The Cannabinoid CB(1) 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).

Intracellular emetic signals involved in the cannabinoid CB(1) 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-ERK(1/2)) 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, ERK(1/2), and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK(1/2), GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), L-type Ca(2+) channel (LTCC), store-operated Ca(2+) entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT(3)-, and D(2/3)-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, ERK(1/2), PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca(2+) mobilization linking extracellular Ca(2+) entry via plasma membrane Ca(2+) channels (LTCC, SOCE, TRIPV1R) and intracellular Ca(2+) release via IP3Rs and RyRs. The 5-HT(3), NK(1), and D(2/3) receptors also contribute to SR141716A-mediated vomiting.