naloxone and Colitis

Topics: Administration, Oral; Animals; Body Weight; Colitis; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Fertility; Haplorhini; Injections, Subcutaneous; Lethal Dose 50; Male; Mice; Naloxone; Naltrexone; Rats; Reproduction; Rhinitis; Teratogens

Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis.. The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days.. Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group.. Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Topics: Aniline Compounds; Animals; Butyrates; Colitis; Disease Models, Animal; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Inflammation; Ligands; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Peroxidase; Receptors, G-Protein-Coupled; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides; Thiophenes; Xanthenes

Mucosal CD4

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; CD4-Positive T-Lymphocytes; Colitis; Cytokines; Epithelial Cells; Inflammation; Interleukin-10; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; Naloxone; Narcotic Antagonists; Permeability; Piroxicam; Quaternary Ammonium Compounds; Receptors, Opioid; Severity of Illness Index

Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.. Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca. Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca. Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.

Topics: Adult; Aged; Animals; beta-Endorphin; Biopsy; Chronic Disease; Colitis; Colon; Cytokines; Ganglia, Spinal; Humans; Mice; Mice, Inbred C57BL; Middle Aged; Naloxone; Nociceptors; Patch-Clamp Techniques; Signal Transduction; Stress, Psychological

The present study aimed to expand our previous findings regarding the therapeutic effects and underlying mechanisms of acupuncture at GV01 in colitis. Our results showed that acupuncture at GV01 has antinociceptive effects on referred somatic pain induced by experimental colitis, and that endogenous opioid pathways may mediate these effects.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Colitis; Immunohistochemistry; Male; Naloxone; Neurons; Pain Threshold; Pain, Referred; Periaqueductal Gray; Proto-Oncogene Proteins c-fos; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors; Trinitrobenzenesulfonic Acid

Oriental medicine uses acupuncture at the GV01 acupoint with great success to treat diarrhea. It significantly reduced the colonic motility and inflammation in colitic rats. Naloxone pretreatment blocked these effects. The therapeutic effects of acupuncture at GV01 in colitis may involve endogenous opioid pathways.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Colitis; Colon; Disease Models, Animal; Gastrointestinal Motility; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

The physiologic role of the mu opioid receptor (MOR) in gut nociception, motility, and secretion is well established. To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4(+) T cells in mice. This therapeutic effect was almost completely abolished by concomitant administration of the opioid antagonist naloxone. Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring 3 days after TNBS administration. The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD). These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4-Positive T-Lymphocytes; Colitis; Colon; Cytokines; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Naloxone; Narcotic Antagonists; Oligopeptides; Peroxidase; Receptors, Opioid, mu; Trinitrobenzenesulfonic Acid

The objective of this study was to examine the antinociceptive effects of peripherally restricted kappa-opioid receptor agonists (ORAs) in a rat model of inflammatory bowel disease produced by intracolonic instillation of trinitrobenzine sulfonic acid (TNBS). Antinociceptive effects of mu-(morphine) and kappa-ORAs (EMD 61,753 and ICI 204,488) were evaluated in a behavioral model of visceral nociception. The effects of these agonists and a delta-ORA (SNC 80) on responses of pelvic nerve afferent fibers innervating the colon were also tested. In the behavioral study, systemic injections of morphine and both kappa-ORAs dose-dependently inhibited the visceromotor response to colorectal distension in rats with uninflamed or inflamed colons. The inhibitory effects of kappa-ORAs, but not morphine, were significantly greater in rats with colons inflamed 4 days previously by TNBS. A mu-receptor-selective dose (30 microg/kg) of naloxone methiodide (NLXM) blocked the inhibitory effect of morphine, but not of EMD 61,753. In the single-fiber study, neither morphine nor the delta-ORA SNC 80 attenuated the responses of pelvic nerve afferent fibers, whereas kappa-ORAs dose-dependently inhibited responses of pelvic nerve afferent fibers with significantly greater potency in the inflamed colon. Pretreatment with a non-opioid receptor-selective dose (2 mg/kg) of NLXM produced a rightward shift in the dose-response function of EMD 61,753. The greater potency of kappa-ORAs in the TNBS-inflamed condition suggests a peripheral upregulation of kappa-opioid receptors in colonic inflammation.

Topics: Acetamides; Action Potentials; Analgesics, Opioid; Animals; Benzamides; Chronic Disease; Colitis; Colon; Electrophysiology; Male; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Neurons, Afferent; Pain Measurement; Piperazines; Pressure; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Rectum; Trinitrobenzenesulfonic Acid

The objective of this study was to evaluate the effects of kappa-opioid receptor agonists on pressor and visceromotor responses to colorectal distension in awake, unrestrained rats, a model of visceral pain. Because visceral pain can be enhanced in the presence of inflammation, the study was conducted in rats that had been given either intracolonic saline or 5% acetic acid 6 hr before drug administration. We developed a method of staircase colorectal distension as a means of obtaining stimulus-response functions over a short period of time. Kappa-opioid receptor agonists, given i.v. in a cumulative dose paradigm, dose-dependently attenuated both the pressor and visceromotor responses to colorectal distension. In addition, all drugs tested also increased response threshold. The rank order of potency of the drugs tested was: CI977 > U69,593 > U50,488 > or = morphine > or = EMD61,753 > ICI204,448. Effective doses of these drugs were antagonized by naloxone, but not by either of two kappa-opioid receptor-selective antagonists (nor-binaltorphimine and 2-(3,4-dichlorophenyl)-N-methyl-N-(1-[3-isothiocyanate phenyl]-2-[1-pyrrolidinyl]ethyl)-acetamide). Acute inflammation of the colon did not lead to changes in the potency of the agonists tested. The present results provide further evidence that kappa-opioid receptor agonists significantly attenuate visceral nociception and, in conjunction with other information, suggest that a peripherally restricted kappa-opioid receptor agonist would be therapeutically effective in relieving visceral pain.

Topics: Acute Disease; Analgesics, Opioid; Animals; Colitis; Colon; Electromyography; Male; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Rectum

Acute inflammation of the sigmoid wall was induced by perendoscopic injection of formalin (50 microliters, 5%) under brief anesthesia in rats. The procedure was followed by behavioral patterns that significantly differed from those in animals injected with isotonic saline instead of formalin. Analysis of the formalin-induced behaviors allowed for the calculation of a pain score that evolved in a biphasic manner along the 3 h of test. The score was dose-dependently reduced by morphine (0.5-4 mg/kg), and the analgesic effect of the largest morphine dose was abolished by naloxone (2.4 mg/kg). These results suggest that formalin into the sigmoid colon is a new model of visceral pain, presumably through direct irritation at injection site and/or localized acute inflammation of the intestinal wall.

Topics: Acute Disease; Animals; Colitis; Disease Models, Animal; Female; Formaldehyde; Morphine; Naloxone; Pain; Pain Measurement; Palliative Care; Rats; Rats, Sprague-Dawley; Sodium Chloride; Viscera