Research reportExpression and regulation of cholecystokinin and cholecystokinin receptors in rat nodose and dorsal root ganglia
Introduction
The vagus nerve is a mixed nerve containing primary afferent fibers which transmit viscero-sensory information from the gastrointestinal tract and cardio-respiratory organs (see Refs. [60], [65]). The cell bodies of these fibers are located in the nodose ganglion (NG), and central branches terminate in the nucleus of the solitary tract [27], [41], [42], [43], [64], [78], where this information is relayed onto second-order sensory neurons projecting to multiple brain sites (see Ref. [72]). The vagus nerve conveys signals elicited by both mechanical, e.g., gastric tension [35], as well as chemical, e.g., specific nutrients [38], [51], stimulation that serves to regulate food intake on a short-term basis, i.e., by inducing meal termination.
Vagal signalling is modulated by specific systemic/paracrine messenger molecules. A major role in this regulation has been suggested for the hormone/neuropeptide cholecystokinin (CCK) [59], which is produced by enteroendocrine cells in the upper gastrointestinal tract [62] (see Ref. [82]), and increases in plasma concentration in response to a meal [32]. CCK was first postulated as an important endogenous satiety factor following the demonstration by Gibbs et al. [26] that intraperitoneal administration of the peptide produces dose-dependent inhibition of food intake (see Ref. [67]), an effect dependent on an intact afferent vagal system [79], [80]. Pharmacological studies have indicated that of the two CCK receptor (CCK-R) subtypes known, the CCKA- and the CCKB-Rs [36], [85], [86], it is primarily the CCKA-R that is responsible for mediating satiety induced by peripheral CCK [29], [68]. CCK binding sites are found both in the vagus nerve [55], [56], [92] and the NG [25], [88]. The presence of CCKA- and CCKB-R mRNAs has also been reported in the NG [10], [57], [69] and dorsal root ganglia (DRGs) [9], [93].
Here, we have attempted to define the neuronal populations expressing CCK-Rs. Previous research has shown that vagotomy can produce dramatic changes in the expression of peptides and transmitter-related enzymes in the NG [28], [94] (see Refs. [95], [96]), similar to the neurochemical alterations in DRG neurons following peripheral axotomy (see Ref. [34]). We have thus in the following investigated if the expression of CCK and its receptors in the NG is subject to vagotomy-induced changes. To determine if physiological challenges involving the digestive apparatus can influence transcription of these molecules, we have also studied their expression in the NG following starvation and a high-fat regimen.
Several lines of evidence point to a role for CCK in the regulation of nociception [3], [12], [23], [37], [81]. While CCK mRNA as well as CCKB-R mRNA expression in DRGs normally is low [15], [77], [93], both mRNA species increase following axotomy [8], [84], [93]. The only study so far available on CCKA receptor mRNA expression in DRGs has demonstrated a small increase in response to the capsaicin analogue, resiniferatoxin [9]. However, the neurons expressing the CCKA receptor have not been further characterized. In the following, we present in situ hybridization data on CCKA-R expression in DRG neurons from normal, axotomized and inflammation-challenged animals.
Section snippets
Animals
Male Sprague–Dawley rats (250–300 g; B&K Universal, Stockholm, Sweden) were used. The experiments had been approved by the local ethical committee, Stockholms norra djurförsöksetiska nämnd. The animals were kept under regular light conditions (lights on at 06.00 and off at 18.00 h) in a temperature-controlled environment and had free access to standard rodent chow (if not otherwise stated; B&K Universal) and tap water. For studies of the NG, six groups of animals were used. One group of animals
Results
Radioactive in situ hybridization on normal rat NGs demonstrated that a large proportion of NPs (32.7±0.8%; Fig. 2) express CCKA-R mRNA (Fig. 1, Fig. 5). Following unilateral vagotomy, the number of NPs expressing CCKA-R mRNA was markedly attenuated (8.1±0.5%; P<0.01; Fig. 1, Fig. 2, Fig. 5). In NGs from rats that had had their food removed 48 h prior to dissection, as in controls, the number of NPs expressing CCKA-R mRNA (33.2±1.5%; Fig. 2A) was not significantly different from control rats (
Nodose ganglia
In the present study we demonstrate that under normal circumstances, a large population of NG NPs expresses high levels of CCKA-R mRNA and a smaller population expresses CCKB-R mRNA. These results confirm previous reports [10], [57], [69], describing the presence of both receptor mRNAs in the NG. The existence of functional receptors encoded by the mRNA was first indicated by the demonstration of CCK binding in the vagus nerve [92]. These binding sites are transported both peripherally [55],
Acknowledgements
This study was supported by Marianne and Marcus Wallenberg’s Foundation, Knut and Alice Wallenberg’s Foundation, Swedish MRC (04X-2887), Lennander’s Foundation and a Bristol-Myers Squibb Unrestricted Neuroscience Research Grant. We thank Dr. D. Katz, Case Western Reserve University, Cincinnati, OH, USA, for valuable advice.
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2019, NeuropeptidesCitation Excerpt :A role for NS CCK-8 in regulating the short-term control of food intake i.e. MS and IMI length is plausible because one of the main peripheral sources for the peptide is the endocrine I cells of the gut and the peptide is secreted in response to the presence of food in the gut (see review (Rehfeld, 2017)). The CCK-BR, which mediates the physiological responses evoked by NS CCK, is expressed on the vagus nerve (Moriarty et al., 1997), the main innervation of the gut that communicate with the central feeding areas, as well as on the nodose ganglia, hypothalamus, AP, NTS and DMV (Monnikes et al., 1997; Broberger et al., 2001; Monnikes et al., 1997). Furthermore, Clerc et al. reported significant increase in food intake and body weight in CCK-BR deficient mice (Clerc et al., 2007).