The experiments presented here demonstrate an aspecific effect of the benzodiazepine derivative flunitrazepam (FNZ). It differs in sites and mechanisms of action, both from benzodiazepine (BZ) specific effects on gamma-aminobutyric acid (GABA) blocking transmission via central BZ receptors and from BZ effects mediated by peripheral BZ receptors. The aspecific effect of FNZ can suitably be examined on isolated and identified neurons of the mollusc Lymnaea stagnalis (pond snail). The physiological sites of action are outside the synaptic zone, on the neuron somatic membrane and affect 'intrinsic' properties of membrane, including calcium, calcium-activated potassium and chloride channels. The aspecific FNZ effect exerts an influence on the metabolism of the cell by decreasing the permeability of the calcium channel, diminishing the excitability of the neuron membrane, and hyperpolarizing the cell, thus potentiating the specific effect of FNZ. The senile alterations of the neuron function intensify the aspecific effects of FNZ to such a degree that it must be taken seriously in consideration in anesthesia of elderly patients.

Journal Article↗

PubMedDate not supplied

Susceptibility of dopamine D5 receptor targeted mice to cysteamine.

BACKGROUND: Recently we demonstrated that gastric mucosa of rats can synthesize, store and release dopamine. Out of five different subtypes, mRNA of D5 (=D1b) dopamine receptor is very abundant in the gastric epithelium. D1 receptor selective dopamine agonists have been shown to protect against experimental gastro-duodenal lesions. AIMS: To test the hypothesis that protective effects of dopamine involve D5 receptors, mucosal lesions were induced in D5 receptor deficient (KO) and wild-type (WT) mice using cysteamine. Morphology and gastric acid secretion of D5 KO mice were also studied. METHODS: Single doses of 600 mg/kg, 300 mg/kg cysteamine or vehicle were administered subcutaneously to fasted animals. After 24 h, number and severity of gastro-duodenal lesions were analyzed. Basal and histamine-induced maximal gastric acid output were measured by a stomach-sac wash-through method. RESULTS: All the KOs in the 600 mg/kg cysteamine group died within 4 h showing symptoms of toxicity while three out of four WTs survived (P<0.05). Mortality after 300 mg/kg cysteamine was significantly higher in KOs versus the WTs: 6/14 versus 2/11, P<0.05. Gastric lesion-index was also significantly higher in KOs (median, middle quartile): four (3-9) versus 0 (0-0), P<0.05. Duodenal lesions did not develop from this single dose of cysteamine in either genotype. Basal and histamine-induced maximal gastric acid output were comparable in the two genotypes. CONCLUSIONS: This study demonstrates that loss of D5 receptor causes mucosal vulnerability and increased toxicity of cysteamine in genetically manipulated mice. Thus, D5 receptor subtype is indeed likely to be involved in protective effects of dopamine in the stomach.

Animals↗

PubMedDate not supplied

Influence of spatial orientation of the C-6-OH group in ring C of morphine derivatives on opioid activity.

The effect of epimerization on agonist and antagonist activities of morphine and dihydromorphine, and those of their N-allyl, -propyl and -cyclopropylmethyl derivatives, were studied in rat tail flick, hot plate and mice hot plate and in isolated guinea-pig ileum assays, respectively. Using the rat tail flick, hot plate and mice hot plate tests, isomorphine and dihydroisomorphine were observed to produce dose-dependent, naloxone-reversible agonist (antinociceptive) actions, in a similar dose range as their parent molecules (relative potencies: 0.6-1.9). Also, these compounds produced agonist activities in isolated tissue preparations in a naloxone-reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorphine failed to produce antinociceptive activities in the rat tail flick test, they proved to be strong agonists in the guinea-pig ileum experiments, although the Ke values of naloxone were 5-6 times higher against these compounds than against their N-CH3 counterparts. Both the agonist and antagonist activities of the N-cyclopropylmethyl derivatives were found to be most potent in the guinea-pig ileum. The epimerization of morphine and dihydromorphine and their N-substituted derivatives evoked only slight changes in opioid activities in vitro. In vivo, merely the allyl substitution on nitrogen influenced the antagonist activities of epimer pairs. In contrast, substantial changes in opioid profile were observed when N-methyl was replaced by allyl-, propyl- or cyclopropylmethyl. Changes performed this way evoked, on the one hand, an enhancement of the affinities of compounds to mu-receptors, with simultaneous loss of intrinsic efficacy at these receptors, and, on the other hand, promoted the appearance of an agonist profile on a distinct (kappa) opioid receptor.

Analgesia↗