Methisergide Selective Inhibition of Opioid Acute Physical Dependence in Isolated Tissues

Anna      Capasso

doi:10.2174/157340608784872253

Abstract

Dependence can be induced and measured in vitro by using guinea-pig ileum. Tissues from untreated animals, after a brief exposure to opioids, show a strong naloxone-induced contracture indicating that the cellular mechanisms of dependence may occur very rapidly following occupation of receptors and that these mechanisms operate within the myenteric plexus. The characteristics of dependence development and the precipitation of withdrawal by naloxone in the guinea-pig ileum are very similar to those of acute dependence in experimental animals and man. Several observations support the hypothesis that brain serotoninergic system has been widely implicated in many of the pharmacological effects of opioids. Manipulations that alter the activity of serotonin in the central nervous system (CNS) modify the effects of morphine. Furthermore, chronic administration of morphine to mice has been reported to increase turnover of 5-HT turnover in the brain thus confirming a strong link between serotoninergic and opioid system. Therefore, the effects exerted by methisergide, a blocker of serotonin receptor, on the acute opiate withdrawal was investigated in vitro. Following a 4 min in vitro exposure to the opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone (80% of contraction vs acetylcholine control). Methisergide (10-7-5x10-7-10-6 M) treatment before or after the opioid agonists was able to respectively prevent or reverse the naloxone-induced contraction in isolated guinea pig ileum exposed to μ(morphine and DAMGO) opiate agonists in a concentration-dependent fascion whereas the k (U50-488H) opiate agonist significantly increased opiate withdrawal. The results of the present study confirm an important functional interaction between the serotoninergic and opioid system.

Keywords: Serotonin, opioid, withdrawal, guinea-pig ileum

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