Aggression, anxiety and vocalizations in animals: GABA A and 5-HT anxiolytics

A continuing challenge for preclinical research on anxiolytic drugs is to capture the affective dimension that characterizes anxiety and aggression, either in their adaptive forms or when they become of clinical concern. Experimental protocols for the preclinical study of anxiolytic drugs typically involve the suppression of conditioned or unconditioned social and exploratory behavior (e.g., punished drinking or social interactions) and demonstrate the reversal of this behavioral suppression by drugs acting on the benzodiazepine-GABA A complex. Less frequently, aversive events engender increases in conditioned or unconditioned behavior that are reversed by anxiolytic drugs (e.g., fear-potentiated startle). More recently, putative anxiolytics which target 5-HT receptor subtypes produced effects in these traditional protocols that often are not systematic and robust. We propose ethological studies of vocal expressions in rodents and primates during social confrontations, separation from social companions, or exposure to aversive environmental events as promising sources of information on the affective features of behavior. This approach focusses on vocal and other display behavior with clear functional validity and homology. Drugs with anxiolytic effects that act on the benzodiazepine-GABA A receptor complex and on 5-HT 1A receptors systematically and potently alter specific vocalizations in rodents and primates in a pharmacologically reversible manner; the specificity of these effects on vocalizations is evident due to the effectiveness of low doses that do not compromise other physiological and behavioral processes. Antagonists at the benzodiazepine receptor reverse the effects of full agonists on vocalizations, particularly when these occur in threatening, startling and distressing contexts. With the development of antagonists at 5-HT receptor subtypes, it can be anticipated that similar receptor-specificity can be established for the effects of 5-HT anxiolytics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46351/1/213_2005_Article_BF02245590.pd

Has a low OTC dose of ibuprofen an antiinflammatory effect?

Information on products containing low doses of ibuprofen available over the counter (OTC) sometimes states that these products are indicated apart from pain and/or fever also for inflammatory disorders. The aim of the present study was to ascertain whether there is a good evidence for antiinflammatory activity in low OTC doses of ibuprofen in medical literature published during 1983-2007. Antiinflammatory effects of ibuprofen at single doses 5-10 mg/kg in children or 200-400 mg in adults were assessed according to their published effects on several biochemical markers of inflammation (such as C-reactive protein) or clinical signs of inflammation. Clinical antiinflammatory effects of ibuprofen were evaluated in rheumatoid arthritis, osteoarthritis, cystic fibrosis and inflammation after oral surgery. The present evaluation was difficult because of differences in methodical standards and orientation of published clinical studies, differences in the number of patients, employment of disparate measures of inflammation, problems in extrapolating effects from dosage used in animals to man or from dosage of S-ibuprofen to that of the usual racemic form of the drug. Published effects of low doses of ibuprofen on activity of cyclooxygenases or biochemical markers of inflammation did not bring evidence for their anti-inflammatory activity (with the exception of one oral surgery study which found that 1200 mg of ibuprofen per day reduced an increase of C-reactive protein). Studies testing doses 5-10 mg/kg of ibuprofen in children confirmed their analgesic and antipyretic activity but did not supply evidence for their anti-inflammatory effects. None of 22 studies assessing effects of ibuprofen in rhematoind arthritis or osteoarthritis reported antiinflammatory effects at low doses of this drug. No publication was found reporting effects of low doses of ibuprofen in cystic fibrosis. In conclusion, the data published until now have not provided good evidence for stating that products containing low OTC doses of ibuprofen have anti-inflammatory activity. This applies particularly to products containing 200 mg of ibuprofen in one dosage form for oral administration in adults

Synergistic interaction between rilmenidine and ibuprofen in the writhing test in mice

Objectives: The aim of the study was to ascertain whether rilmenidine, a second generation imidazoline-alpha-2-adrenoreceptor agonist, is able to increase analgesic effects of ibuprofen in the writhing test in mice. Experimental studies combining these agents have not yet been published. Methods: An acetic acid (0.7%) solution was injected into the peritoneal cavity and the number of writhes was counted. The influence on locomotor performance was tested using the rotarod test. Results: Rilmenidine, ibuprofen, and rilmenidine-ibuprofen fixed-ratio combinations produced dose-dependent antinociceptive effects. ED50 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical additive ED50 value for the rilmenidine-ibuprofen combination was 34.00 +/- 9.39 mg/kg. This value was significantly greater than the observed ED50 value which was 18.07 +/- 5.41 mg/kg, indicating a synergistic interaction. Rilmenidine did not impair motor coordination, as measured by the rotarod test, at antinociceptive and higher doses. Conclusions: The present results suggest that rilmenidine enhances the analgesic activity of ibuprofen. If rilmenidine produces antinociception in humans, then the synergistic antinociception of rilmenidine with ibuprofen could offer therapeutic advantage for clinical treatment of pain

The synergistic interaction between rilmenidine and paracetamol in the writhing test in mice

The aim of the study was to ascertain antinociceptive effects of rilmenidine, a second-generation imidazoline-alpha-2-adrenoreceptor agonist, and to see whether rilmenidine was able to increase the analgesic effects of paracetamol in the writhing test in mice. An acetic acid (0.7%) solution was injected into the peritoneal cavity and the number of writhes was counted. The influence on locomotor performance was tested using the rotarod test. Rilmenidine, paracetamol, and rilmenidine-paracetamol fixed-ratio combinations produced dose-dependent antinociceptive effects. ED(50) values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical additive ED(50) value for the rilmenidine-paracetamol combination was 109.23 +/- 35.05 mg/kg. This value was significantly greater than the observed ED(50) value which was 56.35 +/- 20.86 mg/kg, indicating a synergistic interaction. Rilmenidine did not impair motor coordination, as measured by the rotarod test, at antinociceptive and higher doses

Increased analgesic efficacy in combinations of gabapentin with non-steroidal anti-inflammatory drugs inhibiting cyclooxygenase 2

Background and objectives: Good analgesic efficacy has been reported in combinations of gabapentin with certain non-steroidal anti-inflammatory drugs (NSAIDs); although existing data are limited and ambiguous. In this study, gabapentin was combined with several NSAIDs, cyclooxygenase (COX) inhibitors, to assess analgesic efficacy of the combinations relative to differences in COX-1 and COX-2 inhibition. Methods: Antinociceptive activity was studied using isobolographic analysis following acetic acid induced abdominal constrictions in mice (writhing test). Synergy (supra-additivity) was measured by the interaction index γ (the ratio between experimental and theoretical ED 50; the lower the γ value, the stronger the synergy). Results: All tested drugs produced dose-dependent antinociceptive effects. The isobolographic analysis carried out using equipotent dose ratios showed that synergy (supra-additivity) was strongest in the combination of gabapentin with etoricoxib, the most selective COX-2 inhibitor (γ: 0.13). Combinations of gabapentin with celecoxib, diclofenac, and nimesulide, which are less selective COX-2 inhibitors, was weaker, but still significantly supra-additive, (γ: 0.30, 0.35, 0.58, respectively); in combination with ibuprofen, a nonselective COX inhibitor, the effect was additive (γ: 1.12). In combination of gabapentin with FR 122047, a selective COX-1 inhibitor, the effect was sub-additive (γ: 1.45). The degree of synergy (γ) correlated with the relative efficacy of COX-2 inhibition (IC50 COX-1/COX- 2). Conclusions: Our results suggest that analgesic efficacy of combinations of gabapentin with NSAIDs was directly related to their relative efficacy in inhibiting COX-2. Our results also suggest further investigation into the therapeutic potential of combinations of gabapentinoids with selective or preferential COX-2 inhibitors for pain control