Gq and Gβγ
protein-dependent
phospholipase C (PLC) activation is extensively involved in
G protein-coupled receptor (GPCR)-mediated signaling pathways which are implicated in a wide range of physiological and pathological events. Stimulation of several GPCRs, such as
substance P neurokinin 1-,
dopamine D2/3-,
histamine H1- and
mu-opioid receptors, can lead to
vomiting. The aim of this study was to investigate the role of PLC in
vomiting through assessment of the
emetic potential of a PLC activator (m-3M3FBS), and the
antiemetic efficacy of a PLC inhibitor (
U73122), in the least shrew model of
vomiting. We find that a 50 mg/kg (i.p.) dose of
m-3M3FBS induces
vomiting in ∼90% of tested least shrews, which was accompanied by significant increases in c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem dorsal vagal complex, indicating activation of brainstem
emetic nuclei in m-3M3FBS-evoked
emesis. The m-3M3FBS-evoked
vomiting was reduced by pretreatment with diverse
antiemetics including the antagonists/inhibitors of: PLC (
U73122), L-type Ca2+ channel (
nifedipine), IP3R (2-APB), RyR receptor (
dantrolene), ERK1/2 (
U0126), PKC (
GF109203X), the serotoninergic type 3 receptor (
palonosetron), and
neurokinin 1 receptor (
netupitant). In addition, the PLC inhibitor
U73122 displayed broad-spectrum
antiemetic effects against diverse emetogens, including the selective agonists of
serotonin type 3 (2-Methyl-5-HT)-,
neurokinin 1 receptor (
GR73632),
dopamine D2/3 (
quinpirole)-, and
muscarinic M1 (McN-A-343) receptors, the L-type Ca2+ channel (
FPL64176), and the
sarco/endoplasmic reticulum Ca2+-ATPase inhibitor
thapsigargin. In sum, PLC activation contributes to
emesis, whereas PLC inhibition suppresses
vomiting evoked by diverse emetogens.