ARTICLE IN PRESS Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 www.elsevier.com/locate/neubiorev Review The neural/cephalic phase reflexes in the physiology of nutrition Marı´ a A. ZafraÃ, Filomena Molina, Amadeo Puerto Psychobiology, Department of Experimental Psychology and Physiology of Behavior. Campus de Cartuja, University of Granada, Granada 18071, Spain Received 14 October 2005; received in revised form 15 March 2006; accepted 16 March 2006 Abstract The cephalic phase of nutrition refers to a set of food intake-associated autonomic and endocrine responses to the stimulation of sensory systems mainly located in the oropharyngeal cavity. These reactions largely occur in the digestive system, but they have also been observed in other structures. Most published data indicate that cephalic responses are mediated by the efferent component of the vagus nerve, although other neurobiological components and brain centers must be involved. The physiological significance of all of these reactions has yet to be fully elucidated, but when the cephalic phase of digestion is obviated major physiological and behavioral dysfunctions can be observed. This has led numerous authors to propose that their function may be essentially adaptive, preparing the digestive system for the reception, digestion, and absorption of the food. Study of the neural/cephalic phase and the consequences of its absence may have clinical relevance in the setting of artificial nutrition, and may explain the difficulties of providing enteral nutrition to many of the patients that require it. r 2006 Elsevier Ltd. All rights reserved. Keywords: Cephalic phase; Digestive enzymes; Gastric acid; Gastrointestinal hormones; Immunoglobulins; Vagus nerve; Dorsal motor nucleus of the vagus; Nucleus of the solitary tract; Lateral hypothalamus; Ventromedial hypothalamus; Orexins; Thyrotropin-releasing hormone; Enteral feeding; Disturbances of enteral nutrition Contents 1. Introduction . 1032 2. Reflex responses during the cephalic phase. 1033 2.1. Oral responses . 1034 2.2. Gastric responses . 1035 2.3. Intestinal responses . 1036 2.4. Pancreatic responses . 1036 2.5. Other cephalic responses . 1037 3. Neural mechanisms involved in cephalic responses . 1037 4. Disturbances induced by absence of cephalic phase. 1039 5. Conclusion . 1041 Acknowledgments . 1041 References . 1041 1. Introduction Studies of the physiological processes that participate in nutrition have demonstrated that food intake is dependent ÃCorresponding author. Fax: +34 58246239 on multiple and complex mechanisms involving both E-mail address: [email protected] (M.A. Zafra). central and peripheral nervous systems (Le Magnen, 0149-7634/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2006.03.005 ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1033 1992; Berthoud, 2002; Ritter, 2004). With regard to the post-absorptive consequences of food ingestion (Pav- peripheral mechanisms, researchers have underlined the lov, 1910; Brand et al., 1982; Davis, 1999). Because it is an importance of signals that originate at different levels of invasive technique, a modified sham feeding variant has the digestive system. Thus, emphasis has been placed on been developed for use in humans, in which the food is the role of the gustatory component of food, gastric tasted but not swallowed (Richardson et al., 1977; Jackson distension, gastric emptying rate, nutrient absorption rate, et al., 2001). The shortcoming of this approach is that and different gastrointestinal hormones (Le Magnen, 1992; pharyngeal and esophageal receptors are not stimulated, Phillips and Powley, 1998; Davis, 1999; Ritter, 2004). and it has been suggested that this stimulation may be With regard to oropharyngeal systems, it has been important for generating some secretions during the demonstrated over the past few decades that the stimula- cephalic phase (Brand et al., 1982). Nevertheless, both tion exerted by food at this level of the digestive tract is sham feeding and modified sham feeding allow the cephalic essential to different nutrition-related processes. Thus, phase to be isolated from subsequent phases, enabling these systems are relevant to satiety (Le Magnen, 1992; assessment of its participation in digestive events (Teff and Hetherington, 1996), appetite (Le Magnen, 1992; Davis, Engelman, 1996b). 1999), and the development of preferences and aversions (Deutsch et al., 1976; Sclafani et al., 1999; Zafra et al., 2. Reflex responses during the cephalic phase 2000, 2002, 2006; Mediavilla et al., 2005). Less attention has been paid to the fact that participation of orophar- Reactions to cephalic stimulation are generally rapid and yngeal systems in physiological digestive processes is transient responses mediated by the efferent component of required for optimal nutritive functioning (Brand et al., 1982; Mattes, 1997). Events that occur during food ingestion have usually been divided into different phases according to the part of the digestive system that is stimulated by the food, i.e. a neural/cephalic phase, gastric phase, and intestinal phase (Richardson et al., 1977; Naim et al., 1978; Brand et al., 1982). The neural phase of digestion refers to a set of physiological, endocrine and autonomic responses of the digestive system that result from stimulation of sensory systems at the cephalic level, especially in the orophar- yngeal cavity. Although these responses are preferentially associated with the gustatory/olfactory properties of the food, the sight or anticipation of food or any other circumstance associated with food intake can also stimulate and trigger these responses (Pavlov, 1910; Powley, 1977; Nederkoorn et al., 2000). While the first observations date from 1878 (Moore and Schenkenberg, 1974; Brand et al., 1982), the characteristics of the digestive secretions of the cephalic phase were first documented by Ivan Pavlov (Brand et al., 1982; McGregor and Lee, 1998), who received the Nobel Prize in 1904 for his research on the physiology of digestion, widely known through his book ‘‘The Work of the Digestive Glands’’ (Pavlov, 1910). Although Pavlov introduced the term ‘‘psychic reflex’’ for these responses, subsequent authors agreed to use the designation ‘‘cephalic phase’’ in order to highlight the fact that, unlike gastric or intestinal phases, responses during this stage are essentially mediated by brain mechanisms and peripheral neural systems (Molina, 1978). Fig. 1. Main chemical substances released in the digestive system during Sham feeding is the most frequently used method for the cephalic phase. These secretions, essential for the correct digestion of studying processes related to the cephalic phase. Animals food, occur at both endocrine and exocrine levels. Endocrine secretions are allowed to ingest food in a normal manner but the food include the release of gastrin, leptin, and immunoglobulin from stomach is diverted by gastric or esophageal catheter so that it and of insulin, glucagon, PP, and CCK from pancreas. Exocrine secretions include the release of gastric acid and pepsinogen from stomach, digestive cannot accumulate in the gastric cavity, preventing enzymes from oral cavity, stomach, and pancreas, and bicarbonate from subsequent processing of food in remaining segments of small intestine and pancreas. PP, pancreatic poypeptide; CCK, cholecys- the gastrointestinal tract and allowing disassociation from tokinin. ARTICLE IN PRESS 1034 M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 Table 1 Main responses during the cephalic phase and proposed actions and action mechanisms Responses Actions and mechanisms Oral cavity Saliva Lubricates and protects oral mucosa Dissolves food particles to be transported to the taste buds (essential for taste perception) Initiates breakdown of starch and fats (saliva contains enzymes such as amylase and lingual lipase) Stomach Hydrochloric acid Breakdown of foods Gastrin Contributes to gastric acid secretion Digestive enzymes (lipase) Breakdown of fats Immunoglobulins Protects gastric and intestinal mucosae against any exogenous microorganisms ingested with the food Leptin Contributes to satiation (by acting on leptin receptors in vagal afferents that play a major role in this process) Duodenum Bicarbonate Neutralization of gastric acid upon entry into the duodenum Pancreas Bicarbonate Neutralization of acid contents of duodenum Digestive enzymes (lipase, amylase, trypsin, chymotrypsin) Breakdown of fats, carbohydrates and protein Insulin Anticipatory metabolic role Glucagon To prevent hypoglycemia when protein-rich food is eaten Pancreatic polypeptide Cholecystokinin Other secretions Gallbladder flow Secretin Enzymes in adipose tissue Other non-secretory responses Gastric motor activity Postprandial thermogenesis Cardiac response Respiratory quotient Absorption and transport of nutrients the vagus nerve (see below) (Pavlov, 1910; Mattes, 1997; pancreatic enzyme system (Mattes, 2000; Pedersen et al., Powley, 2000). Most of these reactions imply the release of 2002). chemical substances in the digestive system (see Fig. 1), Saliva is released before food is present in the although some non-secretory responses have also been oropharyngeal cavity, since the mere sight of food or any observed (Pavlov, 1910; Powley, 1977; Brand et al., 1982; other food-related stimulus is sufficient to activate this see Table 1). mechanism. Nevertheless, the volume of saliva markedly increases