Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.

The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.

Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain.

The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower (Helianthus annuus) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.

NaV1.1 inhibition can reduce visceral hypersensitivity.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Apelin targets gut contraction to control glucose metabolism via the brain.

OBJECTIVE: The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. DESIGN: We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. RESULTS: In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. CONCLUSIONS: Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.

Garcinia buchananii bark extract is an effective anti-diarrheal remedy for lactose-induced diarrhea.

ETHNOPHARMACOLOGICAL RELEVANCE: The extract from the stem bark of Garcinia buchananii trees is used as an anti-diarrhea remedy in sub-Saharan Africa. We tested the hypothesis that G. buchananii bark extract and its anti-motility fractions are effective treatments against lactose-induced diarrhea. MATERIALS AND METHODS: A high-lactose (35%) diet was used to induce diarrhea in Wistar rats, which were then treated with either G. buchananii bark extract (0.1, 0.5, 1.0 and 5.0 g bark powder), and its anti-motility fractions isolated using preparative thin layer chromatography; termed PTLC1 (15 mg) and PTLC5 (3.8 mg) or loperamide (8.4 mg). Drug preparations were dissolved in 1L except PTCL1 and PTLC5 that were dissolved in 100mL tap water. Numerous parameters were measured in each condition including consistency, fluid and mucus content of feces, body weight, water and food consumption, urine production and bloating. RESULTS: Diarrheic rats produced watery or loose, mucuoid, sticky, feces. Fluids constituted 86% of stool mass compared with only 42% for control rats fed standard chow. Compared with controls, diarrheic rats produced more urine, lost weight and had bloated ceca and colons. All doses of the extract, its anti-motility fractions and loperamide individually stopped diarrhea within 6-24 h of administration, whilst significantly reducing mucus and fecal fluid content, urine production and intestinal bloating. Rats treated with 0.1g extract, PTLC1 and PTLC5 gained weight, whilst PTLC5 also increased water intake. CONCLUSIONS: Garcinia buchananii extract and its anti-motility fractions are effective remedies against lactose-induced diarrhea. The extract contains compounds that reverse weight loss, promote food and water intake, supporting the notion that characterization of the compounds could lead to new therapies against diarrheal diseases.

Use of natural products in gastrointestinal therapies.

Altered motility, discomfort and pain are common debilitating symptoms of patients with functional gastrointestinal disorders. However, these conditions represent a significant and unmet need for mainstream medical treatment, particularly after high profile therapeutic drug withdrawals due to safety concerns. As such an increasing number of sufferers are turning to alternative medicines in an effort to seek relief from their symptoms. Alternative medicines have traditionally been looked at by mainstream medicine with cynicism. However, new evidence demonstrates that the active components in natural products have actions on specific ion channels and receptors, many of which are located in sensory systems distributed throughout the body. These findings may not only explain the symptomatic benefit of these alternative medicines but also provide novel therapeutic targets for mainstream drug development. As such natural products represent a wealth of untapped potential which is waiting to be unlocked.