Ruolo del sistema colinergico e dei canali del potassio nel meccanismo d'azione del (-)-linalolo quale analgesico

Per caratterizzare ulteriormente il profilo antinocicettivo del (-)-linalolo, abbiamo studiato il suo effetto nell'hot-plate e nel formalin test. Inoltre, per determinare il possibile coinvolgimento del sistema colinergico, abbiamo testato gli effetti dell'atropina e della pirenzepina, un antagonista selettivo dei recettori M1 muscarinici sull'antinocicezione indotta dal (-)-linalolo

Effetti del (-)-linalolo sull'iperalgesia termica indotta dalla carragenina e dal L-glutammato

Una serie di studi condotti nei nostri laboratori hanno dimostrato che il (-)-linalolo, l'enantiomero naturale presente in molti oli essenziali, possiede effetti antinfiammatori ed antinocicettivi in differenti modelli animali

Cyclopentenyl ethylamines active on CNS

Two new cyclopentenylethylamines were prepared and were submitted to a pharmacological screening together with some others previously described and now reprepared. All compounds exhibited different degrees of depressive activity on CNS and good analgesic activity. Compound 5, bearing a phenyl group on the carbon atom to which the amino group is connected, appears rather interesting being the most active as analgesic and the least toxic. Compounds 2 and 3 are able to antagonize in a certain degree lethal doses of physostigmine and also, respectively, of pentylenetetrazole and strychnine

Evaluation of the vehicle effect on release of diphenhydramine hydrochloride from topical formulations: in vitro and in vivo preliminary studies

Diphenhydramine hydrochloride (DPH) is a histamine H1-receptor antagonist, widely used as antiallergic, antiemetic and antitussive drug in many pharmaceutical preparations. The aim of this study was to evaluate the vehicle effect on in vitro diffusion of DPH from new five topical formulations: microemulsion, microemulsion+silica, Na Alginate emulgel, Carbopol cream and hydroxyethylcellulose gel

Synthesis and CNS activities of pyridopyrazinone and pyridodiazepinone derivatives

New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10 and pyrido-diazepine 20a,20b skeletons were synthetized and biologically investigated. The compounds, preliminarily tested on explorative, muscle relaxing, antinociceptive, spontaneous motor activities and influence on the narcotic effect of Evipan, revealed interesting CNS depressant and analgesic activities. The pyrido[2,3-e]pyrrolo[1,2-a]pyrazine structure of 7 appeared the most promising for analgesic and neuroleptic activities. The above compounds were assayed also for their capacity to inhibit DNA synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of inducing a significant inhibition

Synthesis and pharmacological activity of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones

A new series of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones 4a-g have been synthesized and tested for their anti-inflammatory and analgesic properties. Among the tested compounds, only 4f at 1 mmole/Kg showed antiinflammatory activity that was comparable with that of indomethacin (5 mg/Kg) though of shorter duration. Compounds 4a, 4e and especially 4g at 0.2 mmoles/Kg displayed relevant analgesic activity, 4g being the most potent derivative in the writhing test. Compounds 4c and 4g were found to possess analgesic activity also in the hot plate test

Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system

Ethanol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered to be responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. However, acetaldehyde (ACD), the first metabolite of EtOH, has been classically considered to be aversive and useful in the pharmacological therapy of alcoholics. Here we show that EtOH-derived ACD is necessary for EtOH-induced place preference, a pre-clinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH-increased microdialysate dopamine (DA) levels in the rat nucleus accumbens and that this effect is mimicked by intra-ventral tegmental area (VTA) ACD administration. Furthermore, in vitro, ACD enhances VTA DA neuronal firing through action on two ionic currents: reduction of the A-type K+ current and activation of the hyperpolarization-activated inward current. EtOH-stimulating properties on DA neurons are prevented by pharmacological blockade of local catalase, the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in-vivo and in-vitro evidence for a key role of ACD in the motivational properties of EtOH and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well-known peripherally originating aversive properties. Careful consideration of these findings could help in devising new effective pharmacological therapies aimed at reducing EtOH intake in alcoholics

(−)-Linalool inhibits <i>in vitro</i> NO formation: probable involvement in the antinociceptive activity of this monoterpene compound

Recent studies performed in our laboratory have shown that (−)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory, antihyperalgesic and antinociceptive effects in different animal models. The antinociceptive and antihyperalgesic effect of (−)-linalool has been ascribed to the stimulation of the cholinergic, opioidergic and dopaminergic systems, to its local anaesthetic activity and to the blockade of N-Methyl-d-aspartate receptors (NMDA). Since nitric oxide (NO) and prostaglandin E2 (PGE2) play an important role in oedema formation and hyperalgesia and nociception development, to investigate the mechanism of these actions of the (−)-linalool, we examined the effects of this compound on lipopolysaccharide (LPS)-induced responses in macrophage cell line J774.A1. Exposure of LPS-stimulated cells to (−)-linalool significantly inhibited nitrite accumulation in the culture medium without inhibiting the LPS-stimulated increase of inducible nitric oxide synthase (iNOS) expression, suggesting that the inhibitory activity of (−)-linalool is mainly due to the iNOS enzyme activity. In contrast, exposure of LPS-stimulated cells to (−)-linalool failed, if not at the highest concentration, both in inhibiting PGE2 release and in inhibiting increase of inducible cyclooxygenase-2 (COX2) expression in the culture medium. Collectively, these results indicate that the reduction of NO production/release is responsible, at least partially, for the molecular mechanisms of (−)-linalool antinociceptive effect, probably through mechanisms where cholinergic and glutamatergic systems are involved

Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol

Since Chevens’ report, in the early 50&#39;s, that his patients under treatment with the aldehyde dehydrogenase inhibitor, antabuse, could experience beneficial effects when drinking small volumes of alcoholic beverages, the role of acetaldehyde (ACD) in the effects of ethanol has been thoroughly investigated on pre-clinical grounds. Thus, after more than 25 years of intense research, a large number of studies have been published on the motivational properties of ACD itself as well as on the role that ethanol-derived ACD plays in the effects of ethanol. Accordingly, in particular with respect to the motivational properties of ethanol, these studies were developed following two main strategies: on one hand, were aimed to challenge the suggestion that also ACD may exert motivational properties on its own, while, on the other, with the aid of enzymatic manipulations or ACD inactivation, were aimed to test the hypothesis that ethanol-derived ACD might have a role in ethanol motivational effects. Furthermore, recent evidence significantly contributed to highlight, as possible mechanisms of action of ACD, its ability to commit either dopaminergic and opioidergic transmission as well as to activate the Extracellular signal Regulated Kinase cascade transduction pathway in reward-related brain structures. In conclusion, and despite the observation that ACD seems also to have inherited the elusive nature of its parent compound, the behavioral and biochemical evidence reviewed points to ACD as a neuroactive molecule able, on its own and as ethanol metabolite, to exert motivational effects

Effect of vehicle on Diclofenac sodium permeation from new topical formulations: <i>in vitro</i> and <i>in vivo</i> studies

In this study the effect of vehicle on in vitro diffusion of diclofenac sodium (DS) from new different formulations such as Carbopol gel (A), Sodium lauryl sulphate cream (B) and Carbopol cream (C) was evaluated with Franz diffusion cells using hydrophilic and hydrophobic synthetic membranes. The commercial formulation Voltaren® Emulgel was used as reference. Furthermore, the in vivo efficacy of topical formulations was studied in the carrageenan-induced edema and hyperalgesia, whereas the antinociceptive effect was evaluated on thermal pain threshold in rat paw. The flux of DS across hydrophilic membranes showed this rank order: Control ≈ C > A ≈ B. On the other hand, the diffusion rate of DS across hydrophobic membranes resulted in the following order: Control > B > A ≈ C; this suggested a lower interaction between the vehicles and these membranes. The in vivo results indicated that the prepared formulations failed in the inflammatory tests to reduce the development of edema. Nevertheless, treatment with B formulation inhibited the development of acute hyperalgesia induced by carrageenan, and elicited a significant increase in paw withdrawal latencies whereas other formulations were ineffective. The results obtained in this study suggest that Sodium lauryl sulphate cream might be useful in local pain conditions and may be an effective alternative to the presently used systemic routes