i45 VISCERAL PERCEPTION Gut: first published as 10.1136/gut.51.suppl_1.i45 on 1 July 2002. Downloaded from Role of thyrotrophin releasing hormone and corticotrophin releasing factor in stress related alterations of gastrointestinal motor function C Beglinger, L Degen ............................................................................................................................. Gut 2002;51(Suppl I):i45–i49 There is a growing body of experimental and clinical ades ago, pioneer neuropharmacological studies evidence to indicate that stress influences identified the brain as a prime site of action for peptides that alter gastrointestinal function.1–4 gastrointestinal motility. The most common pattern of Over a dozen peptides which modify gastro- gastrointestinal motor alterations induced by a variety of intestinal motor activity and alter transit in rats, different stress factors is that of delayed gastric cats, rabbits, and dogs have been shown to act within the brain.4–7 However, the physiological emptying and accelerated colonic transit. Central role of these peptides is still unclear. The reasons administration of corticotrophin releasing factor mimics for this lack of understanding are threefold. both of these effects. This review focuses on the effects Firstly, specific receptor antagonists are not available for most of these peptides which means of two centrally acting peptides known to influence that it is difficult to examine the endogenous gastrointestinal motility and transit in experimental release of these substances from the CNS in animals: thyrotrophin releasing hormone and response to physical events. Secondly, it is often necessary to undertake experimental studies on corticotrophin releasing factor. The biological actions of surgical preparations or by insertion of needles these peptides are discussed in relation to the motility into brain structures. Although such studies pro- changes and pathways involved in their actions. vide valuable information about the pathways that modulate gastrointestinal functions, their .......................................................................... conclusions cannot be interpreted in terms of normal physiology. The third complication arises SUMMARY from the fact that many of the regulatory circuits http://gut.bmj.com/ Thyrotrophin releasing hormone (TRH) is re- operate under the control of more than one leased from nerve terminals which influence the mechanism. Studies in unconscious animals can activity of vagal neurones projecting to the stom- provide useful data about specific pathways but ach and gastrointestinal tract, and is thought to compensatory processes are involved in intact act as a mediator of vagally stimulated gastro- animals to ensure that the overall physiology intestinal motility during cold or other stressful remains unchanged. stimuli. Corticotrophin releasing factor (CRF) This review focuses on the effects of two on September 30, 2021 by guest. Protected copyright. plays an important role in the regulation of centrally acting peptides known to influence behavioural and autonomic responses to stress, gastrointestinal motility and transit in experi- 14 489 and it has been proposed that hypersecretion of mental animals: TRH and CRF. The biological CRF in the brain may contribute to the patho- actions of these peptides will be discussed in rela- physiology of stress related exacerbation of irrita- tion to the motility changes and pathways ble bowel syndrome (IBS). Centrally adminis- involved in their actions. For example, a growing tered CRF inhibits gastric emptying while body of evidence suggests that TRH and CRF both stimulating colonic motor function. In rats, these play a role in mediating stress induced alterations in gastrointestinal motor function.67 Wherever effects are mediated by CRF2 receptors which modulate vagal and sacral parasympathetic out- possible, the review will also address how these flow. CRF also activates colonic transit and faecal findings relate to normal physiology. excretion elicited by stress. This response involves CRF1 receptors. CRF may also act peripherally, STRUCTURE AND BIOCHEMISTRY OF TRH especially in patients with inflammatory or post- AND CRF infectious conditions. TRH (pGlu-His-Pro-NH2) was the first hypothal- amic releasing peptide to be discovered. Based on See end of article for its actions (regulation of thyrotrophin or thyroid authors’ affiliations INTRODUCTION ....................... During the last three decades, a large number of Correspondence to: brain peptides have been characterised using the ................................................. Professor C Beglinger, techniques of biochemistry, immunohistochemis- Division of try, molecular biology, and physiology. Identifica- Abbreviations: ACTH, adrenocorticotrophic hormone; Gastroenterology, tion of these peptides has led to an explosion in CNS, central nervous system; CRF, corticotrophin releasing factor; IBS, irritable bowel syndrome; LPS, lipopoly University Hospital, 4031 our understanding of their biological action and Basel, Switzerland; -saccharide; alpha-MSH, melanocyte stimulating hormone; [email protected] function in the central nervous system (CNS), PVN, paraventricular nucleus; TRH, thyrotrophin releasing ....................... spinal cord, and enteric nervous system. Two dec- hormone; 5-HT, serotonin. www.gutjnl.com i46 Beglinger, Degen stimulating hormone secretion) it was primarily considered to suggest that TRH is released from nerve terminals which be a physiological regulator of pituitary function.10 11 Further influence the activity of vagal neurones projecting into the 429 studies unexpectedly identified TRH in other brain areas, and stomach and the gastrointestinal tract. Gut: first published as 10.1136/gut.51.suppl_1.i45 on 1 July 2002. Downloaded from based on these findings additional experiments were per- Environmental stress such as exposure to cold are known to formed which showed that this peptide exerts behavioural stimulate brain TRH.32–34 Exposure to cold induces similar effects which are independent of its effects on the pituitary- effects on gastric and gastrointestinal motility as those thyroid axis.1 observed following central injection of TRH.4 Perhaps, more CRF is a 41 amino acid peptide that was characterised two importantly, cold exposure has also been shown to be associ- decades ago.12 The peptide plays a regulatory role in the control ated with accelerated gastric emptying and diarrhoea in of pituitary adrenocorticotrophic hormone (ACTH) secretion rats.32 34 These results imply that medullary TRH may act as a and, in common with TRH, it exerts behavioural, endocrine, mediator of vagally stimulated gastrointestinal motility and motility responses to stress by actions that are independ- during cold or other stressful stimuli. ent of those at the pituitary-ACTH axis.12 13 These findings form the basis for ongoing investigations of the role of endog- EFFECT OF CRF ON GASTROINTESTINAL MOTILITY enous CRF in the brain in terms of modifying gastrointestinal A variety of reports have established that CRF injected into the function and a putative role in stress induced changes in cerebrospinal fluid acts in the brain to inhibit gastric and/or gastrointestinal motor activity.4–6 gastrointestinal motility.35 36 Its actions are mediated by an The actions of CRF have been shown to be mediated through interaction with specific high affinity seven transmembrane activation of specific receptors.14 To date, two CRF receptors, bound receptors that are coupled to a guanine nucleotide 14 37 designated CRF1 and CRF2, have been identified through stimulatory factor signalling protein. To date, two distinct 14 molecular cloning from distinct genes in rats and in humans. CRF receptor subtypes, CRF1 and CRF2, have been cloned and 614 Advances have also been made in the development of potent characterised from rat and human brains. The CRF1 receptor CRF receptor antagonists. These are very helpful tools for is the predominant form localised in the pituitary, olfactory further investigating the physiological importance of CRF. One bulb, and cerebral cortex. The CRF2 receptor is primarily such agent, astressin (cyclo-(30–33)-[D-Phe12, Nle21,38, located in the lateral septum, hypothalamus, amygdala, and 6 Glu30, Lys33] CRF12–41) is a derivative of CRF which has a low brain stem. CRF2 receptors exist in multiple forms (alpha and intrinsic activity and a high affinity for both CRF1 and CRF2 beta) as splice variants differing in their extracellular amino 15 14 receptors. Astressin has been shown to block the effects of acid NH2 terminal domains and in their distribution. 16–18 exogenous CRF on gastric and colonic motor activity and to CRF2 receptor alpha is located on brain neurones, and CRF2 prevent stress related alterations of gastrointestinal motor receptor beta is found in non-neural brain tissue and in the function.717 Other non-peptide antagonists have been devel- periphery (for example, gastrointestinal tract).38 Several stud- 19 oped which display selectivity for CRF1 or CRF2 receptors. ies have established that CRF decreases gastric emptying after injection of the peptide into the cerebrospinal fluid; CRF2 EFFECTS OF CENTRAL TRH ON GASTROINTESTINAL receptors are thought to mediate this action.19 38 In human MOTILITY brain, unlike rat brain, another CRF2 receptor splice variant 38 Intracerebroventricular injection of TRH induces a rapid and has been identified: the CRF2 receptor gamma. long lasting contractile response in the stomach,