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1.
Nat Neurosci ; 14(3): 351-5, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21209617

RESUMO

Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Condicionamento Clássico/fisiologia , Comportamento Alimentar/fisiologia , Neurônios/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Comportamento Animal/fisiologia , Channelrhodopsins , Ingestão de Alimentos , Hipotálamo/citologia , Hipotálamo/metabolismo , Melanocortinas/metabolismo , Camundongos , Estimulação Luminosa , Pró-Opiomelanocortina/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
2.
Eur J Neurosci ; 29(6): 1188-96, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19302154

RESUMO

Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a mu-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.


Assuntos
Analgésicos não Narcóticos/farmacologia , Tolerância a Medicamentos/fisiologia , Bulbo/citologia , Neurônios/efeitos dos fármacos , Dor/patologia , Substância Cinzenta Periaquedutal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Aspirina/farmacologia , Dipirona/farmacologia , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Tempo de Reação/efeitos dos fármacos , Somatostatina/análogos & derivados , Somatostatina/farmacologia
4.
J Physiol ; 586(8): 2061-75, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18276734

RESUMO

Fast-spiking parvalbumin-expressing basket cells (BCs) represent a major type of inhibitory interneuron in the hippocampus. These cells inhibit principal cells in a temporally precise manner and are involved in the generation of network oscillations. Although BCs show a unique expression profile of Ca(2+)-permeable receptors, Ca(2+)-binding proteins and Ca(2+)-dependent signalling molecules, physiological Ca(2+) signalling in these interneurons has not been investigated. To study action potential (AP)-induced dendritic Ca(2+) influx and buffering, we combined whole-cell patch-clamp recordings with ratiometric Ca(2+) imaging from the proximal apical dendrites of rigorously identified BCs in acute slices, using the high-affinity Ca(2+) indicator fura-2 or the low-affinity dye fura-FF. Single APs evoked dendritic Ca(2+) transients with small amplitude. Bursts of APs evoked Ca(2+) transients with amplitudes that increased linearly with AP number. Analysis of Ca(2+) transients under steady-state conditions with different fura-2 concentrations and during loading with 200 microm fura-2 indicated that the endogenous Ca(2+)-binding ratio was approximately 200 (kappa(S) = 202 +/- 26 for the loading experiments). The peak amplitude of the Ca(2+) transients measured directly with 100 microm fura-FF was 39 nm AP(-1). At approximately 23 degrees C, the decay time constant of the Ca(2+) transients was 390 ms, corresponding to an extrusion rate of approximately 600 s(-1). At 34 degrees C, the decay time constant was 203 ms and the corresponding extrusion rate was approximately 1100 s(-1). At both temperatures, continuous theta-burst activity with three to five APs per theta cycle, as occurs in vivo during exploration, led to a moderate increase in the global Ca(2+) concentration that was proportional to AP number, whereas more intense stimulation was required to reach micromolar Ca(2+) concentrations and to shift Ca(2+) signalling into a non-linear regime. In conclusion, dentate gyrus BCs show a high endogenous Ca(2+)-binding ratio, a small AP-induced dendritic Ca(2+) influx, and a relatively slow Ca(2+) extrusion. These specific buffering properties of BCs will sharpen the time course of local Ca(2+) signals, while prolonging the decay of global Ca(2+) signals.


Assuntos
Potenciais de Ação/fisiologia , Artefatos , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Hipocampo/fisiologia , Interneurônios/fisiologia , Projetos de Pesquisa , Animais , Células Cultivadas , Ratos , Ratos Wistar
5.
J Physiol ; 574(Pt 1): 229-43, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16690716

RESUMO

Hyperpolarization-activated channels (Ih or HCN channels) are widely expressed in principal neurons in the central nervous system. However, Ih in inhibitory GABAergic interneurons is less well characterized. We examined the functional properties of Ih in fast-spiking basket cells (BCs) of the dentate gyrus, using hippocampal slices from 17- to 21-day-old rats. Bath application of the Ih channel blocker ZD 7288 at a concentration of 30 microm induced a hyperpolarization of 5.7 +/- 1.5 mV, an increase in input resistance and a correlated increase in apparent membrane time constant. ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC50, 1.4 microm). The effects of ZD 7288 were mimicked by external Cs+. The reversal potential of Ih was -27.4 mV, corresponding to a Na+ to K+ permeability ratio (PNa/PK) of 0.36. The midpoint potential of the activation curve of Ih was -83.9 mV, and the activation time constant at -120 mV was 190 ms. Single-cell expression analysis using reverse transcription followed by quantitative polymerase chain reaction revealed that BCs coexpress HCN1 and HCN2 subunit mRNA, suggesting the formation of heteromeric HCN1/2 channels. ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of Ih in BC axons. Finally, ZD 7288 decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal granule cells, the main target cells of BCs, to 70 +/- 4% of the control value. In contrast, the amplitude of mIPSCs was unchanged, consistent with the presence of Ih in inhibitory terminals. In conclusion, our results suggest that Ih channels are expressed in the somatodendritic region, axon and presynaptic elements of fast-spiking BCs in the hippocampus.


Assuntos
Potenciais de Ação/fisiologia , Relógios Biológicos/fisiologia , Hipocampo/fisiologia , Interneurônios/fisiologia , Canais Iônicos/metabolismo , Potenciais da Membrana/fisiologia , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Ativação do Canal Iônico/fisiologia , Canais de Potássio , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/metabolismo
6.
Pain ; 112(1-2): 113-20, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15494191

RESUMO

The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 microl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 microg/0.5 microl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 microg/0.5 microl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 microg/0.5 microl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.


Assuntos
Analgésicos Opioides/administração & dosagem , Colecistocinina/administração & dosagem , Dipirona/administração & dosagem , Tolerância a Medicamentos/fisiologia , Microinjeções/métodos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Animais , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Sprague-Dawley
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