norbinaltorphimine and Abdominal-Pain

Topics: Abdominal Pain; Analgesics; Animals; Cells, Cultured; Chronic Disease; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Helianthus; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Peptides, Cyclic; Plant Extracts; Receptors, Opioid, kappa; Seeds; Structure-Activity Relationship

Narcotic bowel syndrome (NBS) is a subset of opioid bowel dysfunctions that results from prolonged treatment with narcotics and is characterized by chronic abdominal pain. NBS is under-recognized and its molecular mechanisms are unknown. We aimed to (1) develop a rat model of NBS and (2) to investigate its peripheral and central neurobiological mechanisms.. Male Wistar rats were given a slow-release emulsion that did or did not contain morphine (10 mg/kg) for 8 days. Visceral sensitivity to colorectal distension (CRD) was evaluated during and after multiple administrations of morphine or vehicle (controls). The effects of minocycline (a microglia inhibitor), nor-binaltorphimine (a kappa-opioid antagonist), and doxantrazole (a mast-cell inhibitor) were observed on morphine-induced visceral hyperalgesia. Levels of OX-42, P-p38 mitogen-activated protein kinase, rat mast cell protease II, and protein gene product 9.5 were assessed at different spinal segments (lumbar 6 to sacral 1) or colonic mucosa by immunohistochemistry.. On day 8 of morphine administration, rats developed visceral hyperalgesia to CRD (incipient response) that lasted for 8 more days (delayed response). Minocycline reduced the incipient morphine-induced hypersensitivity response to CRD whereas nor-binaltorphimine and doxantrazole antagonized the delayed hyperalgesia. Levels of OX-42 and P-p38 increased in the spinal sections, whereas rat mast cell protease II and protein gene product 9.5 increased in the colonic mucosa of rats that were given morphine compared with controls.. We developed a rat model of narcotic bowel-like syndrome and showed that spinal microglia activation mediates the development of morphine-induced visceral hyperalgesia; peripheral neuroimmune activation and spinal dynorphin release represent an important mechanism in the delayed and long-lasting morphine-induced colonic hypersensitivity response to CRD.

Topics: Abdominal Pain; Animals; CD11b Antigen; Chymases; Colon; Delayed-Action Preparations; Disease Models, Animal; Gastrointestinal Transit; Hyperalgesia; Immunohistochemistry; Intestinal Mucosa; Male; Mast Cells; Microglia; Minocycline; Morphine; Naltrexone; Narcotic Antagonists; p38 Mitogen-Activated Protein Kinases; Pain Measurement; Pain Threshold; Pressure; Rats; Rats, Wistar; Spinal Cord; Syndrome; Thioxanthenes; Time Factors; Ubiquitin Thiolesterase; Xanthones

Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Topics: Abdominal Pain; Acetic Acid; Afferent Pathways; Animals; Benzyl Compounds; Brain; Capsaicin; Gene Expression Regulation; Genes, fos; Injections, Intraperitoneal; Intestinal Obstruction; Male; Naltrexone; Paraventricular Hypothalamic Nucleus; Propylamines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Solitary Nucleus; Spinal Cord; Supraoptic Nucleus