Morphine as a drug for stress ulcer prevention and healing in the stomach

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Abstract

Morphine pretreatment protects against stress-induced gastric ulceration, however, the exact mechanism is still undefined. Interestingly, the effect of morphine on ulcer healing has not been investigated. In this report, we would like to study these effects in a defined stress ulcer model and to delineate a new implication for morphine to promote stress ulcer healing in rats. Our study showed that cold-restraint stress for 3 h induced hemorrhagic lesions and increased myeloperoxidase activity in the gastric mucosa. Stress also reduced the dimension of layer of periodic acid-Schiff reagent-stained cells in the gastric mucosa by about 50%. Morphine pretreatment (2 or 8 mg/kg, given intraperitoneally) at the time of stress dose-dependently reversed stress-induced gastric ulceration, increase of myeloperoxidase activity and reduction of thickness of mucus-stained cells in the gastric mucosa. Morphine treatment after stress (given at the end of a 3-h stress and also at 3 h thereafter) increased ulcer healing by reducing the ulcer size measured 24 h later. Such action was blocked by naloxone (8 mg/kg) given intraperitoneally 15 min before morphine treatment. Morphine also increased the number of cell proliferation and dimension of layer of cells stained for mucus but not the number of microvessels in the gastric mucosa. Moreover, the number of apoptotic cells was less evidenced in the morphine-treated rats. This study reports for the first time that morphine not only prevents stress ulceration but also promotes healing of stress ulcer through a defined mechanism.

Introduction

It has been suggested that endogenous opioids released during stress may attenuate the pathological effects of stress. Indeed, morphine treatment prior to cold-restraint stress reduced ulcer severity (Glavin, 1985). It was postulated to be due to the activation of kappa opioid receptor (Ray et al., 1993) and induction of prostaglandin production in the gastric mucosa (Ferri et al., 1983). However, blockade of the opioid receptor gave controversial effects. It was reported that opioid receptor antagonists could worsen gastric ulceration Glavin, 1985, Arrigo-Reina and Ferri, 1980. Other report showed that these blockers protected against the formation of stress ulcer in the stomach Morley et al., 1982, Dai and Chan, 1983. How exactly opioid receptor involves in stress ulceration and the mechanisms underlying these actions are yet to be defined. Moreover, there is no report concerning the action of morphine on ulcer healing after ulcer is formed. This action could be equally important as far as the clinical implication for morphine is concerned because patients, especially after surgery, are under different kinds of stress conditions in which complications such as gastric injury and bleeding would likely occur (McGuigan, 1991). Such therapeutic indication is interesting and requires further study. We aim to study whether morphine is effective to prevent ulceration and promote ulcer healing in the stomach in stress conditions. These actions, if any, could likely be due to the strengthening of the defensive mechanisms and increasing the repair system, respectively, in the gastric mucosa.

Section snippets

Animals

Male Sprague–Dawley rats, weighing 200–230 g, were obtained from the Laboratory Animal Unit of the University of Hong Kong. The animals were housed in cages with wide mesh wire bottoms to prevent coprophagy and fed a standard laboratory diet and given free access to tap water. The cages were kept in a room with controlled temperature (22±1 °C), relative humidity (65–70%) and day/night cycle (12:12 light/dark). The protocols of the following experiments were approved by the Committee on the Use

Effects of morphine pre- and posttreatment on stress-induced gastric mucosal damage and its influence by naloxone pretreatment

Cold-restraint stress for 3 h markedly induced gastric mucosal damage together with severe hemorrhage in the stomach. Pretreatment with morphine at doses of 2 or 8 mg/kg dose-dependently and significantly reduced the severity of mucosal damage (Fig. 1A). Stress significantly also increased the mucosal myeloperoxidase activity (Table 1), and morphine pretreatment partially reversed such action (Table 1). The lesion size was similar at 24 h later after a 3-h stress (immediately after a 3-h

Discussion

In this study, the antiulcer effect of morphine pretreatment was confirmed and it was found to be in a dose-dependent manner. Cold-restraint stress induced severe hemorrhagic lesions together with a mark increase in myeloperoxidase activity. This finding may indicate that stress ulceration is a neutrophil-dependent ulcerogenic process, because myeloperoxidase is a marker for neutrophil infiltration during inflammation in the stomach Chow et al., 1997, Tepperman et al., 1991. The increase of

Acknowledgements

We would like to thank the technical assistance of Miss Yu Y. Hang and Mr. C.P. Mok and also the financial support of the University of Hong Kong and Hong Kong Research Grant Council (HKU 7281/02M).

References (28)

  • A. Allen et al.

    Adherent and soluble mucus in the stomach and duodenum

    Dig. Dis. Sci.

    (1985)
  • A. Allen et al.

    The role of mucus in the protection of the gastroduodenal mucosa

    Scand. J. Gastroenterol.

    (1986)
  • H.G. Augustin et al.

    Ovarian angiogenesis, phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression

    Am. J. Pathol.

    (1995)
  • S.A. Bhounsule et al.

    Gastric cytoprotective effect of morphine is probably not mediated by mμ-receptors

    Arch. Int. Pharmacodyn. Ther.

    (1994)
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