Effect of natural and synthetic polyamines on ethanol intake in UChB drinker rats.

Because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic agents have attracted attention for the treatment of ethanol abuse and dependence in preclinical and clinical studies. In the present study, we investigated the effect of pharmacological doses of the natural polyamines putrescine, spermine, and spermidine and the synthetic polyamine N,N'-bis-(3-aminopropyl)cyclohexane-1,4-diamine (DCD) on alcohol consumption in a free-choice paradigm carried out in genetically high-ethanol-consumer UChB rats. Short 3-day treatment with either polyamine, administered p.o., significantly reduced ethanol intake without modifying water and food intakes. Neither polyamine was able to increase markedly blood acetaldehyde in rats submitted to a standard challenge dose of ethanol, to rule out a disulfiram-like effect. Besides, blood ethanol disappearance after a test dose of ethanol was not affected by the synthetic polyamine DCD. Long-term treatment with DCD dose-dependently reduced ethanol intake in UChB rats without producing any observable effect on overt behavior, food consumption, and total fluid intake. The present results indicate that pharmacological doses of polyamines can reduce ethanol consumption in genetically drinking rats without producing significant side effects, suggesting that modulation of brain N-methyl-d-aspartate receptors by polyamines could represent a suitable strategy to reduce appetite for ethanol. However, caution must be exercised in interpreting the results because polyamines can also affect neuronal excitability by acting at other receptor targets, such as AMPA and kainate receptors, as well as at some voltage-dependent ion channels.

A new polyamine derivative, a structural analog of spermine, with in vivo activity as an inhibitor of ethanol appetite.

This report describes the design and synthesis of the synthetic polyamine DCD (N,N'-bis-(3-aminopropyl)cyclohexane-1,4-diamine, tetramethanesulfonate), a structural analog of spermine, and its in vivo activity as an inhibitor of alcohol consumption in a free-paradigm carried out on genetically high-ethanol-consuming UChB rats. After acute treatment with DCD (daily single dose, 20 mg/kg, p.o., 3 days), a 19% decrease in ethanol intake was obtained, without affecting the levels of food and water intake. After chronic treatment (daily single dose, 20mg/kg, p.o., 60 days) a decrease of up to 60% in ethanol intake with respect to the basal period was provoked; this effect was significantly maintained during the post-treatment period and, according to the data obtained from the determination of acetaldehyde levels in blood, was not related to a possible disulfiram-like effect. The design of this new compound was carried out using molecular modeling techniques, with the structures of natural polyamines (putrescine, spermidine, and spermine) and biosynthetically related diamines (1,3-diaminopropane; DAP) as templates. These polyamines have shown activity as inhibitors of ethanol appetite in the same experimental model.

Analgesic and behavioral effects of amphetamine enantiomers, p-methoxyamphetamine and n-alkyl-p-methoxyamphetamine derivatives.

The analgesic effects of (+)- and (-)-amphetamine (AMPH), (+/-)-p-methoxyamphetamine (MA), (+/-)-N-methyl-p-methoxyamphetamine (MMA) and (+/-)-N-ethyl-p-methoxyamphetamine (EMA) were compared using two different algesimetric tests in rats. In the formalin test, (+)-AMPH elicited significant antinociception at doses of 0.2, 2 and 8 mg/kg (i.p.); (-)-AMPH was active at 2 and 8 mg/kg, but not at 0.2 mg/kg; MA elicited very potent and long-lasting antinociception; MMA was less active than MA; EMA showed significant effects only at doses of 2 and 8 mg/kg. In the C-fiber evoked nociceptive reflex assay, i.v. (+)- and (-)-AMPH were ineffective, but the methoxy derivatives showed a similar pattern of action combining inhibitory and excitatory actions. To clarify apparent discrepancies between both algesimetric tests, some behavioral motor performance tests were carried out. These tests confirm the motor stimulatory properties of (+)-AMPH, not shared by the methoxylated amphetamine derivatives. The three methoxy derivatives elicited some stereotypies related to dopaminergic activation such as grooming behavior. (+)-AMPH was also the only drug to increase the acquisition of CARs while MA and EMA were without effect. Avoidance conditioning was seriously impaired in rats injected with MMA. This conditioned behavior can be related to the significant decrease of spontaneous motor activity observed with this drug. In conclusion, the introduction of a para-methoxy group strongly increases the analgesic effects of amphetamine without its stimulatory behavioral effects. The introduction of N-alkyl substituents decreases the analgesic potency of MA.

Effect of the synthetic polyamine N,N'-bis-(3-aminopropyl) cyclohexane-1,4-diamine (DCD) on rat spinal cord nociceptive transmission.

In rats submitted to a C-fiber reflex response paradigm, intravenous (i.v.) administration of 2.5, 5 and 10 mg/kg of the synthetic polyamine N,N'-bis-(3-aminopropyl) cyclohexane-1,4-diamine (DCD) dose-dependently reduced both the integrated C reflex responses and wind-up activity. Inhibitory effects of the polyamine on spinal cord nociceptive transmission are likely to be consequence of blockade by extracellular DCD of NMDA receptor channels localized in dorsal horn neurons, although modulatory actions at supraspinal level and at other ion channels could also be possible.

Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats.

To study the antinociceptive synergy resulting from the combination of opioid receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists on neuropathic pain, an isobolographic analysis of equianalgesic combinations of ketamine with methadone or morphine was performed in rats with mononeuropathy produced by placing four constrictive ligatures around the common sciatic nerve. Two weeks later, the antinociceptive effect of subcutaneous administration of the drugs alone or combined was evaluated by using the paw pressure test. Drugs and their combinations produced dose-dependent antinociception. Combinations produced synergy of a supra-additive nature in the neuropathic paw, but only additive antinociception in the normal paw. The ketamine/methadone combination was more effective to produce antinociception in the neuropathic paw than was the ketamine/morphine association, as revealed by the lower ED25. The results indicate supra-additive synergy between NMDA receptor antagonists and opioids, especially methadone, to produce antinociception in experimental neuropathy.

Synergistic antinociceptive effects of ketamine and morphine in the orofacial capsaicin test in the rat.

BACKGROUND: The clinical efficacy of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine for treating orofacial pain has already been reported. Side effects related to psychotomimetic disturbances, however, limit ketamine use as an analgesic. Theoretically, this limitation could be minimized by using low doses of ketamine in combination with other analgesics. In the present study, the potential synergistic antinociceptive interaction between ketamine and morphine in the orofacial capsaicin test in rats was investigated. METHODS: Male Sprague-Dawley rats were subcutaneously injected with solvent, ketamine, morphine, or combination of both drugs. Thirty minutes later, the orofacial capsaicin test was performed by injecting of 1.5 microg/25 microl of a capsaicin solution into the vibrissa pad. Animal behavior was recorded on videotape and analyzed off-line. The total time spent on rubbing-scratching nociceptive behavior during a period of 42 min was measured. RESULTS: Subcutaneously administered ketamine (0.4, 1.25, 4, 12.5 mg/kg), morphine (0.5, 1, 2, 4 mg/kg) and ketamine + morphine (0.20 + 0.12, 0.40 + 0.24, 0.80 + 0.49, 1.61 + 0.97, 3.21 + 1.94 mg/kg) reduced the rat facial rubbing-scratching behavior in a dose-dependent manner. Isobolographic analysis showed that the ketamine + morphine association inhibited the studied behavior in a superadditive manner. CONCLUSIONS: These results indicate that ketamine and morphine have antinociceptive effects on the orofacial capsaicin test. Furthermore, their combination produces synergistic antinociception. It is therefore suggested that, used together, ketamine and morphine might be clinically efficient at lower doses than those currently used when administered separately. This could provide a useful strategy for the clinical management of orofacial pain.

Revisión de las relaciones entre endorfinas y esquizofrenia / Review of the relationships between endorphins and schizophrenia

Hemos hecho una revisión concerniendo la teoría de una posible disfunción de los sistemas endorfínicos como factor etiológico de las sicosis endógenas de tipo esquizofrénico. Encontramos información contradictoria clínica y experimental de la cual no es posible extraer una conclusión definida, acerca de cual es la alteración específica presente en la esquizofrenia y sus diferentes manifestaciones. Sin embargo, los resultados terapéuticos y las líneas de investigación que se siguen hoy en día, ofrecen nuevas perspectivas para aclarar los mecanismos biológicos alterados en esta enfermedad, así como la esperanza de desarrollar recursos terapéuticos más específicos. Se proponen las modificaciones que habría que tener presente en nuevas investigaciones en este campo