Methylnaltrexone in the treatment of opioid-induced constipation

Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral–cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies

Stereotaxic Exposure of the Central Nucleus of the Amygdala to Corticosterone Increases Colonic Permeability and Reduces Nerve-Mediated Active Ion Transport in Rats

Background: Irritable bowel syndrome (IBS) is characterized by visceral pain and abnormal bowel habits that are worsened during stress. Evidence also suggests altered intestinal barrier function in IBS. Previously, we demonstrated that stereotaxic application of the stress hormone corticosterone (CORT) onto the central nucleus of the amygdala (CeA) induces colonic hyperalgesia and anxiety-like behavior in a rat model, however the effect on intestinal permeability and mucosal function remain to be evaluated.Methods: Male Fischer 344 rats underwent bilateral stereotaxic implantation of CORT or inert cholesterol (CHOL)-containing micropellets (30 μg) onto the dorsal margin of the CeA. Seven days later, colonic tissue was isolated to assess tissue permeability in modified Ussing chambers via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). Secretory responses to electrical field stimulation (EFS) of submucosal enteric nerves as well as activation with forskolin were used to assess movements of ions across the isolated colonic tissues. In a separate cohort, colonic histology, and mast cell infiltration was assessed.Key Results: Compared to CHOL-implanted controls, we determined that exposing the CeA to elevated levels of CORT significantly increased macromolecular flux across the colonic epithelial layer without changing TEER. Nerve-mediated but not cAMP-mediated active transport was inhibited in response to elevated amygdala CORT. There were no histological changes or increases in mast cell infiltration within colonic tissue from CORT treated animals.Conclusion and Inferences: These observations support a novel role for the CeA as a modulator of nerve-mediated colonic epithelial function

Fundamentals of neurogastroenterology: Basic science

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled Rome IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs, and new areas for future research into their pathophysiology

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing

Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus

ABSTRACT Ghrelin and ghrelin mimetics stimulate appetite and enhance gastric motility. The present study investigates whether ipamorelin, a selective growth hormone secretagogue and agonist of the ghrelin (GRLN)-receptor, would accelerate gastrointestinal (GI) transit and ameliorate the symptoms in a rodent model of post-operative ileus (POI). Methods: Fasted male rats were subjected to laparotomy and intestinal manipulation. At the end of surgery a dye marker was infused in the proximal colon to evaluate post-surgical colonic transit time, which was the time to the first bowel movement. In addition, fecal pellet output, food intake and body weight were monitored regularly for 48 h. Ipamorelin (0.01-1 mg/kg), GHRP-6 (20 µg/kg) or vehicle (saline) were administered via i.v. bolus infusion following a single dosing or a 2 day repetitive dosing regimen (4 doses a day at 3-h intervals). Compared to the vehicle, a single dose of ipamorelin (1 mg/kg) or GHRP-6 (20 µg/kg) decreased the time to the first bowel movement, but had no effect on cumulative fecal output, food intake or body weight gain measured 48-h after the surgery. In contrast, repetitive dosing of ipamorelin (0.1 or 1 mg/kg) significantly increased the cumulative fecal pellet output, food intake and body weight gain. The results suggest that post-surgical i.v. infusions of ipamorelin may ameliorate the symptoms in patients with POI