Neurosteroids and GABA-A Receptor Function

Wang, Mingde

doi:10.3389/fendo.2011.00044

Cited by 143 publications

(118 citation statements)

References 342 publications

(522 reference statements)

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“…Studies have also demonstrated FAE-induced decreases in allopregnanolone potentiation of [ 3 H]flunitrazepam binding to hippocampal GABA A Rs in guinea pigs [100], age-dependent changes in a5 GABA A R subunit expression in mice [101], and increased d GABA A R subunit expression and sensitivity to THIP in cerebellar granule neurons of rats after early postnatal (P2-12) EtOH vapor exposure [102]. Neurosteroids, such as 3a,5a-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) and 3a;5a-tetrahydrodeoxycorticosterone (THDOC), are potent endogenous modulators of d subunitcontaining GABA A Rs [103]. Acute EtOH dynamically regulates local 3a,5a-THP levels in several subcortical regions of adult rats, independent of the adrenal glands [104,105].…”

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confidence: 99%

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

et al. 2014

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Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH's many pharmacological targets is the c-aminobutyric acid type A receptor (GABA A R), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABA A R subtypes, whereas chronic EtOH leads to persistent alterations in GABA A R subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH's intoxicating effects in vivo and in vitro at enhancing GABA A R function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABA A R function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0 g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5 g/kg) rats tested on postnatal days (P) 25-32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patchclamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5 g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (I tonic ) to potentiation by zolpidem (0.3 lM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of I tonic decreased in DGCs from FAE rats. Coadministration of EtOH (1.5 or 2.5 g/kg) with DHM (1.0 mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABA A R function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABA A R function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.

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confidence: 99%

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

et al. 2014

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“…Neurosteroids exert their non-genetic functions mainly by enhancing the inhibitory effect of GABA A Rs [6][7][8]. To test whether they participated in the analgesic effect of neurosteroids, we injected bicuculline, a powerful GABA A R antagonist [37,38], into the lateral thalamus 0.5 h before the delivery of AC-5216, AP, or DOC.…”

Section: Gaba a Receptors Participated In The Analgesic Effects Of Nementioning

confidence: 99%

“…Neurosteroids have potent and selective effects on GABA A Rs [6][7][8]. PREG, PROG, and DOC are positive modulators in a non-genomic manner, while AP and THDOC potentiate synaptic GABA A R function and activate delta-subunit containing extrasynaptic GABA A Rs that mediate tonic currents [9,10].…”

Section: Gaba a Receptors Were Involved In The Analgesic Effect Of Nementioning

confidence: 99%

“…In general, neurosteroids execute their functions through not only classic steroid hormone nuclear receptors, but also ion-gated neurotransmitter receptors such as c-aminobutyric acid A receptors (GABA A Rs) [6][7][8]. Direct binding of neurosteroids to GABA A Rs, extrasynaptic receptors containing the d subunit in particular, results in the potentiation of GABA A R-mediated inhibitory currents [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

et al. 2016

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Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of c-aminobutyric acid A receptors (GABA A Rs), which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-performance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids (pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone) in the chronic stage of neuropathic pain (28 days after spared nerve injury) in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus (AP -3.0 mm, ML ±3.0 mm, DV 6.0 mm) alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were significantly attenuated by the GABA A R antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

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“…This binding forces a conformation where GABA displays a higher affinity increasing the frequency of opening of the ion channel [234]. Similarly, several neurosteroids such as allopregnanolone will bind to the GABA-A ionophore and force conformational changes enhancing GABA effects [235,236]. Immunohistochemical studies have shown dense staining in spinal Rexed laminae for several alpha, beta and gamma subunits likely corresponding to primary afferents [237,238] presumably localized on primary afferent terminals.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Neurosteroids and GABA-A Receptor Function

Cited by 143 publications

References 342 publications

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

Current and Future Issues in the development of spinal agents for the management of pain

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