RESUMEN
Licorice has been used as an antitussive and expectorant herbal medicine for a long history. This work evaluated the activities of 14 major compounds and crude extracts of licorice, using the classical ammonia-induced cough model and phenol red secretion model in mice. Liquiritin apioside (1), liquiritin (2), and liquiritigenin (3) at 50â¯mg/kg (i.g.) could significantly decrease cough frequency by 30-78% (pâ¯<â¯.01). The antitussive effects could be partially antagonized by the pretreatment of methysergide or glibenclamide, but not naloxone. Moreover, compounds 1-3 showed potent expectorant activities after 3â¯days treatment (pâ¯<â¯.05). The water and ethanol extracts of licorice, which contain abundant 1 and 2, could decrease cough frequency at 200â¯mg/kg by 25-59% (pâ¯<â¯.05), and enhance the phenol red secretion (pâ¯<â¯.05), while the ethyl acetate extract showed little effect. These results indicate liquiritin apioside and liquiritin are the major antitussive and expectorant compounds of licorice. Their antitussive effects depend on both peripheral and central mechanisms.
Asunto(s)
Antitusígenos/farmacología , Tos/tratamiento farmacológico , Expectorantes/farmacología , Glycyrrhiza/química , Fenolsulfonftaleína/metabolismo , Extractos Vegetales/farmacología , Administración Oral , Amoníaco , Animales , Antitusígenos/antagonistas & inhibidores , Antitusígenos/química , Tos/inducido químicamente , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Expectorantes/química , Expectorantes/aislamiento & purificación , Gliburida/farmacología , Masculino , Metisergida/farmacología , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
AIMS: The anterior pretectal nucleus (APtN) and electroacupuncture (EA) activate descending mechanisms to modulate nociceptive inputs in the spinal dorsal horn. This study examines qualitatively whether mechanisms in the APtN participate in the EA-induced analgesia in rats. MAIN METHODS: The tail-flick test was utilized to examine the changes produced by non-selective antagonists of serotonergic (methysergide, 37 pg), muscarinic (atropine, 10 ng) and opioid (naloxone, 10 ng) receptors; selective antagonists against µ (CTOP, 6.4 µg), δ (ICI174,864, 6.9 µg) or κ (nor-BNI, 7.3 µg); 5HT1 (methiothepin, 0.47 µg), 5HT2 (ketanserin, 5.4 µg), or 5HT3 (MDL 72222, 15.7 µg); and GABAA (bicuculline, 150 ng) receptors injected into the dorsal (d) or ventral (v) APtN on the antinociception induced by a 20-min EA applied at 2- or 100-Hz frequency to the Zusanli and Sanyinjiao acupoints. KEY FINDINGS: The 2-Hz EA-induced analgesia was blocked by naloxone, CTOP or atropine, was less intense after bicuculline, was shorter after methysergide or methiothepin in dAPtN, and was less intense after methysergide, methiothepin and bicuculline in vAPtN. The 100-Hz EA-induced analgesia was less intense after methysergide, methiothepin and CTOP in vAPtN, and remained unchanged after injection of the antagonists into the dAPtN. SIGNIFICANCE: The 2-Hz EA-induced analgesia utilizes cholinergic muscarinic, µ-opioid, GABAA and 5-HT1 mechanisms in the dAPtN and µ-opioid and 5-HT1 mechanisms in the vAPtN, while 100-Hz EA-induced analgesia utilizes µ-opioid and 5-HT1 mechanisms in the vAPtN but does not utilize them in the dAPtN.
Asunto(s)
Analgesia/métodos , Electroacupuntura/métodos , Mesencéfalo , Manejo del Dolor/métodos , Animales , Atropina/farmacología , Bicuculina/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Mesencéfalo/efectos de los fármacos , Metiotepina/farmacología , Metisergida/farmacología , Antagonistas Muscarínicos/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Somatostatina/análogos & derivados , Somatostatina/farmacologíaRESUMEN
Transcutaneous electrical nerve stimulation (TENS) is defined as the application of an electrical current to the skin through surface electrodes for pain relief. Various theories have been proposed in order to explain the analgesic mechanism of TENS. Recent studies have demonstrated that part of this analgesia is mediated through neurotransmitters acting at peripheral sites. The aim of this study was to investigate the effects of low frequency (LF: 10 HZ) TENS and high frequency (HF: 130 HZ) TENS on hyperalgesia and edema when applied before the serotonin (5-HT) administered into the rat paw. LF and HF TENS were applied to the right paw for 20 min, and 5-HT was administered immediately after TENS. The Hargreaves method was used to measure nociception, while the hydroplethysmometer (Ugo Basile®) was used to measure edema. Neither HF nor LF TENS inhibited 5-HT-induced edema. However, LF TENS, but not HF TENS, completely reduced 5-HT-induced hyperalgesia. Pre-treatment of the paw with naltrexone, prior to application of TENS, (Nx: 50 µg; I.pl.) showed a complete blockade of the analgesic effect induced by low frequency TENS. Thus, our results confirmed the lack of an anti-inflammatory effect through the use of TENS as well as the participation of peripheral endogenous opioid receptors in LF TENS analgesia in addition to its central action.
Asunto(s)
Edema/inducido químicamente , Edema/prevención & control , Hiperalgesia/prevención & control , Nocicepción/fisiología , Serotonina/efectos adversos , Estimulación Eléctrica Transcutánea del Nervio , Animales , Relación Dosis-Respuesta a Droga , Metisergida/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Pizotilina/farmacología , Ratas , Antagonistas de la Serotonina/farmacologíaRESUMEN
Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.
Asunto(s)
Antipsicóticos/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal , Anfetaminas/farmacología , Animales , Clozapina/farmacología , Dimerización , Relación Dosis-Respuesta a Droga , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Metisergida/farmacología , Ratones , Oocitos , Canales de Potasio de Rectificación Interna/metabolismo , XenopusRESUMEN
UNLABELLED: We evaluated the effectiveness of intrathecal antagonists of α1- (WB4101) and α2- (idazoxan) adrenoceptors and serotonergic (methysergide), opioid (naloxone), muscarinic (atropine), GABA(A) (bicuculline) and GABA(B) (phaclofen) receptors in blocking 2- or 100-Hz electroacupuncture (EA)-induced analgesia (EAIA) in the rat tail-flick test. EA was applied bilaterally to the Zusanli and Sanyinjiao acupoints in lightly anesthetized rats. EA increased tail-flick latency, where the effect of 2-Hz EA lasted longer than that produced by 100-Hz EA. The 2-Hz EAIA was inhibited by naloxone or atropine, was less intense and shorter after WB4101 or idazoxan, and was shorter after methysergide, bicuculline, or phaclofen. The 100-Hz EAIA was less intense and shorter after naloxone and atropine, less intense and longer after phaclofen, shorter after methysergide or bicuculline, and remained unchanged after WB4101 or idazoxan. We postulate that the intensity of the effect of 2-Hz EA depends on noradrenergic descending mechanisms and involves spinal opioid and muscarinic mechanisms, whereas the duration of the effect depends on both noradrenergic and serotonergic descending mechanisms, and involves spinal GABAergic modulation. In contrast, the intensity of 100-Hz EAIA involves spinal muscarinic, opioid, and GABA(B) mechanisms, while the duration of the effects depends on spinal serotonergic, muscarinic, opioid, and GABA(A) mechanisms. PERSPECTIVE: The results of this study indicate that 2- and 100-Hz EA induce analgesia in the rat tail-flick test activating different descending mechanisms at the spinal cord level that control the intensity and duration of the effect. The adequate pharmacological manipulation of such mechanisms may improve EA effectiveness for pain management.
Asunto(s)
Analgesia/métodos , Anestésicos Intravenosos/uso terapéutico , Electroacupuntura/métodos , Manejo del Dolor , Cola (estructura animal)/fisiopatología , Adyuvantes Anestésicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Atropina/farmacología , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/farmacología , Biofisica , Dioxanos/farmacología , Modelos Animales de Enfermedad , GABAérgicos/farmacología , Masculino , Metisergida/farmacología , Modelos Biológicos , Análisis Multivariante , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/fisiopatología , Dimensión del Dolor/métodos , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Tiopental/uso terapéutico , Factores de TiempoRESUMEN
BACKGROUND AND OBJECTIVES: Although the mechanism of action of laser phototherapy (LPT) is not known, it is a promising analgesic method. The aim of this study was to evaluate whether the action of LPT depends on the activation of peripheral opioid or serotonergic receptors. METHOD: Inflammatory pain was induced through the injection of carrageenin in the left posterior paw of male Wistar rats. The InGaAIP visible laser diode (660 nm) with fluency of 2.5 J*cm(-2) was used. Von Frey filaments were used to analyze mechanical hyperalgesia. Animals were separated into five groups: Carrageenin; Laser (LPT); Non-coherent light; LPT + Naloxone; and LPT + Methysergide. RESULTS: Low-Level Laser phototherapy proved to be an effective analgesic method, while non-coherent light did not show a similar effect. The use of naloxone blocked the analgesic effect of LPT, while methysergide did not affect LPT-induced analgesia. CONCLUSIONS: According to the parameter used in this study, LPT produced analgesia. Analgesia induced by laser phototherapy is mediated by peripheral opioid receptors. Laser phototherapy does not seem to interact with peripheral serotonergic receptors.
Asunto(s)
Analgesia , Terapia por Luz de Baja Intensidad , Metisergida/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/radioterapia , Antagonistas de la Serotonina/farmacología , Analgesia/métodos , Animales , Masculino , Ratas , Ratas WistarRESUMEN
AIM OF THE STUDY: Shu-jing-huo-xue-tang (SJHXT) (Japanese name: Sokei-kakketu-to), a traditional Chinese herbal medicine composed of 17 crude drugs, has been prescribed over hundreds of years for treatment of chronic pain syndromes. We evaluated if oral SJHXT could suppress neuropathic pain behaviors in rats with chronic constriction injury (CCI) of the sciatic nerve. MATERIALS AND METHODS: (1) Rats received repeated oral SJHXT 0.5 or 1.0 g/kg once daily for 14 days starting 24 h after CCI surgery, while neuropathic manifestations were evaluated until day 20 post-CCI. (2) Other groups of rats received single oral SJHXT 1.0 g/kg on day 14 post-CCI. (3) Additional groups of rats received oral SJHXT 1.0 g/kg on day 14 post-CCI, concomitantly with intraperitoneal yohimbine 1 mg/kg or methysergide 5 mg/kg. Neuropathic manifestations, including mechanical allodynia and thermal hyperalgesia, were evaluated with paw withdrawal responses to increasing mechanical pressure and radiant heat, respectively. RESULTS: Mechanical allodynia and thermal hyperalgesia developed by day 14 post-CCI. Repeated oral SJHXT for 14 days produced anti-allodynic and anti-hyperalgesic effects that outlasted the period of drug administration. Single oral SJHXT on day 14 also produced significant anti-allodynic and anti-hyperalgesic effects, which were inhibited by yohimbine, an alpha-2 adrenoceptor antagonist, but not by methysergide, a serotonin receptor antagonist. CONCLUSIONS: Oral SJHXT produced anti-hypersensitivity effects by actions on alpha-2 adrenoreceptors in CCI-neuropathic rats, and chronic oral administration of SJHXT could produce the long-lasting anti-hypersensitivity effects.
Asunto(s)
Analgésicos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Fitoterapia , Neuropatía Ciática/tratamiento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Analgésicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Constricción , Medicamentos Herbarios Chinos/farmacología , Calor , Magnoliopsida , Masculino , Metisergida/farmacología , Presión , Ratas , Ratas Sprague-Dawley , Nervio Ciático/lesiones , Antagonistas de la Serotonina/farmacología , Yohimbina/farmacologíaRESUMEN
The relevance of serotonin and in particular that of 5-HT(3) receptors is unequivocal with respect to emetic/antiemetic effects, but it is controversial with respect to antidiabetic effects. The effects of tropisetron (5-HT(3) receptor antagonist) and various ginger (Zingiber officinale) extracts (known to interact with the 5-HT(3) receptor channel system) were investigated. Serotonin (32 to 500 microM) inhibits insulin release (RIA) from INS-1 cells which is reversed by tropisetron (10 to 100 microM) and two different ginger extracts (spissum and an oily extract). Their effects are obvious even in the absence of serotonin but are more pronounced in its presence (doubled to tripled). Specific 5-HT(3) binding sites are present in INS-1 cells using 0.4 nM [3H] GR65630 in displacement experiments. The in vitro data with respect to ginger are corroborated by in vivo data on glucose-loaded rats showing that blood glucose (Glucoquant) is decreased by approximately 35% and plasma insulin (RIA) is increased by approximately 10%. Both the spissum extract and the oily ginger extract are effective in two other models: they inhibit [(14)C] guanidinium uptake into N1E-115 cells (model of 5-HT(3) effects) and relax rat ileum both directly and as a serotonin antagonistic effect. Other receptors addressed by ginger are 5-HT(2) receptors as demonstrated by using methysergide and ketanserin. They weakly antagonize the serotonin effect as well. It may be concluded that serotonin and in particular the 5-HT(3) receptor channel system are involved in modulating insulin release and that tropisetron and various ginger extracts can be used to improve a diabetic situation.
Asunto(s)
Células Secretoras de Insulina/efectos de los fármacos , Insulina/metabolismo , Canales Iónicos/metabolismo , Extractos Vegetales/farmacología , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas de la Serotonina/farmacología , Zingiber officinale/química , Animales , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus/tratamiento farmacológico , Guanidina/metabolismo , Indoles/farmacología , Insulina/sangre , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Canales Iónicos/antagonistas & inhibidores , Ketanserina/farmacología , Metisergida/farmacología , Ratas , Ratas Wistar , Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT3 , TropisetrónRESUMEN
The perifornical (PF) region of the posterior hypothalamus plays an important role in the regulation of sleep-wake states and motor activity. Disinhibition of PF neurons by the GABA(A) receptor antagonist, bicuculline, has been used to study the mechanisms of wake- and motor activity-promoting effects that emanate from the PF region. Bicuculline activates PF neurons, including the orexin-containing cells that have major excitatory projections to brainstem noradrenergic and serotonergic neurons. Since premotor aminergic neurons are an important source of motoneuronal activation, we hypothesized that they mediate the excitation of motoneurons that results from disinhibition of PF neurons with bicuculline. In urethane-anesthetized, paralyzed and artificially ventilated rats, we found that PF bicuculline injections (1mM, 20 nl) made after combined microinjections into the hypoglossal (XII) nucleus of alpha(1)-adrenergic and serotonergic receptor antagonists (prazosin and methysergide) increased XII nerve activity by 80+/-16% (SE) of the control activity level. Thus, activation of XII motoneurons originating in the hypothalamic PF region was not abolished despite effective elimination by the aminergic antagonists of the endogenous noradrenergic and serotonergic excitatory drives to XII motoneurons and abolition of XII motoneuronal activation by exogenous serotonin or phenylephrine. These results show that a major component of XII motoneuronal activation originating in the posterior hypothalamus is mediated by pathways other than the noradrenergic and serotonergic projections to motoneurons.
Asunto(s)
Nervio Hipogloso/fisiología , Hipotálamo/fisiología , Bulbo Raquídeo/fisiología , Neuronas Motoras/fisiología , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Serotonina/metabolismo , Potenciales de Acción/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacología , Animales , Bicuculina/farmacología , Antagonistas del GABA/farmacología , Nervio Hipogloso/efectos de los fármacos , Masculino , Bulbo Raquídeo/efectos de los fármacos , Metisergida/farmacología , Microinyecciones , Neuronas Motoras/efectos de los fármacos , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacologíaRESUMEN
Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.
Asunto(s)
Electroacupuntura , Neuralgia/fisiopatología , Neuralgia/terapia , Plasticidad Neuronal , Células del Asta Posterior , Sinapsis , Potenciales de Acción , Animales , Bicuculina/farmacología , Maleato de Dizocilpina/farmacología , Combinación de Medicamentos , Electroacupuntura/métodos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Hiperestesia/fisiopatología , Ligadura , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Metisergida/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Fibras Nerviosas Amielínicas , Umbral del Dolor , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacología , Nervios Espinales , Factores de TiempoRESUMEN
Although the mechanism of action of acetaminophen (AAP) is not fully understood, some studies suggest that AAP and phenacetin (PHE) are selective cyclooxygenase (COX)-3 inhibitors. To examine the participation of COX-3 in memory formation, water maze performance was studied in mice treated with AAP, PHE or other COX inhibitors. Mice received intraperitoneal injections of drugs immediately after each training session. Administration of high-dose AAP [302.3 mg/kg (IC50 for COX-2)] or PHE [179.2 mg/kg (IC50 for COX-2)] and of non-specific (indomethacin: 20 mg/kg) or specific COX-2 (NS-398: 10 mg/kg) inhibitor impaired the performance in hidden platform (HP) not visible platform (VP) tasks, whereas low-dose (15.1 mg/kg) AAP facilitated performance in HP and VP tasks. The facilitation of performance by low-dose AAP was reversed by co-administration with a 5-HT(1/2) receptor antagonist (methysergide: 0.47 mg/kg). The middle-dose [69.5 mg/kg (IC50 for COX-3)] of AAP, the PHE [17.9 mg/kg (IC50 for COX-3)] and a specific COX-1 inhibitor (piroxicam: 10-20 mg/kg) did not influence performance in either task. These results suggest that the memory impairment by high-dose AAP and PHE and facilitation of performance by low-dose AAP could involve endogenous COX-2 and serotonergic neuronal activity, but not COX-3, respectively.
Asunto(s)
Acetaminofén/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/fisiología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Acetaminofén/administración & dosificación , Animales , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/administración & dosificación , Relación Dosis-Respuesta a Droga , Concentración 50 Inhibidora , Inyecciones Intraperitoneales , Masculino , Memoria/efectos de los fármacos , Metisergida/farmacología , Ratones , Fenacetina/administración & dosificación , Fenacetina/farmacología , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Antagonistas de la Serotonina/farmacologíaRESUMEN
In this study, the antinociceptive effect of shakuyakukanzoto was investigated using streptozotocin-induced diabetic mice to certify its analgesic effect on diabetic patients. Shakuyakukanzoto (0.5 and 1.0 g/kg, p.o.) significantly increased the nociceptive threshold in diabetic mice. The antinociceptive activity of shakuyakukanzoto in diabetic mice was not antagonized by beta-funaltrexamine, naltrindole, or nor-binaltorphimine. The increased antinociceptive activity of (1.0 g/kg, p.o.) in diabetic mice was abolished by yohimbine (15 microg, i.t.), but not by NAN-190 (1 microg, i.t.), methysergide (15 microg, i.t.), or MDL-72222 (15 microg, i.t.). In shakuyakukanzoto diabetic mice treated with 6-hydroxydopamine (20 microg, i.t.) chemically lesioned noradrenergic pathways, shakuyakukanzoto (1.0 g/kg, p.o.) failed to exhibit an antinociceptive effect. Furthermore, the antinociceptive activity induced by norepinephrine (0.06 - 2 microg, i.t.) was markedly more potent in diabetic mice than in non-diabetic mice at the same dose. These results suggest that the antinociceptive effect of shakuyakukanzoto in diabetic mice is not mediated by the opioid systems and that this effect appears via selective activation of the spinal descending inhibitory alpha2-adrenergic systems without activating the serotonergic systems. The spinal alpha2-adrenoceptor-mediated analgesic mechanism was enhanced in diabetic mice, suggesting that shakuyakukanzoto exhibits its effect by activating the descending noradrenergic neurons.
Asunto(s)
Analgésicos , Diabetes Mellitus Experimental/psicología , Medicamentos Herbarios Chinos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Glycyrrhiza , Masculino , Medicina Kampo , Metisergida/farmacología , Ratones , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Oxidopamina/farmacología , Paeonia , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacología , Simpaticolíticos/farmacología , Tropanos/farmacología , Yohimbina/farmacologíaRESUMEN
Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.
Asunto(s)
Antieméticos/farmacología , Capsaicina/análogos & derivados , Trastornos Migrañosos/prevención & control , Vómitos/prevención & control , Animales , Butanoles/farmacología , Capsaicina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Dihidroergotamina/farmacología , Difenhidramina/farmacología , Diterpenos , Domperidona/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Indometacina/farmacología , Malatos , Metisergida/farmacología , Metoclopramida/farmacología , Ondansetrón/farmacología , Piperidinas , Rojo de Rutenio/farmacología , Escopolamina/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Musarañas , Sumatriptán/farmacología , Factores de Tiempo , Tropanos/farmacología , Vómitos/inducido químicamenteRESUMEN
OBJECTIVES: To evaluate the effect of St. John's wort (SJW), an effective and safe herbal antidepressant, on rat bladder contractility. Recent data have suggested a strong association between depression and urinary incontinence. METHODS: Strips were cut from the bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation (EFS) and, in some experiments, by exogenous alpha,beta (alpha,beta)-methylene adenosine triphosphate. RESULTS: St. John's wort was significantly more active in inhibiting the EFS-induced contractions than the alpha,beta-methylene adenosine triphosphate-induced contractions, suggesting both a presynaptic site of action and a direct inhibition of bladder smooth muscle. The inhibitory effect of SJW on EFS-induced contractions was unaffected by methysergide, haloperidol, phentolamine plus propranolol (antagonists that block the action of the neurotransmitters 5-hydroxytriptamine, dopamine, and noradrenaline on their own receptors), the L-type calcium channel antagonist verapamil, capsazepine (which blocks the vanilloid receptor), or cannabinoid CB1 receptor antagonist SR141716A. However, the opioid receptor antagonist naloxone significantly reduced the inhibitory effect of SJW on EFS-induced contractions. Among the chemical constituents of SJW tested, hyperforin and, to a lesser extent, the flavonoid kaempferol showed inhibitory effects. CONCLUSIONS: The results of our study demonstrated that SJW inhibits excitatory transmission of the rat urinary bladder and also directly inhibits smooth muscle contractility. The inhibitory effect on excitatory transmission could involve, at least in part, opioid receptors. SJW may be evaluated for its possible use in treating urinary incontinence in depressed patients.
Asunto(s)
Adenosina Trifosfato/análogos & derivados , Antidepresivos/farmacología , Capsaicina/análogos & derivados , Hypericum , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Perileno/análogos & derivados , Floroglucinol/análogos & derivados , Extractos Vegetales/farmacología , Quercetina/análogos & derivados , Vejiga Urinaria/efectos de los fármacos , Acetilcolina/farmacología , Adenosina Trifosfato/farmacología , Animales , Antracenos , Atropina/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Capsaicina/farmacología , Depresión/complicaciones , Depresión/tratamiento farmacológico , Estimulación Eléctrica , Femenino , Haloperidol/farmacología , Quempferoles/farmacología , Masculino , Metisergida/farmacología , Naloxona/farmacología , Perileno/farmacología , Fentolamina/farmacología , Floroglucinol/farmacología , Piperidinas/farmacología , Propranolol/farmacología , Pirazoles/farmacología , Quercetina/farmacología , Ratas , Ratas Wistar , Rimonabant , Rutina/farmacología , Terpenos/farmacología , Tetrodotoxina/farmacología , Incontinencia Urinaria/complicaciones , Incontinencia Urinaria/tratamiento farmacológico , Verapamilo/farmacologíaRESUMEN
Transcutaneous electrical nerve stimulation (TENS) is a form of non-pharmacological treatment for pain. Involvement of descending inhibitory systems is implicated in TENS-induced analgesia. In the present study, the roles of spinal 5-HT and alpha(2)-adrenoceptors in TENS analgesia were investigated in rats. Hyperalgesia was induced by inflaming the knee joint with 3% kaolin-carrageenan mixture and assessed by measuring paw withdrawal latency (PWL) to heat before and 4 h after injection. The (1). alpha(2)-adrenergic antagonist yohimbine (30 microg), (2). 5-HT antagonist methysergide (5-HT(1). and 5-HT(2). 30 microg), one of the 5-HT receptor subtype antagonists, (3). NAN-190 (5-HT(1A), 15 microg), (4). ketanserin (5-HT(2A), 30 microg), (5). MDL-72222 (5-HT(3), 12 microg), or (6). vehicle was administered intrathecally prior to TENS treatment. Low (4 Hz) or high (100 Hz) frequency TENS at sensory intensity was then applied to the inflamed knee for 20 min and PWL was determined. Selectivity of the antagonists used was confirmed using respective agonists administered intrathecally. Yohimbine had no effect on the antihyperalgesia produced by low or high frequency TENS. Methysergide and MDL-72222 prevented the antihyperalgesia produced by low, but not high, frequency TENS. Ketanserin attenuated the antihyperalgesic effects of low frequency TENS whereas NAN-190 had no effect. The results from the present study show that spinal 5-HT receptors mediate low, but not high, frequency TENS-induced antihyperalgesia through activation of 5-HT(2A) and 5-HT(3) receptors in rats. Furthermore, spinal noradrenergic receptors are not involved in either low or high frequency TENS antihyperalgesia.
Asunto(s)
Hiperalgesia/fisiopatología , Receptores de Serotonina/metabolismo , Médula Espinal/metabolismo , Estimulación Eléctrica Transcutánea del Nervio , Antagonistas Adrenérgicos alfa/administración & dosificación , Antagonistas Adrenérgicos alfa/farmacología , Animales , Carragenina , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Inyecciones Espinales , Caolín , Masculino , Metisergida/administración & dosificación , Metisergida/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptores de Serotonina 5-HT3 , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Yohimbina/administración & dosificación , Yohimbina/farmacologíaRESUMEN
4-Methylthioamphetamine (4-MTA), also known as p-methylthioamphetamine, is a new amphetamine derivative which in humans has been increasingly associated with severe intoxications and several deaths. As hyperthermia is considered to be one of the most life-threatening acute physiological consequences of amphetamine-related intoxications, it was our aim to determine whether 4-MTA induces changes in body temperature in a mouse model. Accordingly, we measured the subcutaneous temperature after acute administration of 4-MTA in CD1 mice. Because hyperthermia seems to result from the central and peripheral actions of catecholamines and serotonin (5-hydroxytriptamine or 5-HT), we also investigated the possible interactions of some catecholaminergic and serotonergic receptor blockers and the inhibition of monoamine oxidase (MAO) with this effect. 4-MTA induced hyperthermia in CD1 mice. Blockade of the 5-HT receptors with methysergide and MAO inhibition with pargyline resulted in the potentiation of the 4-MTA-induced hyperthermic effect. Blockade of the alpha(1)-adrenergic receptors with prazosin completely reverted the 4-MTA-induced hyperthermia while with the beta-adrenergic receptor blocker dl-propranolol this reversal was not complete. Blockade of the alpha(2)-adrenergic receptors with yohimbine had no effect on the hyperthermia induced by 4-MTA. These results suggest that 4-MTA-induced hyperthermia is highly influenced by the catecholaminergic and serotonergic receptor activation and the MAO activity.
Asunto(s)
Anfetaminas/toxicidad , Temperatura Corporal/efectos de los fármacos , Catecolaminas/fisiología , Hipertermia Inducida , Serotonina/fisiología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Temperatura Corporal/fisiología , Masculino , Metisergida/farmacología , Ratones , Ratones Endogámicos , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Pargilina/farmacología , Prazosina/farmacología , Receptores Adrenérgicos/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
Platycodin D administered intracerebroventricularly (i.c.v.) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick assay. The antinociception induced by platycodin D was maintained at least 1 h. MK-801 [(+/-)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine maleate], a competitive N-methyl- D-aspartic acid (NMDA) receptor antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a non-NMDA receptor antagonist, muscimol (a GABA(A) receptor agonist), or baclofen (a GABA(B) receptor antagonist), or sulfated cholecystokinin (CCK-8 s; CCK A receptor agonist), injected i.c.v. significantly reduced the inhibition of the tail-flick response induced by platycodin D administered i.c.v. Additionally, intrathecal (i.t.) pretreatment with yohimbine (an alpha 2 -adrenergic receptor antagonist) or methysergide (a serotonin receptor antagonist) dose-dependently attenuated inhibition of the tail-flick response induced by i.c.v. administered platycodin D. However, naloxone (an opioid receptor antagonist) did not affect the inhibition of the tail-flick response induced by platycodin D. Our results suggest that platycodin D has an antinociceptive effect when it is administered supraspinally, and supraspinal GABA(A), GABA(B), NMDA and non-NMDA receptors are involved in platycodin D-induced antinociception. Furthermore, platycodin D administered supraspinally produces antinociception by stimulating descending noradrenergic and serotonergic, but not opioidergic, pathways.
Asunto(s)
Analgésicos/farmacología , Platycodon , Saponinas/farmacología , Sincalida/análogos & derivados , Triterpenos/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacología , Animales , Baclofeno/farmacología , Secuencia de Carbohidratos , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Metisergida/farmacología , Ratones , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Muscimol/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Receptores de Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Saponinas/química , Antagonistas de la Serotonina/farmacología , Sincalida/farmacología , Cola (estructura animal)/efectos de los fármacos , Triterpenos/química , Yohimbina/farmacologíaRESUMEN
The aim of this study was to determine if the psychostimulants, khat and amphetamine, exert similar effects in two tests of motor behaviors. Dose-response relationships were obtained for khat extract and D- and L-amphetamine given to mice by the intragastric route. Head twitch responses were significantly increased by khat and amphetamines. The latter were more potent than khat; dose-response curves for amphetamines had inverted U shapes. Khat extract decreased spontaneous motor activity, as measured by a photoactometer. Effects of amphetamines in this test were more variable and subject to dose dependent reversal. Other behaviors produced by higher doses of amphetamines interfered with specific motor responses under evaluation. Pretreatment with methysergide, a serotonin antagonist, significantly blocked head twitch responses but not spontaneous activity. Conversely, pretreatment with haloperidol decanoate, a dopamine receptor antagonist, prevented inhibition of spontaneous motor activity ordinarily evoked by khat and low dose D-amphetamine. We conclude that motor effects of khat and amphetamine resemble one another, but only at certain doses. Unlike khat, amphetamine causes additional behaviors that obscure motor responses of the types examined here. Results with transmitter receptor blockers suggest that motor effects of khat, like those of amphetamine, may be modulated by serotonin and dopamine.
Asunto(s)
Anfetamina/farmacología , Catha , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Anfetamina/administración & dosificación , Animales , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Masculino , Metisergida/farmacología , Ratones , Extractos Vegetales/administración & dosificación , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
The relative contribution of serotonin (5HT) neurotransmission within the medulla (rostral ventromedial medulla) and forebrain (amygdaloid central nucleus and nucleus parafascicularis thalami) to the antinociceptive action of morphine microinjected into the ventrolateral periaqueductal gray (vPAG) was evaluated. The 5HT receptor antagonist methysergide was microinjected into the medulla, forebrain, (or both) after injection of morphine into the vPAG. The contribution of 5HT to the antinociceptive action of morphine was observed to depend on (a) the dose of morphine administered into the vPAG, (b) the site(s) at which methysergide was administered, and (c) the level of the neuraxis at which the behavioral assay was organized. Results of the present study were combined with those of previous studies from this laboratory and presented as a model of the mechanisms by which morphine administered into the vPAG generates its antinociceptive action.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Analgésicos Opioides/farmacología , Bulbo Raquídeo/metabolismo , Morfina/farmacología , Umbral del Dolor/fisiología , Sustancia Gris Periacueductal/fisiología , Serotonina/metabolismo , Tálamo/metabolismo , Analgésicos Opioides/administración & dosificación , Animales , Masculino , Metisergida/farmacología , Modelos Biológicos , Morfina/administración & dosificación , Ratas , Ratas Long-Evans , Antagonistas de la Serotonina/farmacologíaRESUMEN
The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate (p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including "Vomiting," "Stomach Pain," and "Miserable." These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).