naloxone and Peptic-Ulcer

The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the mu-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Female; Fungi; Indomethacin; Isoenzymes; Male; Membrane Proteins; Molecular Structure; Naloxone; Pain Measurement; Peptic Ulcer; Peroxidases; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Pyrazolones; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Recombinant Proteins; Sulfoxides

In Wistar rats of both sexes stress(restraint)- and drug (indomethacin)-induced gastric, as well, as cysteamine-induced duodenal ulceration was treated by morphine and nalorphine, given either alone or in combination. Neither morphine nor nalorphine had a significant anti-ulcerogenic effect. In contrast, the combined morphine + nalorphine treatment showed a highly significant anti-ulcerogenic action in the case of gastric ulceration but it was ineffective on duodenal ulcer formation. It seems that the chi and sigma endogenous opiate receptors play a significant role in the anti-ulcerogenic effect, while the mu receptors are involved to a considerably lesser degree. Moreover, the experimental results strengthen the view that gastric and duodenal ulceration are two different pathological entities and that ulcer formation is only a common consequence.

Topics: Animals; Cysteamine; Female; Indomethacin; Male; Morphine; Nalorphine; Naloxone; Peptic Ulcer; Rats; Rats, Inbred Strains; Receptors, Opioid; Restraint, Physical

Activities of lysosomal hydrolases have been evaluated in relation to indomethacin and naloxone, using purified lysosomal fractions from rat intestinal mucosa. Indomethacin treatment significantly decreased (p less than 0.001) lysosomal enzyme activities in purified lysosomes, while an increase in the activities was observed in intestinal homogenates. However, indomethacin could not affect lysosomal system in animals pretreated with naloxone, thereby establishing that naloxone neutralises the effect of indomethacin.

Topics: Animals; Hydrolases; Indomethacin; Intestinal Mucosa; Lysosomes; Male; Naloxone; Peptic Ulcer; Rats; Rats, Inbred Strains; Reference Values

On the basis of our investigations it seems that: The opiate antagonist naloxone in a dose of 5.0 mg/kg has a significant protective effect in stress-ulcer model in the rat; No such effect was seen in drug (indomethacin) or cysteamine induced (duodenal) ulcer models; The interaction of naloxone with indomethacin seems to show a sex-difference.

Topics: Animals; Cysteamine; Disease Models, Animal; Female; Gastric Mucosa; Indomethacin; Male; Naloxone; Peptic Ulcer; Rats; Rats, Inbred Strains; Receptors, Opioid; Sex Factors; Stress, Physiological