Browsing by Author "Pérez-García, Carmen"

Acute administration of the alpha-2 adrenoceptor agonist clonidine and chronic administration of the alpha2 antagonist yohimbine both inhibit opioid withdrawal signs in experimental models of dependence and also in clinical studies with opiate abusers. There are exceptions to this general rule: restlessness or self-reported abstinence in humans and withdrawal-induced escape behaviour in rodents are resistant to inhibition by acute clonidine. 1-% have explored the effect of the alpha-2 antagonist yohimbine on morphine withdrawal-induced escape behaviour in a mouse model that we have proposed to differentiate between the urge to escape (number of jumps) and non-specific sedative/motor actions (height of jumps). Morphine dependence was induced by s.c. administration of a sustained-release preparation (1 g!kg). Naloxone (1 mg/kg) was injected to precipitate withdrawal jumping 72 hours after morphine injection. Co-treatment with yohimbine dissolved in the tap water (70mgll) decreased the number of jumps upon na{oxone challenge, an effect which did not seem to be related with a sedative or toxic effect of the drug. This result confirms previous data and suggests that yohimbine could prevent the development of opioid dependence being active ta decrease withdrawal-induced escape behaviour. The mechanisms of this action are discussed.

Histamine H3 receptors were first described in the eighties but finally cloned four years ago. They are G-protein coupled, mostly presynaptic, and are involved in the control of the synthesis and/or release of different neurotransmitters both in the central nervous system and the periphery. The availabiliy of specific ligands has permitted the study of potential therapeutic applications of either stimulating or blocking the function of these receptors. There is experimental evidence that drugs targeted at histamine H3 receptors could be beneficial for neurodegenerative diseases such as Alzheimer and Parkinson’s disease, epilepsy, drug abuse and several affective, appetite and sleeping disorders, among others. This review presents recent advances in this field.

Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus–hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the α2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs. Pleiotrophin gene expression was not altered by any treatment; however midkine mRNA levels were increased after chronic treatment with morphine. Chronic administration of yohimbine alone also increased midkine expression levels, whereas yohimbine and morphine administered together exhibited summatory effects on the upregulation of midkine expression levels. The data suggest that midkine could play a role in the prevention of opioid-induced neuroadaptations in hippocampus by yohimbine.

A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These cyclopropanes are useful for the preparation of novel H3 receptor agents.

Lewis and Fischer 344 (F344) rats differ in their physiological and pharmacological responses to a variety of environmental stimuli, which have been partially attributed to endogenous opioid function. Since opioid and a2-adrenoceptor mechanisms are closely related, we have comparatively examined the contribution of both systems to antinociception in female Lewis and F344 rats by the tail-flick method. Basal responses of F344 and Lewis rats were found to be similar, both showing a slight but significant increase in reaction time along the experimental period which was not completely reversed by naloxone. Morphine exhibited a bell-shaped dose–response curve in Lewis rats, these animals being more sensitive than F344 at 1 and 5 mg/kg but less sensitive at 10 mg/kg. Clonidine up to 0.1 mg/kg was more active in F344 rats. The a2-adrenoceptor antagonist yohimbine provoked a higher hyperalgesic effect in Lewis rats and decreased morphine antinociception in both strains. The existence of a balanced contribution of opioid and a2-adrenoceptor mechanisms to control pain transmission in both strains is discussed.