Stimulation of α1-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABAA receptors and T-type Ca2+ channels

Yuan, Wei; Chen, Shao‐Rui; Chen, Hong; Pan, Hui Lin

doi:10.1016/j.neuroscience.2008.11.022

Cited by 28 publications

(32 citation statements)

References 56 publications

(89 reference statements)

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“…Presynaptic GABA A receptor activation, which is produced by the release of GABA from spinal interneurons, inhibits glutamatergic input from primary afferents to dorsal horn neurons (Yuan et al, 2009). In this study, we demonstrated that nerve injury induced a depolarizing shift of E GABA in DRG neurons and that intrathecal KCC2 gene transfer completely reversed this depolarizing shift.…”

Section: Discussionmentioning

confidence: 99%

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Chen

et al. 2016

Cell Reports

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SUMMARY Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR) activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain. However, the reciprocal relationship between synaptic inhibition and excitation in neuropathic pain is unclear. Here we show that intrathecal delivery of K+-Cl− cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores Cl− homeostasis disrupted by nerve injury in both spinal dorsal horn and primary sensory neurons. Remarkably, restoring Cl− homeostasis normalizes both presynaptic and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn. Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways through disrupting Cl− homeostasis in spinal dorsal horn and primary sensory neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for treating neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Chen

et al. 2016

Cell Reports

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“…Presynaptic α1-ARs’ activation mediates inhibition of GABA-releasing cells in rat hippocampal cultures, auditory cortex, cerebellum and spinal dorsal horn neurons (Mouradian et al, 1991, Croce et al, 2003, Yuan et al, 2009, Salgado et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Alpha-1 adrenoreceptors modulate GABA release onto ventral tegmental area dopamine neurons

et al. 2015

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The ventral tegmental area (VTA) plays an important role in reward and motivational processes involved in drug addiction. Previous studies have shown that alpha1-adrenoreceptors (α1-AR) are primarily found presynaptically at this area. We hypothesized that GABA released onto VTA-dopamine (DA) cells is modulated by presynaptic α1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28–50 days postnatal) using whole-cell voltage clamp technique. Phenylephrine (10µM; α1-AR agonist) decreased the amplitude of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) evoked by electrical stimulation of afferent fibers (n=7; p<0.05). Prazosin (1µM, α1-AR antagonist), blocked this effect. Paired-pulse ratios were increased by phenylephrine application (n=13; p<0.05) indicating a presynaptic site of action. Spontaneous IPSCs frequency but not amplitude, were decreased in the presence of phenylephrine (n=7; p<0.05). However, frequency or amplitude of miniature IPSCs were not changed (n=9; p>0.05). Phenylephrine in low Ca2+ (1mM) medium decreased IPSC amplitude (n=7; p<0.05). Chelerythrine (a protein kinase C inhibitor) blocked the α1-AR action on IPSC amplitude (n=6; p<0.05). Phenylephrine failed to decrease IPSCs amplitude in the presence of paxilline, a BK channel blocker (n=7; p<0.05). Taken together, these results demonstrate that α1-ARs at presynaptic terminals can modulate GABA release onto VTA-DA cells. Drug-induced changes in α1-AR could contribute to the modifications occurring in the VTA during the addiction process.

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“…In the CNS, facilitation of rat spinal motoneuron activity [145] and of vasopressin release [146] are reported to be mediated by a1-adrenoceptors. a1-Adrenoceptor activation stimulates inhibitory GABAergic neurotransmission in rat spinal cord [147], rat cerebellum [148], mouse accessory olfactory bulb [149] and mouse hypothalamus [150]. The a1-adrenoceptor-mediated facilitation may involve protein kinase C and increases in intracellular calcium [146,148,151].…”

Section: A1-adrenoceptor-mediated Inhibitionmentioning

confidence: 99%

Subtypes of functional α1-adrenoceptor

Docherty

2009

Cell. Mol. Life Sci.

155

127

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In this review, subtypes of functional alpha1-adrenoceptor are discussed. These are cell membrane receptors, belonging to the seven-transmembrane-spanning G-protein-linked family of receptors, which respond to the physiological agonist noradrenaline. alpha1-Adrenoceptors can be divided into alpha1A-, alpha1B- and alpha1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A fourth alpha1-adrenoceptor, the alpha1L-, represents a functional phenotype of the alpha1A-adrenoceptor. alpha1-Adrenoceptor subtype knock-out mice have refined our knowledge of the functions of alpha-adrenoceptor subtypes, particuarly as subtype-selective agonists and antagonists are not available for all subtypes. alpha1-Adrenoceptors function as stimulatory receptors involved particularly in smooth muscle contraction, especially contraction of vascular smooth muscle, both in local vasoconstriction and in the control of blood pressure and temperature, and contraction of the prostate and bladder neck. Central actions are now being elucidated.

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Stimulation of α1-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABAA receptors and T-type Ca2+ channels

Cited by 28 publications

References 56 publications

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Alpha-1 adrenoreceptors modulate GABA release onto ventral tegmental area dopamine neurons

Subtypes of functional α1-adrenoceptor

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