Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat

Abstract

Horn CC, De Jonghe BC, Matyas K, Norgren R. Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat. Am J Physiol Regul Integr Comp Physiol 297: R1375-R1382, 2009. First published August 26, 2009 doi:10.1152/ajpregu.00284.2009.-Anticancer agents, such as cisplatin, stimulate nausea, vomiting, and behaviors indicative of malaise. Rats and mice do not possess a vomiting response, and, therefore, in these species, the ingestion of kaolin clay (a pica response) has been used as an index of malaise. In the rat, cisplatininduced kaolin intake is inhibited by antiemetic treatments. In addition, cisplatin activates vagal afferent fibers in the gut, and kaolin intake induced by cisplatin is largely dependent on an intact vagus. Nevertheless, little is known about the brain pathways controlling pica. We investigated the role of the lateral parabrachial nucleus (lPBN), a major visceral afferent link between the hindbrain and forebrain, in cisplatin-induced c-Fos expression and pica. Injection of cisplatin (6 mg/kg ip) produced c-Fos expression in the ventrolateral (external) lPBN, a region receiving viscerosensory input. In rats with bilateral ibotenic acid lPBN lesions, cisplatin treatment substantially increased kaolin intake compared with controls (ϳ30 g vs. ϳ5 g, respectively, over 24 h). Food intake was reduced by cisplatin treatment and by apomorphine, an emetic agent that acts centrally. Unlike cisplatin, however, apomorphine stimulated kaolin intake to a similar degree in both the lesioned and control rats, suggesting that lPBN damage neither produces nonspecific effects nor enhances malaise in general. These data suggest that lPBN-lesioned animals not only demonstrate pica after cisplatin treatment, but, in fact, show an exaggerated response that is greatly in excess of any treatment known to produce kaolin intake in rats.emesis; nausea; pica; vagus; anorexia CANCER CHEMOTHERAPY AGENTS, such as cisplatin, stimulate nausea, vomiting, anorexia, and other behaviors indicative of malaise (for a review, see Refs. 2, 21, 27, 51). Several species, including dogs, cats, ferrets, pigs, and shrews, have been used to study emesis after treatment with chemotherapy agents (16,18,31,33,58). In contrast, laboratory rats and mice appear to lack a vomiting response (see Ref. 2 for review). For these species, kaolin intake has been used as a proxy for emesis (60,64). A wide variety of stimuli, including cisplatin, induce kaolin consumption in rats (36,53,59,60,65). Like emesis, geophagia appears to be a defensive response. Clay may serve to bind or dilute a toxin in the gastrointestinal (GI) tract, thus reducing its adverse effects (45, 46). After injection with cisplatin, rats consuming kaolin show less body weight loss and a smaller reduction in food intake than rats without kaolin access (12). The consumption of clay by humans is also recognized as a potential detoxification strategy (48).Despite the use of kaolin intake as an index of malaise in rats, very little is known about...

Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting

“…The activation of the PB might be particularly important as a relay between the emetic circuitry and forebrain areas since this region receives sensory input from the NTS (Fig. 2) and demonstrates neural activity in animal models treated with emetic stimuli (De Jonghe and Horn, 2009; Horn, 2009; Horn et al, 2007; Horn et al, 2009; Suzuki et al, 2012). Furthermore, during sustained nausea the insular, cingulate, orbitofrontal, and prefrontal cortices were also recruited (Napadow et al, 2012).…”

Appetite and body weight regulation after bariatric surgery

“…Earlier literature has identified the PBN as a site of integration of viscerosensory information, including gastric distension and taste . The PBN, particularly its lateral subnuclei, is activated by a number of diverse stimuli including intraperitoneal administration of the satiety hormones CCK‐8 , GLP‐1 , Exendin‐4 , PYY and amylin , electrical stimulation of vagal afferents , the 5‐HT reuptake inhibitor dexfenfluramine , systemic administration of LiCl , lipopolysaccharide (LPS) and other immune‐activation signals , and the cancer chemotherapy drug cisplatin . Importantly, a common effect of all these challenges is a reduction of food intake.…”

Integrative responses of neurons in parabrachial nuclei to a nauseogenic gastrointestinal stimulus and vestibular stimulation in vertical planes

“…Because the PBN/KF complex is a relay through which visceral signals reach higher centers of the brain, this region is believed to be critical in generating affective responses and sensations, such as nausea following interoceptive stimuli (4). Evidence that PBN/KF neurons are part of the nausea-generating pathway includes observations that these neurons express the intermediate-early gene c-fos during emetic stimuli (15) and that lesions of this area affect behaviors in rodents that are believed to indicate the presence of malaise, including pica responses (29) and acquisition of conditioned taste aversions (44,48,50,51,57,58).…”