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ABSTRACT: It is now well established that major depression is accompanied and characterized by altered responses of the immune-inflammatory system. In this study we investigated the pro-inflammatory activation of monocytes isolated from depressed patients as a parameter not influenced by such confounds as the time of day, the nutritional and exercise status or the age and gender of patients. Monocytes from depressed patients and from healthy controls were isolated in vitro; after 24-h incubation under basal conditions, cells were exposed for 24-h to 100 ng/ml of endotoxin (bacterial lipopolysaccharide, LPS). We found that monocytes from drug-free depressed patients and controls release the same amounts of prostaglandin E2 (PGE2) under basal conditions, whereas monocytes from patients are dramatically less reactive to LPS (8.62-fold increase vs previous 24 hrs) compared to healthy controls (123.3-fold increase vs previous 24 hrs). Such blunted prostanoid production was paralleled by a reduction in COX-2 gene expression, whereas other pro-inflammatory mediators, namely interleukin-1β (IL-1 β) and -6 (IL-6) showed a trend to increased gene expression. The above changes were not associated to increased levels of circulating glucocorticoids. After 8 months of antidepressive drug treatment, the increase in PGE2 production after the endotoxin challenge was partially restored, whereas the increase in IL-1 β and -6 levels observed at baseline was completely abolished. In conclusion, our findings show that the reactivity of monocytes from depressed patients might be considered as a marker of the immune-inflammatory disorders associated to depression, although the lack of paired healthy controls at follow-up does not allow to conclude that monocyte reactivity to endotoxin is also a marker of treatment outcome.
PLoS ONE 01/2013; 8(1):e52585. · 4.09 Impact Factor
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ABSTRACT: Combination therapy with two drugs is a straightforward strategy to improve the risk-benefit ratio of analgesic treatments. Flupirtine is a non-opioid analgesic drug acting via the enhancement of so-called M currents, associated to Kv7 potassium channels in the central nervous system. In this study we used the orofacial formalin test as a model of acute inflammatory pain in the rat; putative synergistic interactions between flupirtine and morphine or tramadol, given in various combinations, were investigated. We found that flupirtine exerts antinociception in the second phase of the test, whereas morphine and tramadol induced analgesia both in the first and in the second phase. An isobolographic analysis of data was carried out, showing a synergistic interaction between flupirtine and morphine, as well as between flupirtine and tramadol, in the second phase of the test. Conversely, in the first phase of the test only a single combination of morphine plus flupirtine, but not any of the combinations of tramadol and flupirtine, resulted in a synergistic interaction. Our data clearly indicate that flupirtine enhances in a synergistic manner the acute antinociceptive effects exerted by opioids in this paradigm.
Pharmacology Biochemistry and Behavior 11/2010; 97(3):544-50. · 2.53 Impact Factor
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ABSTRACT: Combination of two or more analgesics is widely used for the treatment of moderate and severe pain syndromes, allowing usage of lower doses of each compound and thereby limiting side effects; there is currently a large interest in investigating the potential advantages of combinations between opioids and non-steroidal inflammatory drugs (NSAIDs), coxibs in particular. The rat orofacial formalin test is a useful pre-clinical model of inflammatory trigeminal pain for evaluating antinociceptive activity of analgesics and their combinations. Injection of formalin in the rat wiskerpad induces a stereotyped response (rubbing), consisting of two distinct phases: a first 'phasic' phase and a second 'tonic' phase. In this work we tested a partial agonist to mu-opioid receptors, buprenorphine, and a selective cyclo-oxygenase-2 inhibitor, lumiracoxib, each of which given i.p. either alone or in combination. Buprenorphine reduced nociception both in the first and in the second phase, whereas lumiracoxib induced antinociception in the second phase only. The interaction between the two drugs was assessed through isobolographic analysis after combined administration at a fixed dose ratio. Such combination produced a dose-dependent antinociceptive effect in both phases. We observed a statistical difference between the theoretical and the experimental ED(50), which indicated synergistic interaction in the second phase. Concerning the first phase, we assumed that the antinociceptive effects were almost completely to be attributed to buprenorphine, since lumiracoxib was ineffective when administered alone. However, we found an unexpected difference between the theoretical and experimental ED(50), suggesting synergism in the first phase as well.
European journal of pharmacology 02/2009; 605(1-3):57-62. · 2.59 Impact Factor
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ABSTRACT: Naloxone has been used to antagonize opioid effects for many years, even though at low doses it can exert antinociceptive effects. This 'paradoxical' analgesia has been detected after systemic administration of naloxone given alone or in combination with opioid drugs. In the present study, we investigated possible peripheral antinociceptive effects of low doses of naloxone using both an in vivo and in vitro model of trigeminal nociception. Low doses of naloxone injected locally into the rat wiskerpad elicited antinociceptive activity in the rat orofacial formalin test. The block of primary afferents with local administration of capsaicin suggested that naloxone acts both directly on sensory neurons and indirectly, by modulating the inflammatory component of the second phase of formalin test. Naloxone analgesia is maintained in rats made tolerant to the mu-receptor agonist DAMGO, suggesting the involvement of delta- and kappa-opioid receptors. Subsequently, the effects of very low doses of naloxone were tested in primary cultures of rat trigeminal neurons activated with bradykinin, in order to elucidate the mechanisms of action underlying naloxone antinociceptive effects. Naloxone inhibited bradykinin-evoked CGRP release in two different experimental paradigms, i.e. primed and unprimed cultures, acting at the level of delta- and kappa-opioids receptors. These results suggest that low doses of naloxone can directly modulate the activation of the trigeminal neurons by modulating the activity of specific opioid receptors, and this effect may be clinically relevant in combined therapies where an increased analgesic effect is sought through the potentiation of peripheral mechanisms.
Neuropharmacology 58(4-5):784-92. · 4.81 Impact Factor
