Receptor-selective agonists induce emesis and Fos expression in the brain and enteric nervous system of the least shrew (Cryptotis parva)

Abstract

Research on the mechanisms of emesis has implicated multiple neurotransmitters via both central (dorsal vagal complex) and peripheral (enteric neurons and enterochromaffin cells) anatomical substrates. Taking advantage of advances in receptor-specific agonists, and utilizing Fos expression as a functional activity marker, this study demonstrates a strong, but incomplete, overlap in anatomical substrates for a variety of emetogens. We used cisplatin and specific agonists to 5-HT 3 serotonergic, D 2 /D 3 dopaminergic, and NK 1 tachykininergic receptors to induce vomiting in the least shrew (Cryptotis parva), and quantified the resulting Fos expression. The least shrew is a small mammal whose responses to emetic challenges are very similar to its human counterparts. In all cases, the enteric nervous system, nucleus of the solitary tract, and dorsal motor nucleus of the vagus demonstrated significantly increased Fos immunoreactivity (Fos-IR). However, Fos-IR induction was notably absent from the area postrema following the dopaminergic and NK 1 receptor-specific agents. Two brain nuclei not usually discussed regarding emesis, the dorsal raphe nucleus and paraventricular thalamic nucleus, also demonstrated increased emesis-related Fos-IR. Taken together, these data suggest the dorsal vagal complex is part of a common pathway for a variety of distinct emetogens, but there are central emetic substrates, both medullary and diencephalic, that can be accessed without directly stimulating the area postrema.

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

“…Thus, the blood-brain barrier permeable agent FPL64176 (Jinnah et al, 1999; 2000 and 2003) could excite emetic neurons directly in the NTS and DMNX. The absence of expected increase in Fos-immunoreactivity in the AP may be explained by findings that systemic administration of some emetics may not involve the AP (Miller and Leslie, 1994; Ray et al, 2009a). …”

“…Our lab has utilized c-Fos induction in the brainstem DVC emetic nuclei to demonstrate central responsiveness to peripheral administration of diverse emetogens (Chebolu et al, 2010; Ray et al, 2009a and 2009c; Zhong et al, 2016). In the current study participation of central emetic neurons in FPL64176-induced vomiting is further indicated by upregulated c-Fos expression in brainstem emetic nuclei NTS, a key site for integration of diverse emetic signals (Ray et al, 2009a and 2009c), and DMNX, which receives axonal projections from NTS (Travagli and Anselmi, 2016). Thus, the blood-brain barrier permeable agent FPL64176 (Jinnah et al, 1999; 2000 and 2003) could excite emetic neurons directly in the NTS and DMNX.…”

“…Sections were observed under a light microscope and those containing the DVC were subjected to immunostaining using rabbit anti-c-Fos polyclonal antibody (1:10000, PC38, CalBiochem, San Diego, CA) which were performed according to our published studies (Ray et al, 2009a and 2009c). Photomicrographs of the DVC containing AP, NTS and DMNX were taken by Nikon Eclipse E600 microscope.…”

“…The means of each region per animal was further compared. Our lab has well described the circumventricular organ AP and the different cytoarchitectonic detail such as cell size and packing differentiating DMNX from NTS within the DVC, as part of a stereotaxic atlas of the least shrew brainstem (Ray et al, 2009a). This criterion has been well recognized (Chebolu et al, 2010; Darmani et al, 2008; Ray et al, 2009a and 2009c; Zhong et al, 2014b and 2016).…”

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

“…In fact 2-Me-5-HT-induced emesis has been shown to be associated with enhanced Fos-immunoreactivity in both the DVC emetic nuclei and in the ENS of the least shrew [14]. Moreover, 5-HT 3 R-selective antagonists such as tropisetron [10] or palonosetron [15], can suppress vomiting caused by 2-Me-5-HT.…”