RESUMO
RATIONALE AND OBJECTIVES: Ghrelin, an orexigenic (appetite stimulating) peptide activates binding sites in the ventral tegmental area (a structure linked with the neural reward system) allowing it to participate in reward-seeking behavior. An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine, and nicotine abuse. However, the role of ghrelin, in opioid effects, has rarely been examined. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit markers of morphine-induced activation of the neural reward system, namely morphine-induced increase of dopamine in the nucleus accumbens and behavioral changes in rats. METHODS: We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens shell in rats following morphine (MO, 5, 10 mg/kg s.c.) administration with and without ghrelin antagonist pretreatment (JMV2959, 3, 6 mg/kg i.p., 20 min before MO). Induced behavioral changes were simultaneously monitored. RESULTS: JMV2959 significantly and dose dependently reduced MO-induced dopamine release in the nucleus accumbens shell and affected concentration of by-products associated with dopamine metabolism: 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). JMV2959 pretreatment also significantly reduced MO-induced behavioral stimulation, especially stereotyped behavior. CONCLUSIONS: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.
Assuntos
Dopamina/metabolismo , Glicina/análogos & derivados , Morfina/farmacologia , Receptores de Grelina/antagonistas & inibidores , Triazóis/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Dopamina/análogos & derivados , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Grelina/metabolismo , Glicina/administração & dosagem , Glicina/farmacologia , Ácido Homovanílico/farmacologia , Masculino , Microdiálise , Morfina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de Grelina/metabolismo , Recompensa , Comportamento Estereotipado/efeitos dos fármacos , Triazóis/administração & dosagemRESUMO
OBJECTIVES: There is good evidence that opioids can potentiate analgesic activity of some older non-opioid analgesics (such as paracetamol or ibuprofen) but it is not known whether this also holds true for newer non-opioid analgesics that selectively inhibit cyclooxygenase 2 (coxibs). This study was undertaken to determine the nature of the interaction between codeine and celecoxib or etoricoxib in peritoneal irritation-induced visceral pain in mice. For comparison, interactions of codeine with paracetamol and ibuprofen were also tested using the same method. MATERIAL AND METHODS: A small volume of a weak acetic acid (0.6%) was injected into the peritoneal cavity and the number of writhes (contractions of abdominal muscles) was counted. All drugs were given orally. Their interaction was characterized using isobolographic analysis. RESULTS: Codeine, etoricoxib, celecoxib, ibuprofen and paracetamol all independently produced dose-dependent suppression of writhing. The isobolographic analysis carried out using equipotent dose ratios showed that the interactions between codeine and etoricoxib or celecoxib were sub-additive or additive, respectively. This was in contrast to combinations of codeine with ibuprofen or paracetamol, which were supra-additive. Interaction indexes γ, determined as a ratio between experimental and theoretical ED50 values of the mixture, were as follows: 2.7 for codeine + etoricoxib, 0.62 for codeine + celecoxib, 0.43 for codeine + ibuprofen and 0.33 for codeine + paracetamol. CONCLUSIONS: These and other results suggest that opioids do not seem to potentiate analgesic effects of selective COX-2 inhibitors, in contrast to nonselective COX inhibitors or paracetamol.
Assuntos
Acetaminofen/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Codeína/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ibuprofeno/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético/efeitos adversos , Animais , Celecoxib , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Sinergismo Farmacológico , Etoricoxib , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Animais , Dor/induzido quimicamente , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Análise de Regressão , Sulfonamidas/uso terapêutico , Sulfonas/uso terapêuticoRESUMO
OBJECTIVES: Paracetamol is converted to an active metabolite AM404 via fatty acid amide hydrolase (FAAH). The aim of the present study was to ascertain whether a FAAH inhibitor URB597 antagonizes paracetamol analgesic activity (and to asses by this way the role of FAAH in analgesic activity of paracetamol). METHODS: The interaction between a FAAH inhibitor URB597 and paracetamol was investigated in the writhing test in mice using an isobolographic analysis. RESULTS: URB597 or paracetamol alone and in combinations produced dose-dependent antinociceptive effects. ED50 values were estimated for the individual drugs and an isobologram was constructed. The observed ED50 value for the URB57-paracetamol combination was 0.097 (0.062-0.247) mg/kg. This value did not differ significantly from the theoretical additive ED50 value for the URB597-paracetamol combination which was 0.108 (0.059-0.198) mg/kg. Thus, inhibition of FAAH by URB597 was not followed by the lack of analgesic activity in paracetamol. CONCLUSION: The present results suggest that the analgesic activity of paracetamol is not dependent solely on FAAH metabolic conversion to AM404 and that paracetamol exerts analgesic activity also by additional mechanisms.
Assuntos
Acetaminofen/farmacologia , Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Carbamatos/farmacologia , Medição da Dor/efeitos dos fármacos , Analgésicos não Narcóticos/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Modelos Lineares , Masculino , CamundongosRESUMO
The aim of the present study was to evaluate and compare the analgesic activity and serum levels of meloxicam (CAS 71125-38-7) after administration of meloxicam associated with beta-cyclodextrin (BCD, CAS 7585-39-9) and unmodified meloxicam. The analgesic activity was measured using the plantar test (rats) and the writhing test (mice). In the plantar test, BCD-meloxicam (3 mg/kg and 10 mg/kg orally) showed higher analgesic activity than corresponding doses of meloxicam alone; in the writhing test BCD-meloxicam (7 mg/kg and 15 mg/kg orally) showed stronger analgesic activity than unmodified meloxicam. Serum levels of meloxicam were significantly higher, at 0.5 h and 1 h after administration of BCD-meloxicam orally than those of unmodified meloxicam (both dosed at 10 mg/kg). The present results suggest that association with beta-cyclodextrin increases the analgesic activity of meloxicam. This may be due to an icreased systemic bioavailability of meloxicam after oral administration of its complex with beta-cyclodextrin.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Tiazinas/sangue , Tiazinas/farmacologia , Tiazóis/sangue , Tiazóis/farmacologia , beta-Ciclodextrinas/sangue , Animais , Anti-Inflamatórios não Esteroides/sangue , Carragenina , Hiperalgesia/induzido quimicamente , Masculino , Meloxicam , Camundongos , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Veias/efeitos dos fármacos , Veias/fisiologiaRESUMO
OBJECTIVES: Previously, we found that guaifenesin enhances analgesia induced by paracetamol. The aim of the present study was to determine whether guaifenesin is able to also increase analgesic activity in the non-steroid anti-inflammatory drugs ibuprofen, nimesulide and celecoxib. In addition we investigated the influence of guaifenesin on plasma levels of nimesulide. METHODS: A model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test) was used. Levels of nimesulide in plasma were measured by HPLC. All drugs were given orally and tested in mice. RESULTS: Guaifenesin alone did not produce any antinociceptive effect. Simultaneous administration of guaifenesin (200 mg/kg) and subanalgesic doses of ibuprofen (10 and 30 mg/kg), nimesulide (10 and 20 mg/kg) or celecoxib (1 and 5 mg/kg) resulted in a significant antinociceptive effects. The plasma levels of nimesulide were significantly higher in combination with guaifenesin at 30, 60 and 90 min after oral administration in comparison to nimesulide monotherapy. CONCLUSION: The present results suggest that guaifenesin might enhance the analgesic activity of various non-steroidal anti-inflammatory drugs.
Assuntos
Analgesia , Sinergismo Farmacológico , Guaifenesina/administração & dosagem , Ibuprofeno/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Ácido Acético/toxicidade , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Expectorantes/administração & dosagem , Masculino , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Sulfonamidas/sangueRESUMO
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.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Analgésicos não Narcóticos/farmacologia , Ibuprofeno/farmacologia , Oxazóis/farmacologia , Dor/tratamento farmacológico , Ácido Acético , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Dor/induzido quimicamente , Medição da Dor , Rilmenidina , Teste de Desempenho do Rota-RodRESUMO
OBJECTIVES: Some individually-housed male mice behave aggressively during encounters with strange males, while others are timid or sociable in the same situation. The objective of the present study was to examine concentrations of glutamate, aspartate, and GABA in the brain of aggressive, timid, and sociable mice. METHODS: Random-bred albino mice were housed individually for three weeks and then classified in three groups (aggressive, timid, and sociable mice) according to their behavior during social interaction with non-aggressive group-housed male mice in a neutral cage. One week after categorization, by means of the social conflict test, levels of glutamate, aspartate, and GABA were measured by in vivo microdialysis of the medial prefrontal cortex (mPFC) of the isolated and group-housed mice. RESULTS: Sociable mice had almost triple the levels of GABA in their mPFC than aggressive or timid mice. No significant differences in aspartate and glutamate levels were found in these three types of individually-housed mice. Forebrain chemistry of group-housed mice did not differ from that of individually-housed mice with the exception of levels of glutamate and GABA which were significantly lower in group-housed mice than in sociable individually-housed mice. CONCLUSION: The present results suggest that GABA might play a role in sociable behavior. Results also corroborate other findings indicating that the GABAergic system represents an important molecular and neuronal substrate for the selective attenuation of anxiety and aggression.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Aminoácidos Excitatórios/metabolismo , Comportamento Social , Ácido gama-Aminobutírico/metabolismo , Agressão/fisiologia , Animais , Ácido Aspártico/análise , Ácido Aspártico/metabolismo , Aminoácidos Excitatórios/análise , Ácido Glutâmico/análise , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microquímica/métodos , Microdiálise/métodos , Modelos Biológicos , Timidez , Desejabilidade Social , Ácido gama-Aminobutírico/análiseRESUMO
OBJECTIVES: Preemptive versus therapeutic effects of levetiracetam were investigated in a model of postoperative incisional pain in rats. METHODS: Levetiracetam (250, 500, and 1000 mg/kg intraperitoneal (i.p.) or morphine (5 mg/kg i.p.) was administered either 1 h before (preemptive administration) or 1 h after (therapeutic administration) incisional surgery to the hind paw of rats. The effects of levetiracetam were evaluated based on thermal hyperalgesia measured by the plantar test. RESULTS: All preoperatively treated levetiracetam groups showed a significant, dose dependent, increase in paw withdrawal latency. However, post-incisional administration of levetiracetam produced no antihyperalgesic effect at any dose or at any time. In contrast, post-incisional administration of morphine reduced thermal hyperalgesia, while preemptive administration of morphine did not produce any significant antihyperalgesic effects. CONCLUSION: The present results suggest that levetiracetam might possess preemptive analgesic activity.
Assuntos
Analgésicos/farmacologia , Anticonvulsivantes/farmacologia , Dor Pós-Operatória/prevenção & controle , Piracetam/análogos & derivados , Pré-Medicação , Analgésicos/administração & dosagem , Análise de Variância , Animais , Anticonvulsivantes/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Levetiracetam , Masculino , Morfina/administração & dosagem , Piracetam/administração & dosagem , Piracetam/farmacologia , Cuidados Pré-Operatórios , Distribuição Aleatória , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacologia , Agressão/efeitos dos fármacos , Medetomidina/análogos & derivados , Comportamento Agonístico/efeitos dos fármacos , Animais , Nível de Alerta/efeitos dos fármacos , Dominação-Subordinação , Relação Dose-Resposta a Droga , Masculino , Medetomidina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Comportamento Social , Meio Social , Isolamento SocialRESUMO
Cultural evolution has predominated over biological evolution in modern man (Homo sapiens sapiens). Cultural evolution differs from biological evolution not only by inheritance of acquired characteristics but also, as is proposed in the present essay, by another kind of selection mechanism. Whereas selection in biological evolution is executed according to a criterion of reproductive success (the natural selection), selection in cultural evolution appears to be carried out according to human and humanistic criteria (success or fitness in meeting human needs, interests and humanistic values--"humanistic selection"). Many humanistic needs or values do not seem to be prerequisite for reproductive success, yet some of them (e.g. a need for freedom) seem to be inborn. Innateness, humanistic selection (decisive at a community level) and hierarchy of some human needs, interests and values appear to give cultural evolution a generally upward trend although long periods of stagnation or even regression may occur. Modern humans appear to be still at the early stage of their cultural evolution. A further cultural evolution of man appears to be, in contrast to biological evolution, predictable (with an optimistic outlook) and testable. The problem is that the hopeful result of this test will probably be known only in the fairly remote future provided that this species will not become extinct before that.
Assuntos
Evolução Biológica , Seleção Genética , Evolução Cultural , Previsões , HumanosRESUMO
Levels of cyclooxygenase-2 (COX-2) mRNA, but not those of COX-1, were reported to be raised significantly after peripheral inflammation in the rat spinal cord. The aim of the present study was to ascertain whether this pattern of COX-2 and COX-1 expression applies also to other pain conditions induced by surgical procedure. Experiments were performed on two types of pain models. In a model of postoperative pain, 1 cm longitudinal incision was made through skin, fascia and muscle of the plantar aspect of the right hind paw in anaesthetized rats. In the second model, peripheral inflammation was induced by unilateral, intraplantar injection of carrageenan in the right hind paw. Carrageenan injection or skin incision produced marked and significant reduction of paw withdrawal latencies to noxious radiant heat stimuli after 2 and 6 hr. Under the acute inflammation 2 and 6 hr after carrageenan injection levels of COX-2 mRNA were markedly raised (7.8 and 15.5 times; P<0.001, respectively) while spinal levels of COX-1 mRNA were not significantly altered (n.s.). In contrast, spinal levels of COX-2 mRNA were raised less markedly in a model of postoperative pain (4.9 times at 2 hr; P<0.001 and 2.9 times (n.s.) at 6 hr after surgery) whilst levels of COX-1 mRNA in the lumbar spine were increased significantly (2.3 times; P<0.001) 6 hr after surgery. The present findings indicate that expression of COX-2 mRNA in the spine is less dominant in postoperative pain than in inflammatory pain and that spinal COX-1 mRNA is upregulated in postoperative pain.
Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Inflamação/enzimologia , Dor Pós-Operatória/enzimologia , RNA Mensageiro/genética , Medula Espinal/enzimologia , Animais , Carragenina/administração & dosagem , Carragenina/toxicidade , Modelos Animais de Doenças , Expressão Gênica/genética , Membro Posterior/enzimologia , Membro Posterior/metabolismo , Membro Posterior/cirurgia , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Medição da Dor/métodos , Dor Pós-Operatória/genética , Dor Pós-Operatória/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Medula Espinal/metabolismo , Regulação para Cima/genéticaRESUMO
Dexmedetomidine is a highly specific alpha2-adrenoreceptor agonist, which is now clinically used to induce sedation in patients in the intensive care units. Behavioural effects of dexmedetomidine have been little studied so far. The drug was reported to reduce behaviour such as locomotion or measures of anxiety or aggression in animals. The aim of the present study was to ascertain whether dexmedetomidine inhibits behaviour uniformly or with respect to particular stimuli or situations. Therefore, behavioural effects of dexmedetomidine were studied in the social conflict test in male mice (after three weeks of individual housing), which provides a wide spectrum of behavioural activities in two types of animals (aggressive and sociable mice) as well as in the activity cage. Dexmedetomidine (5-40 microg/kg i.p.) decreased locomotion in the activity cage and this effect was fully antagonized by atipamezole, a selective alpha2-adrenereceptor antagonist. However, dexmedetomidine did not reduce locomotion during social conflict. The only significant effects during social conflict were a selective and dose-dependent antiaggressive effect in aggressive mice and a selective reduction of social investigation ('sociability') in sociable mice. Thus, dexmedetomidine appears to inhibit predominantly dominant behaviour evoked by biologically important stimuli. The ability of dexmedetomidine to reduce aggression might be utilized for treatment of aggressive states. Sedation caused by dexmedetomidine can be easily disrupted and thus the drug may have an advantage over benzodiazepines or neuroleptics, which are used in this indication.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Agressão/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Dexmedetomidina/farmacologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Comportamento Social , Agonistas alfa-Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Conflito Psicológico , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacosRESUMO
OBJECTIVE: To determine the patterns of consumption in calcium channel blockers (CCB) groups in the Czech Republic between 1992 and 1999 and make a comparison with selected countries. METHODS: This was part of a drug utilization study using WHO methodology [Anatomical Therapeutic Chemical classification/defined daily doses (ATC/DDD)]. The wholesale data collected by drug distributors were used. Utilization was calculated as the DDDs for 1000 inhabitants per day. In focus was the consumption of short-acting nifedipine. Comparison with wholesale data from Finland, Norway, Germany and Australia was made. RESULTS: There was a decreasing tendency to use short-acting nifedipine in the Czech Republic over the period 1993-1999. Four years after publication of warning evidence, short-acting nifedipine still accounted for 23% of all calcium channel blockers in our country. The abundance of second-generation CCBs increased from less than 1% in 1993 to 43% in 1999. The consumption of short-acting nifedipine in the Czech Republic and Germany is probably three times more frequent than in Nordic countries and Australia. CONCLUSIONS: Consumption of short-acting nifedipine in the Czech Republic 4 years after recognition of its risks still remains very high. This suggests that implementation of clinical trial results to clinical practice is very slow and ineffective.