein kinase B (Akt), GSK-3α/β, ERK1/2, and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK1/2, GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca2+/calmodulin-dependent protein kinase II (CaMKII), L-type Ca2+ channel (LTCC), store-operated Ca2+ entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT3-, and D2/3-receptor antagonists, and the transient receptor potential vanilloid 1 receptor (TRPV1R) agonist. SR141716A appears to evoke vomiting via inverse agonist activity involving emesis-associated kinases, including cAMP/PKA, ERK1/2, PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca2+ mobilization linking extracellular Ca2+ entry via plasma membrane Ca2+ channels (LTCC, SOCE, TRIPV1R) and intracellular Ca2+ release via IP3Rs and RyRs. The 5-HT3, NK1, and D2/3 receptors also contribute to SR141716A-mediated vomiting.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms26209884

Authors: Yina Sun, Louiza Belkacemi, Weixia Zhong, Zollie Daily, Nissar A. Darmani

Institution: Western University of Health Sciences

Language: English

Topic: Nausea and vomiting management

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499