Antiemetic effect of baclofen against exendin-4-induced emesis in Suncus murinus

Abstract

<b>Objective</b>: Our previous study using S. <i>murinus</i> demonstrated that the emetic and anorectic effects of the GLP-1 receptor agonist, exendin-4, may involve the paraventricular hypothalamic nucleus (PVH). γ-aminobutyric acid (GABA) is the most abundant inhibitory amino acid neurotransmitter in the central nervous system and is hypothesized to be involved in emesis control. The present studies investigated whether exendin-4-induced emetic and anorectic effects involve GABA receptors by using the selective GABA_B agonist, baclofen.

<b>Methods</b>: Animals were anaesthetized with 3% isoflurane and then stereotaxically implanted with a guide cannula into the PVH and allowed 7-days to recover before further experimentation. After overnight fasting, animals were pretreated with saline (2 mL/kg, s.c.) or baclofen (1, 3 and 10 mg/kg, s.c.) for 30 min followed by intracerebral paraventricular hypothalamic (iPVH) injection of exendin-4 (300 pmol, 2 μL). Behaviour, food and water intake, were then measured for 6 h. The locomotor activity was also recorded using EthoVision software during the experiments.

<b>Results</b>: Pretreatment with baclofen (1, 3 and 10 mg/kg, s.c.) did not induce emesis, but baclofen at 10 mg/kg, s.c. non-significantly produced a trend to reduce distance travelled and velocity by 87.7% and 68.3%, respectively. Exendin-4 (300 pmol, iPVH) significantly induced 23.1 ± 5.9 episodes of emesis with 165.3 ± 58.8 retches and 20.7 ± 5.7 vomits, with a median latency of 41.8 min. Baclofen at 10 mg/kg, s.c., significantly reduced exendin-4-induced emesis by 66.7% (n = 7, p < 0.05); the doses of 1 or 3 mg/kg, s.c., were ineffective. Conversely, baclofen had no effect on the exendin-4-induced inhibition of food and water intake, or locomotor activity.

<b>Conclusions</b>: Our data suggests that the exendin-4-induced emesis, but not the associated inhibition of food and water intake, may be mediated via the GABA_B receptors. These studies were fully supported by a grant from the Research Grants Council of the Hong Kong SAR, China (Project no. UGC/FDS11/M03/22).