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Aims Combinations of non-steroidal anti-inflammatory drugs (NSAIDs) and cannabinoids are promising because of their potential synergistic effects in analgesia, resulting in a reduction in dosage and minimizing adverse reactions. The analgesic effect of acetylsalicylic acid (ASA), probably due to a central mechanism, also implicates changes in the central monoaminergic system. Therefore, we decided to evaluate the antinociceptive interaction between the CB 1 receptor agonist, HU210, and ASA in tests involving central pain in rats as well as the implication of the central serotonergic system thereon. Main methods The selective CB 1 antagonist SR141716A and the potent cannabinoid agonist HU210 were evaluated alone and in combination with ASA in both algesimetric tests (hot-plate and formalin tests) and for 5-HT activity and 5-HT 2 receptor density and affinity. Key findings ASA or HU210 alone showed a dose-dependent effect in both tests. HU210, at an inactive dose, significantly increased the antinociceptive effect of the sub-active dose of ASA. SR141716A (1.5 mg/kg i.p.) was ineffective per se and failed to modify antinociception induced by the HU210 plus ASA combination in either test. HU210 plus ASA significantly decreased the 5-HIAA/5-HT ratio and the 5-HT 2 receptor density in the frontal cortex, changes not antagonized by SR141716A. Significance The present study provides evidence that mutual potentiation of the antinociceptive effects of HU210 and ASA may, at least partly, depend on serotonergic mechanisms, with an indirect participation of cannabinodiergic mechanism. In conclusion, combinations of low doses of cannabinoids and NSAIDs may be of interest from the therapeutic point of view.

Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, especially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient s compliance. Also incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Finally, recent data strongly suggest that dual inhibitors may have specific protective activity also in neurodegeneration.

The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(-)-2-(3 furylmethyl)-normetazocine] (MR 2266), a kappa-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. The values, expressed in pmol/g tissue, were: control = 2.83 +/- 0.20; paracetamol (100) = 2.60 +/- 0.23; morphine (3) = 2.73 +/- 0.24; paracetamol + morphine = 1.34 + 0.16 (P < 0.05). The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through kappa-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.

1. Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA.

In adult male rats, the intracerebroventricular (i.c.v.) injection of pinacidil, a potassium channel opener, at the doses of 100, 200 or 300 micrograms/rat, dose-dependently reduced the display of the most typical behavioral symptoms (excessive grooming, stretching, yawning, penile erections) induced by the i.c.v. administration of ACTH-(1-24) (4 micrograms/rat). These data indicate that the complex mechanism of the melanocortin-induced behavioral syndrome involves closure of potassium channels in target neurons, and provide further experimental support to the idea that melanocortins are functional antagonists of opioids.

In an experimental condition of hyperthyroidism, obtained by repeated administration of triiodothyronine in adults rats (100 μg/kg/day, sc for 7 consecutive days), there is an increased susceptibility to the convulsant effect of isoniazid (300 mg/kg, ip) and picrotoxin (4 mg/kg, ip). On the other hand, the characteristics of brain [ 3 H] flunitrazepam binding sites are not modified. These data afford further experimental evidence of the influence of thyroid hormones on brain function.

It is recognized that paracetamol undergoes a metabolic transformation to N-arachydonylphenolamine (AM404), a CB(1) receptor ligand and anandamide uptake inhibitor. Using hot-plate and paw pressure tests, we decided to establish whether AM404 may act through opioidergic and serotonergic mechanisms. Thus, we pretreated rats with opioid mu(1) (naloxonazine) and kappa (MR2266) or 5-HT(1A) (NAN-190), 5-HT(2) (ketanserin), and 5-HT(3) (ondansetron) receptor antagonists. We investigated the possible changes in 5-hydroxyindoleacetic acid/serotonin ratio in the frontal cortex and pons. The antinociceptive effect of AM404 (10 mg/kg, intraperitoneally) or paracetamol (400 mg/kg, intraperitoneally) in either test was abolished by naloxonazine or MR2266. Ondansetron prevented AM404 activity; NAN-190 and ketanserin were ineffective. Ketanserin antagonized paracetamol activity; NAN-190 and ondansetron were inactive. AM404 did not change serotonergic activity, while paracetamol decreased serotonin turnover. The diverse antinociceptive potency of the compounds might be explained by the different influence on the serotonergic system, despite a similar involvement of opioidergic one.

Nociceptin/orphanin FQ (N/OFQ) is involved in many behavioural patterns; in particular, it exerts a modulating effect on nociception. Like other proposed antiopiates, nociceptin/orphanin FQ has been shown to have analgesic, hyperalgesic as well as antianalgesic properties. Among the various effects proposed on nociceptive sensitivity at supraspinal level, the antagonistic activity toward morphine analgesia seems to be of interest. Therefore, we decided to investigate whether nociceptin/orphanin FQ and [Arg14, Lys15] nociceptin/orphanin FQ (R-K, a nociceptin analogue) can have the same effect on the analgesia produced by nonopioid analgesics. In this study, we examined the antianalgesic effect of nociceptin/orphanin FQ and its analogue R-K on paracetamol-induced analgesia and evaluated by means of the hot plate test in rats. Nociceptin/orphanin FQ was intracerebroventricularly administered, and, after 5 min, a dose of 400 mg/kg paracetamol was injected intraperitoneally, 30 min before the hot plate test. Nociceptin/orphanin FQ and R-K showed a dose-dependent antagonism on the antinociceptive effect of paracetamol, and the activity of both drugs was significantly reduced by the antagonist [Nphe1] Arg14, Lys15-N/OFQ-NH2 (UFP-101). These data indicate that nociceptin/orphanin FQ and R-K have an antianalgesic effect on the analgesia produced by a nonopioid analgesic drug, like paracetamol, that seems to develop within the brain.

A number of studies have reported that exposure to stress provoked behavioural changes, including analgesia, in rodents. Differences have been observed in these responses to different types of stress and a link between hormones and neurotransmitters proposed. We studied the effect of acute noise stress on nociception and the possible changes in the serotonergic and opioidergic systems in young mice of both sexes. Naloxone pre-treatment was also investigated. Noise stress was produced by a sound source, nociception was measured by the hot-plate test and binding characteristics were evaluated by a radioligand binding technique using membrane preparation from the total frontal cortex. Acute noise stress provoked an antinociceptive effect, associated with an increase in plasma corticosterone levels, a decrease in the number of 5-HT2 receptors in stressed male and female mice and a decrease in the number of mu receptors in both sexes. The behavioural and biochemical effects were antagonized by 1 mg/kg of naloxone. Acute noise stress behaves like other types of stress on nociception. The opioidergic system seems to be involved in this behaviour but also the serotonergic system may play a role. Sex differences were detected in the number of 5-HT2 and mu receptors between male and female mice not subjected to stress, while the percentage decrease in 5-HT2 and mu receptors did not differ significantly between the two sexes.

Nitroglycerin is a nitric oxide (NO) donor which activates nuclei involved in nociceptive transmission following systemic administration. The effect of nitroglycerin on the nociceptive threshold was studied in rats by means of two experimental tests that explore different modalities of pain: the tail-flick test and the formalin test. Nitroglycerin induced a significant reduction in the latency of the tail flick 2 and 4 h after its administration. Similarly, formalin-induced pain-related behaviour increased significantly 2 and 4 h after nitroglycerin administration.

Objective: We investigated the effect of pre-treatment with ondansetron or CP 93129 (a 5-HAT1B agonist) on the antinociceptive activity of paracetamol and the changes in central 5-HT3 receptors induced by paracetamol alone or co-administered with ondansetron. Materials and Subjects: Male Wistar rats (eight per group) were injected with ondansetron (2 and 4 mg/kg s.c.) or CP 93129 (0.5, 1 and 2 mg/kg s.c.) 15 min before paracetamol (400 mg/kg, i.p.). Methods: Pain threshold was evaluated in the hot-plate or in the paw pressure test 30 min after the last treatment. 5-HT3 receptor binding capacity was measured in the frontal cortex, temporal-parietal cortex and midbrain by means of radioligand binding technique. Statistical analysis was done using ANOVA followed by Student-Newman-Keuls test and 2 X 2 factorial analysis when appropriate. Results: Pre-treatment with ondansetron, at doses of 2 and 4 mg/kg, did not affect the antinociceptive activity of paracetamol in the hot-plate test and in the paw pressure test. Paracetamol did not change the characteristics of 5-HT3 receptors in all the areas investigated. Ondansetron (4 mg/kg s.c) per se significantly increased the 5-HT3 receptor number in the areas used, the effect not being modified by co-administration with paracetamol. On the other hand, CP 93129 (2 mg/kg s.c.) significantly prevented the effect of paracetamol in both algesimetric tests used. Conclusions: Our data indicate that 5-HT1B but not 5-HT3 receptors are involved in the antinociceptive effect of paracetamol in our experimental conditions.

Male Wistar rats were treated with ondansetron (1 and 2 mg/kg s.c.), ketanserin (0.2, 1 and 5 mg/kg s.c.) or NAN-190 (1, 3 and 5 mg/kg i.p.) 15 min before acetylsalicylic acid (ASA, 400 mg/kg i.p.), and 30 min thereafter the pain threshold was evaluated. The antinociceptive activity of ASA in the hot-plate test was variously affected by ondansetron, ketanserin and NAN-190: at the highest dose (2 mg/kg s.c.) ondansetron abolished it while ketanserin (5 mg/kg s.c.) significantly reduced it, and NAN-190 (1–5 mg/kg) did not significantly modify the effect of ASA. Binding experiments indicate that both ondansetron and ketanserin completely prevented the decrease in the maximum number of 5-HT2 receptors (Bmax) provoked by ASA. These data indicate that the central antinociceptive activity of ASA is modulated in a different manner by serotonin receptor antagonists, and that 5-HT2 and 5-HT3 receptors may exert a pivotal role in nociception, alone or in association.

Rheumatic diseases are the most prevalent causes of disability in western countries, and non-steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies. However, NSAIDs cause several serious adverse effects, the most important being from gastric injury to gastric ulceration and renal damage. Attempts to develop non-steroidal anti-inflammatory remedies devoid of these shortcomings-especially gastrointestinal toxicity-have followed several strategies. Non-steroidal anti-inflammatory drugs have, therefore, been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression; however, a combination therapy introduces other problems of pharmacokinetics, toxicity, and patient's compliance. More recently, incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity; however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, targeted at the inducible isoform of prostaglandin synthase (COX-2); they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies have raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, a growing body of evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. More recent and puzzling data shows that COX-2 is induced during the resolution of an inflammatory response, and at this point it produces anti-inflammatory (PGD2 and PGF2alpha), but not proinflammatory (PGE2) prostaglandins; inhibition of COX-2 at this point thus results in persistence of the inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The generation of other very important products of the arachidonic acid cascade (besides cyclooxygenase-produced metabolites) is inhibited neither by non-selective nor by COX-2 selective NSAIDs. The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation; indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents. Moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). These data and considerations explain the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases, the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of a more definitive treatment. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium.

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic sistem modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.

Acetylsalicylic acid and morphine are the most widely distributed and most frequently used drugs in the relief of pain, but their analgesic activity has adverse side-effects. Mixtures containing these two drugs are frequently used to relieve mild to moderate pain despite the paucity of relevant experimental evidence so far published. We set out to study the possible antinociceptive effect of a combination of subactive doses of the two drugs in rats. A combination of low doses of acetylsalicylic acid (50 mg/kg i.p.) and morphine (3 mg/kg s.c.) was administered and the pain threshold was evaluated in the hot-plate and formalin tests, and 5-HT2 receptor binding capacity, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in the cortex and pontine areas of the brain. The combination of acetylsalicylic acid and morphine had an analgesic effect in both tests that was associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors in the cortex. These effects were either completely abolished or partially prevented by i.p. pretreatment with naloxone (1 mg/kg i.p.). Our results demonstrate that subactive doses of acetylsalicylic acid and morphine can exert analgesic and biochemical effects when given in combination in the rat and suggest an involvement of serotonergic and opiatergic systems.

The pain-threshold in the hot-plate test and serotonin (5-HT) receptor binding capacity in the cortex and pontine areas of rat brain were studied after intraperitoneal (ip) administration of acetyl salicylate of lysine equivalent to 400 mg/kg of acetylsalicylic acid (ASA). The antinociceptive activity of ASA was prevented by ip pre-treatment with Parachlorophenylalanine (PCPA) at the rate of 100 mg/kg/day for 4 days. PCPA pre-treatment increased the number of 5-HT receptors and abolished the ASA-induced reduction in 5-HT receptor binding capacity in the cortex but did not affect serum salicylate levels. These results provide support for the hypothesis that the antinociceptive action of ASA, at least in the hot-plate test, involves the central serotonergic system.

1. The lysine salt of acetyl salicylic acid (ASA) at a dose equivalent to 400 mg/kg of acetyl salicylic acid (ASA) was intraperitoneally administered in rats. 2. After 30 and 120 min ASA did not modify the number of receptors nor the affinity of [3H] 8-OH-DPAT binding sites in pons and cerebral cortex. On the other hand, the receptor number in the cortex membranes decreased significantly using [3H] ketanserin as ligand, while the receptor number in the pontine membranes did not change. 3. These data support the involvement of central 5-HT receptors in the mode of action of ASA.

The effect of a treatment with L-triiodothyronine (T3) or propylthiouracil (PTU) on the characteristics of benzodiazepine and chloride ion channel binding sites in rat hippocampus and cerebral cortex was studied using a radiolabelled technique. In our experimental conditions, neither hyper- nor hypothyroidism modified number and affinity of [3H]flunitrazepam or [3H]butylbicycloorthobenzoate (TBOB) binding sites. These data indicate that neither benzodiazepine nor chloride ionophore sites of the GABA complex are modified in an experimental condition of dysthyroidism.

The effects of a chronic treatment with L-triiodothyronine (T 3 ; 100 mg/rat/day s.c. for 7 days) or with propylthiouracil (PTU; 50 mg/rat/day for 35 days by stomach tube) on the characteristics of alpha 1 , alpha 2 , beta, imipramine and GABA binding sites in different brain areas of the adult rat have been studied. T 3 -treatment caused an increase in the number of [ 3 H]dihydroalprenolol and a decrease in the number of [ 3 H]muscimol binding sites in the cerebral cortex. PTU-treatment caused a decrease in the number of [ 3 H]prazosin, [ 3 H]yohimbine and [ 3 H]dihydroalprenolol binding sites in the cerebral cortex, while the number of [ 3 H]imipramine binding sites was reduced in the cerebral cortex and hypothalamus, and increased in the hippocampus. Affinity constants were never modified. Concurrent experiments showed that the “in vitro” addition of T 3 and PTU did not influence the binding of any of the ligands employed to control rat brain membranes. The present data further support the view that neurotransmission in the CNS is influenced by the thyroid status.

The effects of various cations on the specific binding of dopamine to its recognition sites are described using guinea-pig heart membranes as a substrate. Only CaCl2 provoked a dose-dependent facilitatory effect, while KCl, NaCl and MgCl2 acted in the opposite sense. Moreover, Na2EDTA also had an inhibitory effect on dopamine binding and completely prevented the facilitatory action of CaCl2 on3H-dopamine binding. This effect is partially counteracted by trifluoperazine but unaffected by verapamil. We can conclude from this that calcium seems to be essential to optimizing3H-dopamine binding to cardiac membrane preparations.

A series of 2-(acylamino)benzenesulfonamides was prepared. Their anti-convulsant effects on two convulsives (electro-shock and pentetrazol) were studied. The structure/effect relationships were compared with those of a series of isomeric 2-aminobenzenesulfon-N-acylamides and of 2-nitrobenzenesulfon-N-acylamides. The possible influence of pKa and log P was examined. Sulfonamide mit Wirkung auf das Zentralnervensystem, 6. Mitt. Es wurde eine Reihe von 2-Acylaminobenzolsulfonamiden synthetisiert und ihre antikonvulsive Wirkung untersucht (Elektroschocktest, Pentetrazolschock). Die Struktur-Wirkung-Beziehungen wurden im Vergleich zu einer Reihe von isomeren 2-Aminobenzolsulfon-N-acylamiden und von 2-Nitrobenzolsulfon-N-acylamiden betrachtet. Der Einflus, den zwei physikalisch-chemische Parameter, der pKa und der Log P, darauf ausuben konnen, wurde untersucht.

Summary Urethane-anesthetized rats were bled to otherwise irreversible haemorrhagic shock (mean arterial pressure=18–25 mmHg) and then i.v. treated with ACTH-(1-24) (160 μg/kg) or saline. In comparison with sham-operated, non-shocked controls, bled rats showed a significant reduction in B max for [ 3 H]Dihydroalprenolol and [ 3 H]Dihydroergocryptine in heart ventricles, and for [ 3 H]Yohimbine in spleen capsule. Neither the K d of heart and spleen adrenoceptors nor the B max or K d of brain adrenoceptors were affected. Treatment with ACTH-(1-24) restored to normal the B max for [ 3 H]Dihydroalprenolol in heart ventricles, and for [ 3 H]Yohimbine in the spleen capsule. These data indicate that the anti-shock effect of ACTH-(1-24) in bled rats is associated with a restoration of heart and spleen responsiveness to adrenergic stimuli.

In adult male rats, castration induces a progressive decrease in the number of [3H]imipramine binding sites in the cerebral cortex and hypothalamus, and a progressive increase in the hippocampus. Testosterone completely prevents this effect of castration, but has no effect on the characteristics of brain imipramine binding sites in intact, non-castrated animals. These data suggest that threshold levels of testosterone are necessary for the maintenance of a normal number of imipramine binding sites in the rat brain, but that these binding sites are not modified by excess testosterone.

Extensive morphological and biochemical investigations have been devoted to the neurological effects induced by zinc deficiency since this trace metal has been recognized as essential during neurogenesis for a normal development of the central nervous system (for a review see Dreosti, 1984; Sandstead, 1984). Less attention, however, has been addressed to the neurological consequences of an increased supplementation of zinc.In this context it must be mentioned that the peripheral acute administration of zinc intravenously or intraperitoneally in doses up to 100 mg/kg has not been associated with the production of convulsive seizures or other behavioral abnormalities (Ebadi et al., 1984). From these results, it has been concluded that after parenteral acute administration, zinc does not induce any effect since: a) by binding to circulating proteins such as albumin, gamma-globulins and probably other proteins (Prasad, 1979; Disilvestro and Cousins, 1983; Ebadi et al., 1984) it is unavailable to the CNS; b) it exists mostly in bound form in the brain (Ebadi et al., 1984). In an attempt to gain more information on the behavioral effects induced by peripheral supplementation of zinc, we obtained the same results with regard to the lack of convulsions. In our experience, however, acute intraperitoneal injections of zinc sulphate or zinc acetate induced, in a dose-related fashion starting from 50 mg/kg, a sedative effect which caused a 50% mortality rate within six hours at 200 mg/kg. Based on physiological considerations and on our present observations, it seems more likely to suggest that zinc enters the brain but does not reach concentrations sufficient to induce epileptic seizures which can be elicited by its intracerebroventricular administration (Itoh and Ebadi, 1982; Ebadi et al., 1984). The levels of zinc tested in six brain areas of these rats did not show significant variation in comparison with controls, whereas zinc plasma levels were found to be increased. Time-course determinations of zinc in blood and brain areas are needed in order to explain these data. On the other hand, there are several question marks concerning the machinery which regulates zinc homeostasis in the brain. Thus, it is difficult to explain cerebral zinc uptake and turnover (Kasarskis, 1984) and the unaltered zinc levels in the brain of zinc deficient rats (Wallwork et al., 1983; Kasarskis, 1984) as well as the mechanisms which regulate the bound/free zinc ratio.

Apomorphine and LY 171555, but not SKF 38393 displaced [ 3 H]Dopamine binding to membranes of guinea-pig heart. Domperidone and l-sulpiride but not SCH 23390 competitively antagonize the [ 3 H]Dopamine binding performed with 100 μM cold dopamine as displacer. In conclusion the DA 2 receptor agonists and antagonists used are able to interfere with the receptors labelled by [ 3 H]Dopamine in cardiac muscle.

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test. ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration. Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA. The serum salicylate concentrations were not affected by pretreatment with naloxone. These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.