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1.
Naunyn Schmiedebergs Arch Pharmacol ; 396(10): 2555-2570, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37014401

RESUMO

6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that is released from the rat isolated vas deferens, and has been characterized as a major modulator of the contractility of rat isolated epididymal vas deferens (RIEVD). Drugs such as tricyclic antidepressants, α1 and ß1ß2 adrenoceptor blockers, act as selective antagonists of the 6-ND receptor in the RIEVD. In the rat isolated atria, 6-ND has a potent positive chronotropic action and causes remarkable potentiation of the positive chronotropic effects induced by dopamine, noradrenaline, and adrenaline. Here, whether 6-ND interacts with the classical catecholamines in the rat isolated vas deferens was investigated. Incubation with 6-ND (0.1 and 1 nM; 30min) caused no contractions in the RIEVD but provoked significant leftward shifts in the concentration-response curves to noradrenaline, adrenaline, and dopamine. Pre-incubation of the RIEVD with 6-ND (1 nM), potentiated the contractions induced by electric-field stimulation (EFS), whereas pre-incubation with 1 nM of dopamine, noradrenaline or adrenaline, did not affect EFS-induced contractions. In tetrodotoxin (1 µM) pre-treated (30 min) RIEVD, pre-incubation with 6-ND (0.1 nM) did not cause leftward shifts in the concentration-dependent contractions induced by noradrenaline, adrenaline, or dopamine. Pre-incubation of the RIEVD with the α2A-adrenoceptor antagonist idazoxan (30 min, 10 nM) did not affect dopamine, noradrenaline, adrenaline, and EFS-induced contractions. However, when idazoxan (10 nM) and 6-ND (0.1 nM) were simultaneously pre-incubated (30 min), a significant potentiation of the EFS-induced contractions of the RIEVD was observed. 6-nitrodopamine causes remarkable potentiation of dopamine, noradrenaline, and adrenaline contractions on the RIEVD, due to activation of adrenergic terminals, possibly via pre-synaptic adrenoceptors.


Assuntos
Norepinefrina , Ducto Deferente , Masculino , Ratos , Animais , Norepinefrina/farmacologia , Epinefrina/farmacologia , Dopamina/farmacologia , Idazoxano/farmacologia , Catecolaminas/farmacologia , Receptores Adrenérgicos , Estimulação Elétrica , Contração Muscular
2.
Neuropharmacology ; 220: 109258, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36116534

RESUMO

Adrenergic receptors (AR) in the ventral tegmental area (VTA) modulate local neuronal activity and, as a consequence, dopamine (DA) release in the mesolimbic forebrain. Such modulation has functional significance: intra-VTA blockade of α1-AR attenuates behavioral responses to salient environmental stimuli in rat models of drug seeking and conditioned fear as well as phasic DA release in the nucleus accumbens (NAc). In contrast, α2-AR in the VTA has been suggested to act primarily as autoreceptors, limiting local noradrenergic input. The regulation of noradrenaline efflux by α2-AR could be of clinical interest, as α2-AR agonists are proposed as promising pharmacological tools in the treatment of PTSD and substance use disorder. Thus, the aim of our study was to determine the subtype-specificity of α2-ARs in the VTA capable of modulating phasic DA release. We used fast scan cyclic voltammetry (FSCV) in anaesthetized male rats to measure DA release in the NAc after combined electrical stimulation and infusion of selected α2-AR antagonists into the VTA. Intra-VTA microinfusion of idazoxan - a non-subtype-specific α2-AR antagonist, as well as BRL-44408 - a selective α2A-AR antagonist, attenuated electrically-evoked DA in the NAc. In contrast, local administration of JP-1302 or imiloxan (α2B- and α2C-AR antagonists, respectively) had no effect. The effect of BRL-44408 on DA release was attenuated by intra-VTA DA D2 antagonist (raclopride) pre-administration. Finally, we confirmed the presence of α2A-AR protein in the VTA using western blotting. In conclusion, these data specify α2A-, but not α2B- or α2C-AR as the receptor subtype controlling NA release in the VTA.


Assuntos
Núcleo Accumbens , Área Tegmentar Ventral , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Autorreceptores/metabolismo , Dopamina/metabolismo , Idazoxano/farmacologia , Masculino , Norepinefrina/metabolismo , Racloprida/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/metabolismo
3.
Naunyn Schmiedebergs Arch Pharmacol ; 395(3): 365-376, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34997272

RESUMO

Agmatine (AG), idazoxan (IDZ), and efaroxan (EFR) are imidazoline receptor ligands with beneficial effects in central nervous system disorders. The present study aimed to evaluate the interaction between AG, IDZ, and EFR with an opiate, tramadol (TR), in a conditioned place preference (CPP) paradigm. In the experiment, we used five groups with 8 adult male Wistar rats each. During the condition session, on days 2, 4, 6, and 8, the rats received the drugs (saline, or TR, or IDZ and TR, or EFR and TR, or AG and TR) and were placed in their least preferred compartment. On days 1, 3, 5, and 7, the rats received saline in the preferred compartment. In the preconditioning, the preferred compartment was determined. In the postconditioning, the preference for one of the compartments was reevaluated. TR increased the time spent in the non-preferred compartment. AG decreased time spent in the TR-paired compartment. EFR, more than IDZ, reduced the time spent in the TR-paired compartment, but without statistical significance. AG reversed the TR-induced CPP, while EFR and IDZ only decreased the time spent in the TR-paired compartment, without statistical significance.


Assuntos
Agmatina/farmacologia , Benzofuranos/farmacologia , Idazoxano/farmacologia , Imidazóis/farmacologia , Tramadol/farmacologia , Analgésicos Opioides/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Interações Medicamentosas , Receptores de Imidazolinas/efeitos dos fármacos , Receptores de Imidazolinas/metabolismo , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
4.
Res Vet Sci ; 135: 175-183, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33529845

RESUMO

Non-selective α2-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α2-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α2C-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α2-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α2C-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α2C-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Benzofuranos/farmacologia , Hipocampo/efeitos dos fármacos , Idazoxano/farmacologia , Quinolizidinas/farmacologia , Animais , Antidepressivos/farmacologia , Dopamina/metabolismo , Hipocampo/metabolismo , Imipramina/farmacologia , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa 2/metabolismo , Serotonina/metabolismo , Estresse Fisiológico
5.
Mol Inform ; 39(7): e1900165, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32078760

RESUMO

Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors - rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2 - adrenoceptors.


Assuntos
Imidazolinas/química , Receptores Acoplados a Proteínas G/metabolismo , Animais , Área Sob a Curva , Benzofuranos/química , Benzofuranos/farmacologia , Células CHO , Cricetulus , Humanos , Idazoxano/química , Idazoxano/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Imidazolinas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Receptores Adrenérgicos alfa 2/metabolismo , Reprodutibilidade dos Testes
6.
Biochem Biophys Res Commun ; 519(4): 697-704, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31542234

RESUMO

At present, whether α2-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related anxiety is unclear. We examined the effects of PrL α2-adrenoceptors on anxiety-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Compared to the sham operation, the lesion induced anxiety-like responses as measured by the open field test and elevated plus-maze test. Intra-PrL injection of the α2-adrenoceptor agonist clonidine (1.25, 2.5 or 5 µg/rat) produced anxiolytic effects in sham-operated and lesioned rats. Furthermore, intra-PrL injection of the α2-adrenoceptor antagonist idazoxan (1, 2 or 4 µg/rat) induced anxiogenic effects in two groups of rats. The effective doses produced by clonidine and idazoxan in lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of clonidine (5 µg/rat) or idazoxan (4 µg/rat) decreased or increased dopamine (DA) and noradrenaline (NA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) and amygdala in sham-operated and lesioned rats, respectively. These results suggest that α2-adrenoceptors in the PrL are involved in the regulation of anxiety-like behaviors, which is attributable to changes in DA, NA and 5-HT levels in the mPFC and amygdala after activation and blockade of α2-adrenoceptors.


Assuntos
Ansiedade/metabolismo , Sistema Límbico/metabolismo , Transtornos Parkinsonianos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/fisiopatologia , Aminas Biogênicas/metabolismo , Clonidina/farmacologia , Idazoxano/farmacologia , Sistema Límbico/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley
7.
Toxins (Basel) ; 11(7)2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288453

RESUMO

Oxaliplatin is a chemotherapeutic agent used for metastatic colon and other advanced cancers. Most common side effect of oxaliplatin is peripheral neuropathy, manifested in mechanical and cold allodynia. Although the analgesic effect of bee venom has been proven to be effective against oxaliplatin-induced peripheral neuropathy, the effect of its major component; melittin has not been studied yet. Thus, in this study, we investigated whether melittin has an analgesic effect on oxaliplatin-induced allodynia. Intraperitoneal single injection of oxaliplatin (6 mg/kg) induced mechanical and cold allodynia, resulting in increased withdrawal behavior in response to von Frey filaments and acetone drop on hind paw. Subcutaneous melittin injection on acupoint ST36 (0.5 mg/kg) alleviated oxaliplatin-induced mechanical and cold allodynia. In electrophysiological study, using spinal in vivo extracellular recording, it was shown that oxaliplatin-induced hyperexcitation of spinal wide dynamic range neurons in response to peripheral stimuli, and melittin administration inhibited this neuronal activity. In behavioral assessment, analgesic effect of melittin was blocked by intrathecal α1- and α2- adrenergic receptor antagonists administration. Based on these results, we suggest that melittin could be used as an analgesic on oxaliplatin-induced peripheral neuropathy, and that its effect is mediated by activating the spinal α1- and α2-adrenergic receptors.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Meliteno/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos/farmacologia , Animais , Antineoplásicos , Temperatura Baixa , Hiperalgesia/induzido quimicamente , Idazoxano/farmacologia , Meliteno/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Prazosina/farmacologia , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , Tato
8.
Alcohol Clin Exp Res ; 43(4): 747-757, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735249

RESUMO

BACKGROUND: Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice. METHODS: Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 µg/mouse), endogenous agmatine enhancers (l-arginine [80 µg/mouse], arcaine [50 µg/mouse], aminoguanidine [25 µg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11. RESULTS: Agmatine (20 to 40 µg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80 µg/mouse) or arcaine (50 µg/mouse) and aminoguanidine (25 µg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I1 receptor agonist, moxonidine, and I2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I1 receptor antagonist, efaroxan, and I2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization. CONCLUSIONS: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.


Assuntos
Agmatina/farmacologia , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Etanol/antagonistas & inibidores , Agmatina/antagonistas & inibidores , Animais , Arginina/administração & dosagem , Arginina/farmacologia , Benzofuranos/farmacologia , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Etanol/farmacologia , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Idazoxano/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/agonistas , Receptores de Imidazolinas/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Camundongos , Microinjeções , Atividade Motora/efeitos dos fármacos
9.
Peptides ; 115: 1-7, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772446

RESUMO

26RFa is an endogenous ligand for the QRFP receptor. We previously found that intracerebroventricular injection of 26RFa produces an analgesic effect in a rat formalin test. In the present study, we directly tested the hypothesis that the analgesic effects of 26RFa in the formalin test are mediated in well-recognized regions of the descending inhibitory pain pathways, such as the rostral ventromedial medulla (RVM), locus coeruleus (LC), and periaqueductal grey (PAG) in rats. Injection cannulae were stereotaxically placed in the RVM, LC, or PAG through a burr hole. 26RFa (15 µg) or saline was delivered in a total volume of 0.5 µL. In a formalin test, 50 µL of 5% formalin was injected subcutaneously into the hind paw. In an antagonist study, idazoxan, an α-2 antagonist, or naloxone, an opioid receptor antagonist, was administered. Microinjection of 26RFa into the RVM had no effect compared with that in saline-injected rats. Microinjection of 26RFa into the LC contralateral, but not ipsilateral, to the formalin injection site significantly decreased the number of flinching behaviors compared with that of saline-injected rats. This effect was antagonized by intrathecal injection of idazoxan. Microinjection of 26RFa into the contralateral, but not ipsilateral, PAG produced an analgesic effect, and this effect was partly antagonized by intraperitoneal naloxone. These data suggest that 26RFa microinjected into the contralateral LC induced noradrenaline release in the spinal cord and produced an analgesic effect. In the contralateral PAG, 26RFa activated the opioid system, and some analgesic effects were mediated by opioid system activation.


Assuntos
Analgésicos/farmacologia , Locus Cerúleo/metabolismo , Microinjeções , Neuropeptídeos/farmacologia , Substância Cinzenta Periaquedutal/metabolismo , Receptores Acoplados a Proteínas G , Animais , Antagonismo de Drogas , Idazoxano/antagonistas & inibidores , Idazoxano/farmacologia , Masculino , Naloxona/antagonistas & inibidores , Naloxona/farmacologia , Neuropeptídeos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo
10.
Addict Biol ; 24(3): 509-521, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29480583

RESUMO

Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a ß or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a ß or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value.


Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Memória/efeitos dos fármacos , Recompensa , Neurônios Adrenérgicos/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Tronco Encefálico/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos beta/fisiologia , Restrição Física , Estresse Psicológico/fisiopatologia , Tegmento Mesencefálico/efeitos dos fármacos , Timolol/farmacologia
11.
Clin Exp Hypertens ; 41(3): 255-262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29764227

RESUMO

Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.


Assuntos
Receptores de Imidazolinas/fisiologia , Bulbo/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Benzofuranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , Clonidina/farmacologia , Estado de Consciência/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Imidazóis/farmacologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/efeitos dos fármacos
12.
Behav Pharmacol ; 30(5): 429-434, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30383551

RESUMO

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.


Assuntos
Hiperalgesia/tratamento farmacológico , Idazoxano/farmacologia , Receptores de Imidazolinas/metabolismo , Analgésicos/farmacologia , Animais , Benzofuranos/farmacologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Fibromialgia/tratamento farmacológico , Hiperalgesia/induzido quimicamente , Idazoxano/metabolismo , Imidazóis/farmacologia , Receptores de Imidazolinas/agonistas , Imidazolinas/metabolismo , Imidazolinas/farmacologia , Masculino , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Quinazolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Reserpina/farmacologia
13.
Respir Physiol Neurobiol ; 258: 25-31, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30292742

RESUMO

Among vertebrate ectotherms, air breathing frequency is generally constrained across warmer temperatures, but decreases during cooling. The brainstem mechanisms that give rise to this ventilatory strategy are unclear. Neuromodulation has recently been shown to stabilize motor circuit output across temperatures. Therefore, we tested the hypothesis that an important neuromodulatory system in respiratory control network, norepinephrine, produces this pattern of respiratory motor activity across temperatures. To this end, we used in vitro brainstem-spinal cord preparations from adult bullfrogs, Lithobates catesbeianus, to assess the role of noradrenergic signaling in shaping the frequency response of the respiratory network during temperature changes. We identified that noradrenergic signaling through the α1 adrenergic receptor constrains motor output from the respiratory network across warm temperatures. In contrast, the α2 adrenergic receptor actively inhibits respiratory motor output during cooling. These results indicate that noradrenergic tuning, rather than passive thermal responses, produces temperature responses of the respiratory circuits.


Assuntos
Tronco Encefálico/fisiologia , Norepinefrina/farmacologia , Respiração , Temperatura , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Tronco Encefálico/citologia , Tronco Encefálico/efeitos dos fármacos , Feminino , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Técnicas In Vitro , Neurônios Motores/efeitos dos fármacos , Prazosina/farmacologia , Rana catesbeiana , Respiração/efeitos dos fármacos , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
14.
Transl Psychiatry ; 8(1): 201, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250120

RESUMO

The dorsal diencephalic conduction system connects limbic forebrain structures to monaminergic mesencephalic nuclei via a distinct relay station, the habenular complexes. Both habenular nuclei, the lateral as well as the medial nucleus, are considered to play a prominent role in mental disorders like major depression. Herein, we investigate the effect of the polyamine agmatine on the electrical activity of neurons within the medial habenula in rat. We present evidence that agmatine strongly decreases spontaneous action potential firing of medial habenular neurons by activating I1-type imidazoline receptors. Additionally, we compare the expression patterns of agmatinase, an enzyme capable of inactivating agmatine, in rat and human habenula. In the medial habenula of both species, agmatinase is similarly distributed and observed in neurons and, in particular, in distinct neuropil areas. The putative relevance of these findings in the context of depression is discussed. It is concluded that increased activity of the agmatinergic system in the medial habenula may strengthen midbrain dopaminergic activity. Consequently, the habenular-interpeduncular axis may be dysregulated in patients with major depression.


Assuntos
Agmatina/farmacologia , Depressão/fisiopatologia , Habenula/efeitos dos fármacos , Habenula/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Benzofuranos/farmacologia , Depressão/prevenção & controle , Feminino , Humanos , Idazoxano/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/agonistas , Receptores de Imidazolinas/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Ratos Wistar , Ureo-Hidrolases/metabolismo
15.
Can J Physiol Pharmacol ; 96(8): 845-849, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29633624

RESUMO

This study evaluated whether imidazolines can induce autophagy in the murine macrophage-like cell line RAW264.7. Idazoxan increased the content of LC3-II, an autophagosomal marker, in RAW264.7 cells. To determine whether this effect was due to the induction of its synthesis or inhibition of its degradation, idazoxan treatment was performed in the presence of bafilomycin A1, which blocks autophagosome-lysosome fusion, as well as Pepstatin A and E-64d, both of which block protein degradation in autolysosomes. An increased content of LC3-II was observed in the presence of bafilomycin A1 as well as the protease inhibitors. Furthermore, an increased number of autophagosomes was observed following idazoxan treatment using an autophagosome-specific dye. This indicated that idazoxan induced autophagy. Other imidazolines, such as efaroxan, clonidine, and 2-(2-benzofuranyl)-2-imidazoline, also increased the LC3-II content in RAW264.7 cells in the presence of bafilomycin A1. Taken together, these results indicate that some imidazolines, including idazoxan, can induce autophagy in RAW264.7 cells.


Assuntos
Autofagossomos/metabolismo , Imidazolinas/farmacologia , Macrófagos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Contagem de Células , Idazoxano/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrolídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Mol Neurobiol ; 55(11): 8438-8454, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29552726

RESUMO

The poor norepinephrine innervation and high density of Gi/o-coupled α2A- and α2C-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2-like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2-adrenoceptors in cortical and striatal tissue, which express α2A-adrenoceptors and both α2A- and α2C-adrenoceptors, respectively. The affinity of dopamine for α2-adrenoceptors was found to be similar to that for D1-like and D2-like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α2A- and α2C-adrenoceptors. Their ability to activate Gi/o proteins through α2A- and α2C-adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α2-adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α2A- and α2C-adrenoceptors was nearly identical to its binding to the crystallized D3 receptor. Therefore, we provide conclusive evidence that α2A- and α2C-adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D2-like receptor ligands, which calls for revisiting previous studies with those ligands.


Assuntos
Dopamina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Adenilil Ciclases/metabolismo , Animais , Córtex Cerebral/metabolismo , Clonidina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Ligantes , Neostriado/metabolismo , Norepinefrina/metabolismo , Fosforilação/efeitos dos fármacos , Quimpirol/farmacologia , Ovinos , Tetra-Hidronaftalenos/farmacologia
17.
Behav Brain Res ; 347: 158-166, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-29526788

RESUMO

Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play-suppressant effect of methylphenidate. To that aim, we tested whether infusion of the α2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the α2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Córtex Cerebral/efeitos dos fármacos , Habenula/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Comportamento Social , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Córtex Cerebral/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Habenula/metabolismo , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Ratos Wistar , Recompensa
18.
Neuropharmacology ; 135: 202-210, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29551688

RESUMO

Tapentadol is an analgesic that acts as an agonist of µ opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9 ±â€¯0.1 Hz) was lower than in naïve animals (1.5 ±â€¯0.1 Hz), and tapentadol's inhibitory effect was also weaker. Alpha2-adrenoceptors blockade by RX821002 (100 µg/kg i.v.) in STZ animals significantly increased the spontaneous activity (from 0.8 ±â€¯0.1 to 1.4 ±â€¯0.2 Hz) and it dampened the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following naloxone pre-treatment (5 mg/kg i.v.) did not alter the spontaneous firing rate (0.9 ±â€¯0.2 vs 0.9 ±â€¯0.2 Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus, diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity seems to be predominantly mediated through its noradrenergic effects rather than its influence on opioid receptors in the STZ model of diabetic polyneuropathy.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/fisiopatologia , Locus Cerúleo/citologia , Inibição Neural/efeitos dos fármacos , Tapentadol/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Naloxona/farmacologia , Neurônios/fisiologia , Medição da Dor/efeitos dos fármacos , Ratos , Tapentadol/antagonistas & inibidores
19.
Brain Res Bull ; 139: 174-181, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29432796

RESUMO

The activation of GABA, opioid or α2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or α2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or α2-adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABAA and GABAB agonists, respectively, 0.5 nmol/0.2 µl) into the LPBN induced strong ingestion of 0.3 M NaCl (45.8 ±â€¯7.3 and 21.8 ±â€¯4.8 ml/240 min, respectively) and water intake (22.7 ±â€¯3.4 and 6.6 ±â€¯2.5 ml/240 min, respectively). Naloxone (opioid antagonist, 150 nmol/0.2 µl) into the LPBN abolished 0.3 M NaCl and water intake to muscimol (2.0 ±â€¯0.6 and 0.9 ±â€¯0.2 ml/240 min, respectively) or baclofen (2.3 ±â€¯1.1 and 0.8 ±â€¯0.4 ml/240 min, respectively). RX 821002 (α2 adrenoceptor antagonist, 10 nmol/0.2 µl) into the LPBN reduced 0.3 M NaCl intake induced by the injections of muscimol or baclofen (26.6 ±â€¯8.0 and 10.1 ±â€¯4.9 ml/240 min, respectively). RX 821002 reduced water intake induced by muscimol (7.7 ±â€¯2.9 ml/240 min), not by baclofen. The results suggest that sodium intake caused by gabaergic activation in the LPBN in normohydrated rats is totally dependent on the activation of opioid mechanisms and partially dependent on the activation of α2 adrenergic mechanisms in the LPBN.


Assuntos
Analgésicos Opioides/metabolismo , Agonistas GABAérgicos/farmacologia , Núcleos Parabraquiais/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Sódio/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Baclofeno/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Interações Medicamentosas , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Muscimol/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Fatores de Tempo
20.
Brain Behav Immun ; 69: 456-469, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29339319

RESUMO

The impact of treatment with the noradrenaline (NA) re-uptake inhibitor atomoxetine and the α2-adrenoceptor (AR) antagonist idazoxan in an animal model of Parkinson's disease (PD) was assessed. Concurrent systemic treatment with atomoxetine and idazoxan, a combination which serves to enhance the extra-synaptic availability of NA, exerts anti-inflammatory and neuroprotective effects following delivery of an inflammatory stimulus, the bacterial endotoxin, lipopolysaccharide (LPS) into the substantia nigra. Lesion-induced deficits in motor function (akinesia, forelimb-use asymmetry) and striatal dopamine (DA) loss were rescued to varying degrees depending on the treatment. Treatment with atomoxetine following LPS-induced lesion to the substantia nigra, yielded a robust anti-inflammatory effect, suppressing microglial activation and expression of the pro-inflammatory cytokine TNF-α whilst increasing the expression of neurotrophic factors. Furthermore atomoxetine treatment prevented loss of tyrosine hydroxylase (TH) positive nigral dopaminergic neurons and resulted in functional improvements in motor behaviours. Atomoxetine alone was sufficient to achieve most of the observed effects. In combination with idazoxan, an additional improvement in the impairment of contralateral limb use 7 days post lesion and a reduction in amphetamine-mediated rotational asymmetry 14 days post-lesion was observed, compared to atomoxetine or idazoxan treatments alone. The results indicate that increases in central NA tone has the propensity to regulate the neuroinflammatory phenotype in vivo and may act as an endogenous neuroprotective mechanism where inflammation contributes to the progression of DA loss. In accordance with this, the clinical use of agents such as NA re-uptake inhibitors and α2-AR antagonists may prove useful in enhancing the endogenous neuroimmunomodulatory potential of NA in conditions associated with brain inflammation.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Idazoxano/farmacologia , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Cloridrato de Atomoxetina/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Idazoxano/uso terapêutico , Lipopolissacarídeos , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Ratos , Ratos Wistar , Resultado do Tratamento
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