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1.
Pharmacol Biochem Behav ; 188: 172835, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805289

RESUMO

Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471-83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.


Assuntos
Estimulação Acústica/métodos , Antagonistas de Receptores Adrenérgicos alfa 2/toxicidade , Medo/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/efeitos adversos , Animais , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos DBA , Reflexo de Sobressalto/efeitos dos fármacos , Especificidade da Espécie , Ioimbina/toxicidade
2.
Toxins (Basel) ; 9(11)2017 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29088102

RESUMO

Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α2-adrenergic receptor antagonist (idazoxan, 50 µg), but not α1-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α2-adrenergic receptor.


Assuntos
Terapia por Acupuntura , Venenos de Abelha/uso terapêutico , Hiperalgesia/terapia , Neuralgia/terapia , Receptores Adrenérgicos alfa 2/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Antineoplásicos Fitogênicos , Venenos de Abelha/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Idazoxano/farmacologia , Masculino , Meliteno/farmacologia , Meliteno/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/fisiopatologia , Paclitaxel , Fosfolipases A2/farmacologia , Fosfolipases A2/uso terapêutico , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
3.
Am J Chin Med ; 43(1): 57-70, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25640847

RESUMO

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Eletroacupuntura , Neuralgia/induzido quimicamente , Paclitaxel/efeitos adversos , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores Opioides/fisiologia , Pontos de Acupuntura , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Camundongos Endogâmicos ICR , Neuralgia/terapia , Paclitaxel/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal
4.
Biol Pharm Bull ; 36(11): 1787-93, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23985901

RESUMO

Oxaliplatin, which is used as one of anti-cancer drugs, commonly induces peripheral neuropathic pain. We have previously reported that an injection of diluted bee venom (DBV) produced a significant anti-nociceptive effects in several pain models of mice or rats. In this study, we evaluated time- and dose-dependent development of oxaliplatin-induced mechanical allodynia in bilateral hind paws of mice, and investigated the effect of DBV injection on this mechanical allodynia. DBV (0.1 mg/kg) was subcutaneously injected into the Zusanli acupoint 2 weeks after oxaliplatin (10 mg/kg) injection. One hour after DBV injection, we observed a significant reduction of mechanical allodynia in the ipsilateral hind paw, but not in the contralateral hind paw to DBV injection site. We subsequently examined whether this effect of DBV was related to the activation of peripheral nerves in DBV injected site, and then whether it was mediated by the activation of spinal cord alpha-2 adrenoceptors or opioid receptors. Subcutaneous pre-injection of 2% lidocaine (40 mg/kg) into the Zusanli acupoint completely blocked the anti-allodynic effect of DBV. Intrathecal pretreatment with yohimbine (25 µg/mouse), an alpha-2 adrenoceptor antagonist, also prevented the anti-allodynic effect of DBV, whereas pretreatment with naloxone (20 µg/mouse), an opioid receptor antagonist, did not block the effect of DBV. Taken together, these findings demonstrate that DBV injection into the Zusanli acupoint significantly reduces ipsilateral mechanical allodynia generated by oxaliplatin in mice, and also suggest that this anti-allodynic effect is dependent on the peripheral nerve activation in injected site and spinal cord alpha-2 adrenoceptors.


Assuntos
Analgésicos/uso terapêutico , Venenos de Abelha/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Injeções , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Receptores Adrenérgicos alfa 2/fisiologia , Ioimbina/farmacologia
5.
Rheumatol Int ; 33(2): 309-14, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22441959

RESUMO

This study was designed to investigate whether alpha- and beta-adrenergic systems mediate the analgesic effect of electroacupucture (EA) on inflammatory pain in a rat model of collagen-induced arthritis (CIA). To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant, followed by a booster injection 14 days later. After induction of arthritis, the inflammatory pain threshold by the tail flick latency decreased as time passed and reached the minimum value at 4th week. Four weeks after the first immunization, low-frequency EA stimulation (2 Hz, 0.07 mA, 0.3 ms) delivered to Zusanli (ST(36)) for 30 min showed the analgesic effect. And also, the analgesic effect of EA was blocked by pretreatment with yohimbine (alpha2-adrenoceptor antagonist, 2 mg/kg, i.p.), but not by pretreatment with prazosin (alpha1-adrenoceptor antagonist, 1 mg/kg, i.p.) and propranolol (non-selective beta-adrenoceptor antagonist, 10 mg/kg, i.p.). These results suggest that the low-frequency EA can relieve the inflammatory pain in CIA, and the analgesic effect of EA can be mediated by alpha2- and beta-adrenoceptor, but not by alpha1-adrenoceptor.


Assuntos
Analgesia por Acupuntura , Artrite Experimental/terapia , Eletroacupuntura , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos beta/fisiologia , Pontos de Acupuntura , Animais , Masculino , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Ioimbina/farmacologia
6.
Br J Anaesth ; 109(2): 245-52, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22628394

RESUMO

BACKGROUND: Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model. METHODS: Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30. RESULTS: EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn. CONCLUSIONS: The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.


Assuntos
Eletroacupuntura/métodos , Hiperalgesia/prevenção & controle , Receptores Adrenérgicos alfa 2/fisiologia , Receptores 5-HT1 de Serotonina/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Modelos Animais de Doenças , Adjuvante de Freund , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores Adrenérgicos alfa 2/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Medula Espinal/metabolismo
7.
Psychopharmacology (Berl) ; 219(1): 99-108, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21710169

RESUMO

RATIONALE: Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). OBJECTIVES: We assessed the effects of idazoxan (an α(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. METHODS: In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. RESULTS: Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. CONCLUSIONS: These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anfetamina/farmacologia , Maleato de Dizocilpina/farmacologia , Idazoxano/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica/métodos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Feminino , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiologia , Reflexo de Sobressalto/fisiologia
8.
Neuroscience ; 178: 89-100, 2011 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-21262322

RESUMO

Two neuronal populations of the lateral hypothalamus that, respectively, produce melanin-concentrating hormone (MCH) and orexin peptides are crucially involved in control of metabolism, feeding and related goal-oriented behaviors. In contrast to orexin neurons, mainly involved in short-term regulation of feeding, MCH neurons participate in long-term control of energy storage and body weight. Beyond its effect on feeding, MCH has also been shown to be involved in regulation of seeking behavior and addiction through modulation of dopamine (DA) metabolism. This regulation is essential for reinforcement-associated behaviors. Moreover, drugs of abuse, which increase extracellular DA levels, are known to decrease food intake. Consistent with this observation, DA has been shown to modulate orexin neurons of the lateral hypothalamus. However, no study is available concerning the effects of DA on MCH neurons. Whole-cell patch-clamp recordings were done in hypothalamic mouse brain slices. MCH neurons were identified by Tau-Cyan-GFP labeling using a transgenic mouse model (MCH-GFP). First, we show that DA (10-200 µM) induces an outward current in MCH neurons. However, this current is not due to activation of DA receptors, but mediated through activation of α2-noradrenergic receptors and subsequent opening of G-protein activated inward rectifier K+ (GIRK) channels. Current-clamp experiments revealed that this GIRK-activation leads to hyperpolarization, thus decreasing excitability of MCH neurons. Furthermore, we confirm that MCH neurons receive mainly GABAergic inputs rather than glutamatergic ones. We show that DA modulates these inputs in a complex manner: at low concentrations, DA activates D1-like receptors, promoting presynaptic activity, whereas, at higher concentrations (100 µM), D2-like receptor activation inhibits presynaptic activity. Overall, DA should lead to a decrease in MCH neuron excitability, likely resulting in down-regulation of MCH release and feeding behavior.


Assuntos
Dopamina/fisiologia , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Potenciais da Membrana/fisiologia , Neurônios/fisiologia , Hormônios Hipofisários/metabolismo , Receptores Adrenérgicos alfa 2/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Hormônios Hipotalâmicos/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Melaninas/genética , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Hormônios Hipofisários/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
9.
J Physiol Pharmacol ; 61(4): 391-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20814066

RESUMO

The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are activated by body salt-fluid variations. Stimulation of alpha(2)-adrenoceptors by an agonist-xylazine (XYL) activates oxytocinergic but not vasopressinergic magnocellular neurons. In this study, tyrosine hydroxylase (TH), corticoliberine (CRH), and neuropeptide Y(NPY) magnocellular phenotypes, were analysed in response to alpha(2)-adrenoceptor manipulations and sustained hyperosmolality in vasopressin deficient homozygous Brattleboro (di/di) rats. Saline (0.9% NaCl, 0.1 ml/100g/bw), XYL (10 mg/kg/bw), atipamezole (ATIP, alpha(2)-adrenoceptors antagonist, 1 mg/kg/bw), and ATIP 5 min later followed by XYL, were applied intraperitoneally. Presence of immunolabeled Fos peptide signalized the neuronal activity. Ninety minutes after injections, the rats were anesthesized and sacrificed by transcardial perfusion with fixative. Coronal sections of 30 mum thickness double immunolabeled with Fos/neuropeptide were evaluated under light microscope. Under basal conditions, di/di in comparison with control Long Evans rats, displayed significantly higher number of TH, CRH, and NPY immunoreactive neurons in the SON and PVN (except NPY cells in PVN) and more than 90%, 75%, and 86% of TH, NPY, and CRH neurons, respectively, displayed also Fos signal in the SON. XYL did not further increase the number of Fos in the PVN and SON and ATIP failed to reduce the stimulatory effect of hypertonic saline in all neuronal phenotypes studied. Our data indicate that hyperosmotic conditions significantly influence the activity of TH, CRH, and NPY magnocellular neuronal phenotypes, but alpha(2)-adrenoceptors do not play substantial role in their regulation during osmotic challenge induced by AVP deficiency.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores Adrenérgicos alfa 2/fisiologia , Núcleo Supraóptico/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Hormônio Liberador da Corticotropina/biossíntese , Ativação Enzimática/genética , Ativação Enzimática/fisiologia , Hipotálamo/citologia , Hipotálamo/enzimologia , Hipotálamo/metabolismo , Masculino , Neurogênese/genética , Neurônios/citologia , Neurônios/enzimologia , Neuropeptídeo Y/biossíntese , Osmose/fisiologia , Núcleo Hipotalâmico Paraventricular/enzimologia , Fenótipo , Ratos , Ratos Brattleboro , Ratos Long-Evans , Receptores Adrenérgicos alfa 2/metabolismo , Núcleo Supraóptico/enzimologia , Tirosina 3-Mono-Oxigenase/biossíntese , Vasopressinas/deficiência , Vasopressinas/genética
10.
J Ethnopharmacol ; 130(1): 187-90, 2010 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-20441789

RESUMO

AIM OF THE STUDY: The purpose of the present study was to screen aromatic essential oils that have antidepressant effects to identify the regulatory mechanisms of selected essential oils. MATERIALS AND METHODS: The antidepressant effects of essential oils of Anthemis nobilis (chamomile), Salvia sclarea (clary sage; clary), Rosmarinus officinalis (rosemary), and Lavandula angustifolia (lavender) were assessed using a forced swim test (FST) in rats. Rats were treated with essential oils by intraperitoneal injection or inhalation. Serum levels of corticosterone were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among the essential oils tested, 5% (v/v) clary oil had the strongest anti-stressor effect in the FST. We further investigated the mechanism of clary oil antidepression by pretreatment with agonists or antagonists to serotonin (5-HT), dopamine (DA), adrenaline, and GABA receptors. The anti-stressor effect of clary oil was significantly blocked by pretreatment with buspirone (a 5-HT(1A) agonist), SCH-23390 (a D(1) receptor antagonist) and haloperidol (a D(2), D(3), and D(4) receptor antagonist). CONCLUSIONS: Our findings indicate that clary oil could be developed as a therapeutic agent for patients with depression and that the antidepressant-like effect of clary oil is closely associated with modulation of the DAnergic pathway.


Assuntos
Antidepressivos/farmacologia , Dopamina/metabolismo , Extratos Vegetais/farmacologia , Salvia/química , Animais , Corticosterona/sangue , Ensaio de Imunoadsorção Enzimática , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Dopaminérgicos/fisiologia , Receptores de GABA/fisiologia , Receptores de Serotonina/fisiologia
11.
Exp Brain Res ; 201(2): 283-96, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19826796

RESUMO

We studied whether stimulation of the primary motor cortex (M1) attenuates pain-related spinal withdrawal responses of neuropathic and healthy control rats, and whether the descending antinociceptive effect is relayed through the noradrenergic locus coeruleus (LC). The assessments of the noxious heat-evoked limb withdrawals reflecting spinal nociception and recordings of single LC units were performed in spinal nerve-ligated neuropathic and sham-operated control rats under light pentobarbital anesthesia. Electric stimulation of M1 produced equally strong spinal antinociception in neuropathic and control rats. Following microinjection into M1, a group I metabotropic glutamate receptor agonist (DHPG; 10 nmol) and a high (25 nmol) but not low (2.5 nmol) dose of glutamate slightly increased on-going discharge rates of LC neurons in neuropathic but not in control animals. Influence of electric stimulation of M1 on LC neurons was studied only in the neuropathic group, in which discharge rates of LC neurons were increased by electric M1 stimulation. Lidocaine block of the LC or block of descending noradrenergic influence by intrathecal administration of a alpha(2)-adrenoceptor antagonist failed to produce a significant attenuation of the spinal antinociceptive effect induced by electric M1 stimulation in the neuropathic or the sham group. The results indicate that stimulation of the rat M1 induces spinal antinociception in neuropathic as well as control conditions. While M1 stimulation may activate the LC, particularly in the neuropathic group, the contribution of coeruleospinal noradrenergic pathways may not be critical for the spinal antinociceptive effect induced by M1 stimulation.


Assuntos
Terapia por Estimulação Elétrica/métodos , Locus Cerúleo/fisiopatologia , Córtex Motor/fisiologia , Manejo da Dor , Dor/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/terapia , Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacologia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Animais , Vias Autônomas/fisiologia , Eletrofisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Temperatura Alta , Injeções Espinhais , Lidocaína/administração & dosagem , Lidocaína/farmacologia , Ligadura , Masculino , Microinjeções , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Resorcinóis/farmacologia , Medula Espinal , Nervos Espinhais/patologia
12.
J Biomed Sci ; 16: 72, 2009 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-19678962

RESUMO

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Atenção/efeitos dos fármacos , Comportamento Impulsivo , Morfolinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Tempo de Reação/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 2 , Animais , Discriminação Psicológica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Comportamento Alimentar/efeitos dos fármacos , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Reboxetina , Comportamento Espacial/efeitos dos fármacos , Percepção do Tempo/efeitos dos fármacos
13.
Pharmacol Res ; 59(5): 355-63, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19416636

RESUMO

We determined the role of the dopamine D2 receptor in or adjacent to the dopaminergic A11 cell group in descending modulation of neuropathic hypersensitivity. Moreover, we determined the spinal neurotransmitter receptors mediating the modulatory effect. Neuropathy was produced by spinal nerve ligation in the rat that had a chronic cannula for drug delivery into A11 or a control site in the locus coeruleus, and a catheter for spinal drug delivery. Hypersensitivity was assessed by a withdrawal response to monofilaments. Quinpirole (a dopamine D2/D3 receptor agonist) in A11 attenuated hypersensitivity, without influencing thermal nociception in the uninjured tail. Quinpirole in the locus coeruleus failed to influence hypersensitivity. L-741,626 (a dopamine D2 receptor antagonist), raclopride (a dopamine D2/D3 receptor antagonist) and bicuculline (a GABA(A) receptor antagonist) in A11 reversed the antihypersensitivity effect of quinpirole. Raclopride or bicuculline alone in A11 had no effects, whereas muscimol (a GABA(A) receptor agonist) alone in A11 suppressed hypersensitivity. Spinal administration of atipamezole (an alpha(2)-adrenoceptor antagonist) or marginally also WAY-100635 (a 5-HT(1A) receptor antagonist), but not raclopride or bicuculline, reduced the antihypersensitivity effect induced by quinpirole in A11. Electrical stimulation of A11 produced thermal antinociception following intrathecal administration of saline but not raclopride. The results indicate that activation of the dopamine D2 receptor in A11 may selectively suppress neuropathic hypersensitivity, due to mechanisms that involve GABA(A) receptors in the hypothalamus and descending noradrenergic pathways acting on spinal alpha(2)-adrenoceptors, possibly together with a slight contribution of descending serotoninergic pathways acting on spinal 5-HT(1A) receptors.


Assuntos
Vias Eferentes/fisiopatologia , Hipotálamo/fisiopatologia , Dor/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Receptores de Dopamina D2/fisiologia , Animais , Antagonistas dos Receptores de Dopamina D2 , Hipotálamo/efeitos dos fármacos , Masculino , Medição da Dor , Estimulação Física , Ratos , Ratos Endogâmicos , Receptor 5-HT1A de Serotonina/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de GABA-A/fisiologia , Medula Espinal/metabolismo
14.
J Med Food ; 10(1): 165-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17472482

RESUMO

Depression is a well-defined illness that afflicts a large population worldwide. Various biochemical theories have been described; however, the pathophysiology of depression is still poorly understood. The present study explores the role of a natural flavonoid, quercetin, in the forced swimming model of depression and its interaction with presynaptic alpha(2) adrenoceptors. Quercetin induced a significant behavioral despair, which was abrogated with pretreatment with yohimbine, an alpha(2) adrenoceptor antagonist, and imipramine, a tricyclic antidepressant. The results of the study support the contention that quercetin utilizes presynaptic alpha(2) adrenoceptors in eliciting its depressant activity in mice.


Assuntos
Depressão/fisiopatologia , Quercetina/farmacologia , Receptores Adrenérgicos alfa 2/fisiologia , Antagonistas Adrenérgicos alfa/administração & dosagem , Animais , Antidepressivos Tricíclicos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Relação Dose-Resposta a Droga , Imipramina/administração & dosagem , Camundongos , Quercetina/administração & dosagem , Quercetina/efeitos adversos , Natação , Ioimbina/administração & dosagem
15.
Pharmacol Biochem Behav ; 86(4): 643-50, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17379285

RESUMO

The compound LXM-10 (2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro [5.5]undecane chloride) is a new spirocyclopiperazinium salt compound. This is the first article to evaluate its antinociceptive effect in the abdominal constriction test induced by acetic acid and the hot-plate test. In the abdominal constriction test, LXM-10 had a significant dose-response effect, and the maximal inhibition ratio was 79.2%. In the hot-plate test, LXM-10 had significant dose-response and time-response effects. The antinociceptive effect began at 1.0 h, peaked at 2.0 h, and persisted 3.0 h after s.c. administration. The hot-plate latency was increased by 126.8% at the dose of 12.0 mg/kg. The antinociceptive effect of LXM-10 was blocked by mecamylamine (a central and peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.25, 0.5, 1.0 mg/kg, i.p.), hexamethonium (a peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), atropine (a central and peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), and atropine methylnitrate (a peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.) in a dose-dependent fashion. In contrast, the effect was not blocked by naloxone (a non-selective opioid receptor antagonist, 2.0 mg/kg, i.p.) or yohimbine (a alpha(2)-adrenergic receptor antagonist, 1.0, 2.5, 5.0 mg/kg, i.p.) in the hot-plate test. Therefore, the antinociceptive effects of LXM-10 involve the peripheral neuronal nicotinic and muscarinic acetylcholine receptors; they are not related to opioid receptors or alpha(2)-adrenergic receptors. LXM-10 did not affect motor coordination, spontaneous activity, or body temperature. These findings with LXM-10 suggest that spirocyclopiperazinium derivatives could provide insight on new analgesics.


Assuntos
Analgésicos/farmacologia , Piperazinas/farmacologia , Analgésicos/química , Animais , Atropina/farmacologia , Derivados da Atropina/farmacologia , Temperatura Corporal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Hexametônio/farmacologia , Masculino , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor , Piperazinas/química , Desempenho Psicomotor/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/fisiologia , Ioimbina/farmacologia
16.
Brain Res ; 1073-1074: 305-10, 2006 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-16457792

RESUMO

The antinociceptive effect and the mechanism of bee venom acupuncture (BVA) on inflammatory pain, especially in the rat model of collagen-induced arthritis (CIA), have not yet been fully studied. This study was designed to investigate the antinociceptive effect and its mu-opioid and alpha2-adrenergic mechanism of BVA in the CIA rat model. To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant followed by a booster injection 14 days later. The antinociceptive effect was evaluated by tail flick latency (TFL). After induction of arthritis, the inflammatory pain threshold decreased as time passed, and there was no big change of the pain threshold after 3 weeks. Three weeks after the first immunization, BVA (0.25 mg/kg) injected into the Zusanli acupoint (ST36) showed the antinociceptive effect. Furthermore, the antinociceptive effect of BVA was blocked by yohimbine (alpha2-adrenergic receptor antagonist, 2 mg/kg, i.p) pretreatment, but not by naloxone (mu-opioid receptor antagonist, 2 mg/kg, i.p.) pretreatment. These results suggest that BVA can relieve inflammatory pain in CIA and the antinociceptive effect of BVA can be mediated by alpha2-adrenergic receptor.


Assuntos
Pontos de Acupuntura , Artrite Experimental/tratamento farmacológico , Venenos de Abelha/administração & dosagem , Manejo da Dor , Receptores Adrenérgicos alfa 2/fisiologia , Antagonistas Adrenérgicos alfa/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/complicações , Comportamento Animal , Colágeno/toxicidade , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Interações Medicamentosas , Masculino , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Dor/etiologia , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Estatísticas não Paramétricas , Ioimbina/administração & dosagem
17.
J Med Food ; 8(4): 529-32, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16379567

RESUMO

The present work was planned to evaluate the antinociceptive activity of quercetin, its site of action, and the involvement of adrenergic receptors in mediating the antinociceptive activity in thermal and chemonociceptive assays. Eight groups were employed in this study: Groups I, II, and III received quercetin alone in different doses, group IV animals were administered clonidine, group V animals were co-administered quercetin and clonidine, group VI animals were administered yohimbine 30 minutes prior to administratin of quercetin, group VII animals were administered yohimbine 30 minutes prior to co-administration of quercetin and clonidine, and group VIII animals were administered 0.5% carboxymethylcellulose in saline (vehicle for quercetin). The thermal nociception was measured by tail flick and hot plate methods. Quercetin produced a significant analgesic effect in a dose-dependent manner. Co-administration of low doses of quercetin and clonidine produced a synergistic analgesic effect. Pretreatment with yohimbine significantly reversed quercetin-as well as clonidine/quercetin combination-induced effects. The results of this study reveal that quercetin induces an antinociceptive effect and that this effect involves primarily the modulation of adrenergic pathways.


Assuntos
Analgesia , Analgésicos , Quercetina , Receptores Adrenérgicos alfa 2/fisiologia , Agonistas alfa-Adrenérgicos/administração & dosagem , Animais , Clonidina/administração & dosagem , Temperatura Alta , Camundongos , Medição da Dor , Quercetina/administração & dosagem , Cauda
18.
Pain ; 115(3): 364-373, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15911163

RESUMO

The alpha2A and alpha2C adrenergic receptor (AR) subtypes mediate antinociception when activated by the endogenous ligand norepinephrine. These receptors also produce antinociceptive synergy when activated concurrently with opioid receptor activation. The involvement of the opioid receptors in the mechanisms governing transcutaneous electrical nerve stimulation (TENS) has been well described. While spinal alpha-2 ARs do not appear to be involved in TENS antihyperalgesia in rats, the noradrenergic analgesic system also involves supraspinal and peripheral sites. Thus, a broader evaluation of the potential contribution of alpha-2 AR to TENS is warranted. The current study compared the antihyperalgesic efficacy of high (100 Hz) and low (4 Hz) frequency TENS in mutant mice lacking a functional alpha2A AR against their respective wildtype counterparts. The degree of secondary heat hyperalgesia induced by intra-articular injection of carrageenan/kaolin (3%) mixture did not differ among the experimental groups. However, the antihyperalgesia induced by both low and high frequency TENS was significantly diminished in alpha2A mutant mice compared to controls. The alpha2 adrenergic receptor selective antagonist, SK&F 86466, reversed TENS-mediated antihyperalgesia when delivered intra-articularly, but not when delivered intrathecally or intracerebroventricularly. These data suggest that peripheral alpha2 ARs contribute, in part, to TENS antihyperalgesia. This pharmacodynamic response is consistent with previous anatomical observations that alpha2A ARs are expressed on primary afferent neurons and macrophages near injured tissue.


Assuntos
Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Receptores Adrenérgicos alfa 2/fisiologia , Estimulação Elétrica Nervosa Transcutânea , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Benzazepinas/farmacologia , Carragenina , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Neurônios Aferentes/fisiologia , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Receptores Adrenérgicos alfa 2/genética , Medula Espinal/fisiologia
19.
J Pain ; 5(6): 297-303, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15336634

RESUMO

UNLABELLED: Chemical acupuncture with diluted bee venom (DBV), termed apipuncture, has been traditionally used in oriental medicine to treat several inflammatory diseases and chronic pain conditions. In the present study we investigated the potential antihyperalgesic and antiallodynic effects of apipuncture in a rat neuropathic pain model. DBV (0.25 mg/kg, subcutaneous) was injected into the Zusanli acupoint 2 weeks after chronic constrictive injury (CCI) of the sciatic nerve. Between 5 and 45 minutes after DBV injection, we observed a significant reduction in the thermal hyperalgesia induced by CCI, but apipuncture failed to reduce CCI-induced mechanical allodynia. We subsequently examined whether this antihyperalgesic effect of apipuncture was related to the activation of spinal opioid receptors and/or alpha2-adrenoceptors. Intrathecal pretreatment with naloxone (10 microg/rat), an opioid receptor antagonist, did not reverse the antihyperalgesic effect of apipuncture, whereas pretreatment with idazoxan (40 microg/rat), an alpha2-adrenoceptor antagonist, completely blocked the effect of apipuncture. These results indicate that DBV-induced apipuncture significantly reduces the thermal hyperalgesia generated by CCI and also suggest that this antihyperalgesic effect is dependent on the activation of alpha2-adrenoceptors, but not opioid receptors, in the spinal cord. PERSPECTIVE: The antinociceptive effect of apipuncture was evaluated in a rodent neuropathic pain model. The relieving effect of apipuncture on thermal hyperalgesia was found to be mediated by spinal alpha2-adrenoceptors, but not opioid receptors. These data suggest that apipuncture might be an effective alternative therapy for patients with painful peripheral neuropathy, especially for those who are poorly responsive to opioid analgesics.


Assuntos
Pontos de Acupuntura , Venenos de Abelha/administração & dosagem , Hiperalgesia/terapia , Manejo da Dor , Receptores Adrenérgicos alfa 2/fisiologia , Antagonistas Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
20.
Neuropsychopharmacology ; 29(7): 1282-93, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15039766

RESUMO

Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). alpha2-Adrenoceptors (alpha2-ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto- and heteroreceptors. Modulation of acoustic startle and its PPI by the alpha2A-AR subtype was investigated with mice lacking the alpha2A-AR (alpha2A-KO) and their wild-type (WT) controls, without drugs and after administration of the alpha2-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the alpha2-AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. alpha2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of alpha2A-KO mice were depleted by D-amph, revealing the alpha2A-AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated alpha2A-KO mice. alpha2A-AR also appeared to be responsible for the startle-modulating effects of alpha2-AR drugs, since the startle attenuation after the alpha2-AR agonist dexmedetomidine was absent in alpha2A-KO mice, and the alpha2-AR antagonist atipamezole had opposite effects on the startle reflex in alpha2A-KO and WT mice.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Anfetamina/farmacologia , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica/métodos , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Comportamento Animal , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Dexmedetomidina/farmacologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Interações Medicamentosas , Estimulação Elétrica/métodos , Feminino , Imidazóis/farmacologia , Inibição Psicológica , Masculino , Camundongos , Camundongos Knockout
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