RESUMEN
BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 µg/50 µL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 µg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 µg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.
Asunto(s)
Benzoxazinas/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Prurito/tratamiento farmacológico , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Médula Espinal/metabolismo , Animales , Benzoxazinas/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/farmacología , Relación Dosis-Respuesta a Droga , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/farmacología , Prurito/inducido químicamente , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/antagonistas & inhibidores , SerotoninaRESUMEN
BACKGROUND: Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing µ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice. METHODS: Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus. RESULTS: Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p < 0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive. CONCLUSIONS: Overall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain.
Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Benzoxazinas/uso terapéutico , Cannabinoides/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Maprotilina/uso terapéutico , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Neuralgia/tratamiento farmacológico , Animales , Frío , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Quimioterapia Combinada , Hiperalgesia/etiología , Hiperalgesia/psicología , Ligadura , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Estimulación Física , Nervio Ciático/lesionesRESUMEN
The antinociceptive effect of dipyrone is partly due to its action upon pain-related central nervous system structures. Despite intensive research, the precise mechanisms mediating its analgesic effects remain unclear. Here, we aimed to determine whether neurotoxic destruction of descending inhibitory pathways affect dipyrone-induced antinociception and whether various spinal serotonergic and adrenergic receptors are involved in this antinociception. The nociceptive response was assessed by the tail-flick test. Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) elicited dose-related antinociception. The neurotoxins 5,7-dihydroxytryptamine (50 µg/mouse) and 6-hydroxydopamine (20 µg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. 3 days after neurotoxin injections, a significant reduction in the antinociceptive effect of dipyrone was observed. Intrathecal administration of monoaminergic antagonists (10 µg/mouse), the 5-HT2a antagonist ketanserin, the 5-HT3 antagonist ondansetron, the 5-HT7 antagonist SB-258719, α1-adrenoceptor antagonist prazosin, α2-adrenoceptor antagonist yohimbine, and the ß-adrenoceptor antagonist propranolol also attenuated dipyrone antinociception. We propose that descending serotonergic and noradrenergic pathways play pivotal role in dipyrone-induced antinociception and spinal 5-HT2a, 5-HT3, and 5-HT7-serotonergic and α1, α2, and ß-adrenergic receptors mediate this effect.
Asunto(s)
Neuronas Adrenérgicas/efectos de los fármacos , Analgésicos/farmacología , Dipirona/farmacología , Receptores Adrenérgicos beta/metabolismo , Receptores de Serotonina/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Médula Espinal/metabolismo , 5,7-Dihidroxitriptamina/farmacología , Analgésicos/administración & dosificación , Animales , Dipirona/administración & dosificación , Relación Dosis-Respuesta a Droga , Inyecciones Espinales , Ketanserina/farmacología , Ratones , Ondansetrón/farmacología , Oxidopamina/farmacología , Dimensión del Dolor , Piperidinas/farmacología , Prazosina/farmacología , Propranolol/farmacología , Médula Espinal/efectos de los fármacos , Sulfonamidas/farmacología , Yohimbina/farmacologíaRESUMEN
Morphine has long been known to have potent effects on body temperature. It has been suggested that both N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) pathway are involved in thermoregulation and also known to play important roles in some of morphine effects. The aim of this study was therefore to investigate the contribution of NMDA receptors and NO to the thermoregulatory effect of morphine. Morphine produced a hypothermic effect, especially at the dose of 10mg/kg. Ketamine (5-40mg/kg, i.p.) and N(G)-nitro-L-arginine-methyl ester (L-NAME, 1-100mg/kg, i.p.) also produced hypothermic effects with their higher doses. At doses which themselves produced no effect on colonic temperature in mice, both ketamine (10mg/kg, i.p.) and L-NAME (10mg/kg, i.p.) enhanced the hypothermic effect of morphine (10mg/kg, i.p.). These results further support the relationship between NO and NMDA receptors and suggest a possible role of NMDA-NO pathway in the thermoregulatory effect of morphine.
Asunto(s)
Analgésicos Opioides/farmacología , Regulación de la Temperatura Corporal/efectos de los fármacos , Morfina/farmacología , Óxido Nítrico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Regulación de la Temperatura Corporal/fisiología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Hipotermia/inducido químicamente , Ketamina/farmacología , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES) in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4, and 4 mg/kg on day 5, twice daily, ip) to deplete mast cell contents. Morphine (0.001-10 mg/kg, ip; N = 20) produced a dose-dependent anticonvulsive effect against MES seizure in mice with non-depleted mast cells, whereas it did not exert any anticonvulsive effect in mice with depleted mast cells. These results indicate that morphine produces its anticonvulsive effect against maximal electroconvulsive shock in mice by liberating histamine from mast cells.
Asunto(s)
Anticonvulsivantes/antagonistas & inhibidores , Electrochoque , Antagonistas de los Receptores Histamínicos H1/farmacología , Morfina/antagonistas & inhibidores , p-Metoxi-N-metilfenetilamina/farmacología , Animales , Mastocitos , RatonesRESUMEN
OBJECTIVE: This controlled experimental study was designed to compare the effects of a well-known NSAID, tenoxicam, with mid-laser irradiation on the inflammatory component of adjuvant-induced arthritis (AIA). Four groups of animals, each consisting of 10 Wistar rats, were included in the study. The primary concern was not to investigate the antiinflammatory effects of tenoxicam, but to compare the previously proven effects of this drug with a physical therapy agent which might be considered to have fewer side effects and/or contraindications. METHOD: The first group received only 0.1 ml of complete Freund's adjuvant (CFA) and served as the control for the other groups. The 2nd, 3rd and 4th groups, after having CFA injected into the plantar surfaces of their right paws, were treated with tenoxicam alone, mid-laser alone, or with a combination of the two, respectively. RESULTS AND CONCLUSION: All 3 groups showed significantly reduced paw edema compared with the control group. Although the reduction in paw edema in the animals treated with tenoxicam or with tenoxicam+ mid-laser was more significant, mid-laser is proposed as an alternative therapy for symptomatic relief in certain conditions well known to limit the use of NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/radioterapia , Terapia por Láser , Piroxicam/análogos & derivados , Animales , Artritis Experimental/patología , Enfermedad Crónica , Pie/patología , Pie/efectos de la radiación , Piroxicam/uso terapéutico , Ratas , Ratas WistarRESUMEN
Morphine is known to release histamine from mast cells and increase the turnover of neuronal histamine. It is also known that histamine receptors mediate some of the morphine effects. The contribution of histamine H1 and H2 receptors to the thermoregulatory effect of morphine in mice was investigated in the present experiments. Morphine produced a hypothermic effect, especially at the dose of 10 mg/kg. Although the histamine H1 receptor antagonist, dimethindene (0.1 mg/kg, i.p.), attenuated the hypothermic effect of morphine (10 mg/kg), a histamine H2 receptor antagonist, ranitidine (100 mg/kg, i.p.), had no effect. These results suggest that the hypothermic effect of morphine in mice is mediated, at least partly, through histamine H1 receptors.
Asunto(s)
Regulación de la Temperatura Corporal , Morfina/farmacología , Receptores Histamínicos H1/fisiología , Animales , Temperatura Corporal/efectos de los fármacos , Colon/fisiología , Dimetindeno/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Ratones , Ranitidina/farmacologíaRESUMEN
Morphine is known to release histamine from mast cells. It is also known that histamine receptors mediate some of morphine's effects on the central nervous system. The contribution of H1- and H2-receptors to the effect of morphine on maximal electroconvulsive shock in mice was investigated in the present experiments. Morphine showed a dose-dependent anticonvulsive effect, but produced spontaneous clonic convulsions at higher doses (100 mg/kg, i.p.). The anticonvulsive effect of morphine (1 mg/kg, i.p.) was antagonized by histamine H1-receptor antagonists, dimethindene (0.1 mg/kg, i.p.) promethazine (0.4 mg/kg, i.p.) and pheniramine (30 mg/kg, i.p.), and naloxone (10 mg/kg, i.p.), but not by the H2-receptor antagonist ranitidine (10-50 micrograms, i.c.v.). These results show that morphine has an anticonvulsive effect via histamine H1-receptors against maximal electroconvulsive shock in mice.
Asunto(s)
Electrochoque , Antagonistas de los Receptores Histamínicos H1/farmacología , Morfina/uso terapéutico , Receptores Histamínicos H1/fisiología , Convulsiones/tratamiento farmacológico , Animales , Dimetindeno/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Feniramina/farmacología , Prometazina/farmacología , Receptores Histamínicos H1/efectos de los fármacosRESUMEN
Contribution of histamine H1- and H2-receptors to the effect of compound 48/80, a potent histamine releaser, upon asphyxiation and body temperature in mice was investigated in the present experiments. Compound 48/80 showed an apparent protective potency against hypoxia and significantly prolonged the latencies for convulsions and death in a dose-dependent manner. Compound 48/80 also decreased the body temperature, which was in relation with the antihypoxic effect. Both the H1-receptor antagonist, dimethindene, and the H2-receptor antagonist, ranitidine, attenuated the hypothermic effect of compound 48/80, indicating the involvement of central histamine through both the H1- and H2-receptors. Ranitidine had no effect on the protective effect of compound 48/80 against hypoxia-induced lethality, whereas dimethindene completely antagonized it. These results suggest that the protective effect of compound 48/80 against hypoxia is mediated through histamine H1-receptors and is not related to its ability to induce hypothermia.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Receptores Histamínicos H1/fisiología , Receptores Histamínicos H2/fisiología , p-Metoxi-N-metilfenetilamina/farmacología , Animales , Hipoxia/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Convulsiones/prevención & controlRESUMEN
In this study, we investigated the behavioral effects of MK-801 (1-20 micrograms) injected into the posterior parts of nucleus accumbens (ACC) and caudate-putamen (CP) in rats. Interactions of diazepam (DZP, 10 micrograms), haloperidol (HPD, 2 micrograms), and scopolamine (SCOP, 10 micrograms) with 20 micrograms of MK-801 were also studied. All injections were done in 2 microliters. In ACC, MK-801 increased locomotion, rearing, and head shakes. The effect of MK-801 especially at 20 micrograms was accompanied by a motor syndrome: head weaves, circling, body rolls, and ataxia. DZP nonsignificantly reduced the locomotion but it significantly (p < 0.05) reduced head shakes, weaves, circling, and body rolls produced by MK-801. HPD reduced grooming and head shakes. SCOP potentiated MK-801 hyperlocomotion, whereas it decreased body rolls, head shakes, and weaves. In CP, MK-801 increased locomotion, but less than in ACC (p < 0.05). The effect of MK-801 was significantly increased by SCOP. MK-801 also increased grooming (reduced by HPD and increased by SCOP) and at 5-20 micrograms induced oral movements that were decreased by HPD. These results indicate that the posterior part of ACC is involved in MK-801 hyperlocomotion and motor syndromes, whereas CP is involved in mediating grooming and oral movements. Blockade of the muscarinic cholinergic receptors seems to facilitate hyperlocomotion and decrease head shakes produced by MK-801. Mechanisms influenced by DZP and HPD appear to be involved in motor syndrome and oral movement, respectively, induced by MK-801, but not in hyperlocomotion.
Asunto(s)
Conducta Animal/efectos de los fármacos , Núcleo Caudado/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Núcleo Accumbens/efectos de los fármacos , Putamen/efectos de los fármacos , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The protective effect of moclobemide, a reversible and highly selective inhibitor of monoamine oxidase-A, against hypoxia-induced lethality was investigated in the present experiment. Moclobemide showed an apparent protective potency against hypoxia and significantly prolonged the latencies for convulsions and death in a dose-dependent manner. Hypothermia is known to protect animals from hypoxia. Moclobemide also decreased body temperature in mice; however, the hypothermic effect was unrelated to the antihypoxic effect. These results suggest that the protective effect of moclobemide in hypoxia is not due to a decrease in body temperature.