Can modulating corticotropin releasing hormone receptors alter visceral sensitivity?

Short abstract

Activation of corticotropin releasing hormone (CRH) receptor 2 (CRH‐R2) reduces visceral sensitivity induced by colorectal distension in conscious rats. This finding is relevant to the increased interest in the potential use of therapeutic agents that act on CRH receptors in the treatment of irritable bowel syndrome

Clarifying the adverse effects of stress on bodily function is a crucial paradigm for medical research. Evidence that psychosocial stress aggravates digestive diseases has been accumulating and stress induced exacerbation of symptoms in patients with functional gastrointestinal disorders is well recognised.¹ Corticotropin releasing hormone (CRH), a 41 amino acids peptide produced mainly in the paraventricular nucleus of the hypothalamus, is considered to be a major mediator of the stress response.² Indeed, stress is known to induce release of hypothalamic CRH, resulting in pituitary secretion of adrenocorticotropic hormone (ACTH). In addition, stress related activation of CRH receptors has been reported to alter gastrointestinal functions.³ Moreover, physical or psychological stress is known to delay gastric emptying,⁴ accelerate colonic transit,⁵ and evoke colonic motility⁶ in rats.

Two major G protein coupled receptors for the CRH have been identified, CRH receptor 1 (CRH‐R1) and receptor 2 (CRH‐R2).⁷,⁸,⁹ CRH‐R1, which is highly expressed in the anterior pituitary, neocortex, hypothalamus, hippocampus, amygdala, locus coeruleus, and cerebellum, has been reported to mediate stress induced physiological changes, including stimulation of the hypothalamo‐pituitary‐adrenal axis, elevation of plasma levels of catecholamines, increased colonic motility,¹⁰ and exaggerated stress related behaviour, especially anxiety.¹¹,¹² In addition, stimulation of this receptor is believed to activate adenylate cyclase, an enzyme that catalyses the formation of cyclic AMP (cAMP).⁷,⁸,⁹

We have previously reported increased colonic motility and visceral perception in response to administration of CRH in patients with irritable bowel syndrome (IBS).¹³ In addition, earlier studies have indicated that gastrointestinal dysmotility¹⁴ and visceral hypersensitivity¹⁵ are major events in the pathophysiology of IBS. Moreover, patients with IBS have been reported to suffer from a variety of chronic or acute psychiatric conditions, including depression, generalised anxiety, panic, social phobia, and somatisation.¹⁶ Various studies have suggested a relationship between stress induced changes in colonic motility and CRH action in the paraventricular nucleus of the hypothalamus.¹⁷ Accordingly, it has been shown that intracerebroventricular injection of CRH stimulates gastrointestinal motility in a way similar to that induced by stress¹⁸ and that intraperitoneal injection of CRH induces defecation and clustered spike bursts longer than basal spike bursts in rats.¹⁰

CRH‐R1 antagonists have been shown to prevent stress‐like gastrointestinal motor responses following central or peripheral injection of CRH.¹⁰ In addition, it has been reported that CRH‐R1 deficient mice show impaired response to stress, as indicated by absence of increased ACTH and corticosterone levels following exposure to stress, as well as less pronounced anxiety related behaviour.¹¹,¹² From these findings, it is reasonable to assume that CRH mediates gastrointestinal and behavioural responses to stress via CRH‐R1. Actually, in a recent study,¹⁹ we have shown that administration of an α‐helical CRH or CRH‐R1 antagonist attenuates hippocampal noradrenaline release and reduces the frequency of abdominal contractions induced by acute colorectal distension in rats. We have also shown that the CRH‐R1 antagonist used in that study¹⁹ reduced plasma ACTH and anxiety after acute colorectal distension but not after chronic colorectal distension, probably due to habituation. Another important finding of our previous study¹⁹ is that pretreatment with the CRH‐R1 antagonist blocked chronic colorectal distension induced increase in rats faecal pellet output. Because the CRH‐R1 antagonist used in our previous study¹⁹ is an agent that crosses the blood‐brain barrier, both central CRH‐R1 and peripheral CRH‐R1 are thought to be responsible for colorectal distension induced sensitisation. Nevertheless, CRH and CRH‐R1 in the brain may play a major role in colorectal distension induced anxiety, ACTH release, visceral hypersensitivity, and changes in colonic motility.

Evidence supporting the concept that peripheral CRH and CRH‐R1 play important roles in brain‐gut sensitisation is increasing. Several studies have identified immunoreactive CRH²⁰ and urocortin ²¹ as well as CRH‐R1 and CRH‐R2 mRNAs in human colonic mucosa.²¹ In addition, reverse transcription‐polymerase chain reaction (RT‐PCR) has revealed expression of CRH‐R1 mRNA in both the myenteric and submucosal plexus in the guinea pig.²² Application of CRH has been shown to evoke depolarising responses associated with elevated excitability in both myenteric and submucosal neurones.²² On the other hand, peripheral injection of CRH has been reported to induce discrete effects on colonic secretory and motor function, and permeability.²³ We have previously reported that intravenous administration of a non‐selective CRH antagonist (α‐helical CRH) blunts the exaggerated motility response in the sigmoid colon to electrical stimulation in IBS patients compared with normal subjects.²⁴ In the same study, we have shown that administration of α‐helical CRH induces a significant increase in barostat bag volume in normal subjects but not in IBS patients, and a significant reduction in the ordinate scale of abdominal pain and anxiety evoked by rectal electrical stimulation in IBS patients. However, plasma ACTH and serum cortisol levels were generally not suppressed following administration of α‐helical CRH at 10 μg/kg. Although the precise sites of action of α‐helical CRH are unknown, we suggested in our previous study that blunting the colonic motor response is mainly due to blockage of peripheral CRH‐R1 and that drug anxiolytic or antinociceptive effects are probably based on inhibition of central CRH‐R1 via circumventricular organs, which are relatively unprotected by the blood‐brain barrier.²⁴ These findings and concepts, which put in the context of existing preclinical and clinical data, support the testing of new CRH antagonists, particularly potent CRH‐R1 antagonists, in IBS and the view that the CRH‐R1 receptor is a promising target for the treatment of IBS.²⁵

In this issue of Gut, however, Million and colleagues²⁶ provide a new theory for modifying gut sensitivity via CRH‐R2 (see page 172). Using RT‐PCR, they proved the existence of CRH‐R2 in the dorsal root ganglia and spinal cord and hypothesised that CRH‐R2 activation may influence visceral pain induced by colorectal distension in conscious rats. By assessing the possible sites and mechanisms of action for CRH‐R2 activation, they showed that two repeated colorectal distensions produced visceral sensitisation and phosphorylation of extracellular signal related kinase 1/2 (ERK 1/2) and that intravenous administration of human urocortin 2, a selective CRH‐R2 agonist, prevented visceral sensitisation and reduced the second response compared with the first one. Million et al also demonstrated that administration of human urocortin 2 dampened distension induced phosphorylation of ERK 1/2 and robust inferior splanchnic afferent spike activity and that treatment with astressin₂‐B, a CRH‐R2 receptor antagonist, reversed the inhibitory effects of human urocortin 2 both in vivo and in vitro.²⁶

CRH‐R2 is highly expressed in the anterior pituitary, hypothalamus, hippocampus, amygdala, lateral septum, and other peripheral tissues, including the spleen, stomach, and gut.⁷,⁸,⁹ Compared with CRH‐R1, the functional role of CRH‐R2 is relatively obscure. However, recent reports put forward the concept that activation of CRH‐R2 signalling pathways may be important to reduce anxiety and stress response.²⁷,²⁸ There are other functional differences between CRH‐R1 and CRH‐R2. For example, activation of CRH‐R1 causes a proinflammatory response whereas stimulation of CRH‐R2 provokes anti‐inflammatory changes.²⁹ In addition, the study by Million and colleagues²⁶ offers evidence of the contrasting roles of CRH‐R1 and CRH‐R2 in visceral nociception. While CRH‐R1 is involved in the pronociceptive effects of visceral pain, CRH‐R2 mediates antinociceptive responses. These findings are supported by a recent report from another group.³⁰

Several questions arise from these animal experiments. Do endogenous CRH‐R2 ligands such as CRH, urocortin 1, urocortin 2, urocortin 3 (stresscopin), and stresscopin related peptides play an inhibitory role in visceral hypersensitivity in IBS patients? If so, are selective CRH‐R1 antagonists more effective for visceral hypersensitivity than non‐selective CRH antagonists? Moreover, do agents that block CRH‐R2 have any adverse effects on the pathophysiology of IBS? Do CRH‐R2 agonists have therapeutic value for IBS and/or allied functional gastrointestinal disorders, even though stress induced inhibition of gastric emptying is mainly mediated via CRH‐R2? What are the major steps from the synthesis of cAMP by activated CRH‐R2 in the dorsal root ganglia and spinal cord to reduced phosphorylation of ERK 1/2 in the laminae I and II? Thus the disclosed nature of CRH‐R2 reported in the present issue of Gut brings us an exciting paradigm on research and drug development of the CRH neuropeptide family.