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Jieying Yu, Dian-Shi Wang, Robert P Bonin, Antonello Penna, Ali Alavian-Ghavanini, Agnieszka A Zurek, Gail Rauw, Glen B Baker, Beverley A Orser
BACKGROUND: Gabapentin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Its anticonvulsant, analgesic and anxiolytic properties suggest that it increases GABAergic inhibition; however, the molecular basis for these effects is unknown as gabapentin does not directly modify GABA type A (GABAA ) receptor function, nor does it modify synaptic inhibition. Here, we postulated that gabapentin increases expression of δ subunit-containing GABAA (δGABAA ) receptors that generate a tonic inhibitory conductance in multiple brain regions including the cerebellum and hippocampus...
March 13, 2019: EBioMedicine
Etienne Côme, Xavier Marques, Jean Christophe Poncer, Sabine Lévi
Neuronal Cl- homeostasis is regulated by the activity of two cation chloride co-transporters (CCCs), the K+ -Cl- cotransporter KCC2 and the Na+ -K+ -Cl- cotransporter NKCC1, which are primarily extruding and importing chloride in neurons, respectively. Several neurological and psychiatric disorders including epilepsy, neuropathic pain, schizophrenia and autism are associated with altered neuronal chloride (Cl- ) homeostasis. A current view is that the accumulation of intracellular Cl- in neurons as a result of KCC2 down-regulation and/or NKCC1 up-regulation may weaken inhibitory GABA signaling and thereby promote the development of pathological activities...
March 11, 2019: Neuropharmacology
Ivan Sergeevich Mokrousov, Valentina Nikolaevna Perfilova, Igor Igorevich Prokofiev, Tamara Alexandrovna Popova, Ekaterina Gennadievna Vodopyanova, Olga Sergeevna Vasil'eva, Ivan Nikolaevich Tyurenkov
OBJECTIVES: The objective of this study was to investigate the effects of a new derivative of GABA, RGPU-207 compound, on the mitochondrial functions of stressed animals. METHODS: RGPU-207 and the comparator drugs (phenibut and piracetam) were administered intraperitoneally to unstressed and stressed male rats at a dose of 9.4, 25 and 400 mg/kg, respectively. The oxygen consumption by cardiac and cerebral mitochondria in state 3 and 4 and Chance's respiratory control ratio (RCR) was investigated...
March 12, 2019: Journal of Pharmacy and Pharmacology
Domenico Chirchiglia, Pasquale Chirchiglia, Rosa Marotta, Luca Gallelli
Aim: The purpose of this study was to treat burning mouth syndrome (BMS) with a combination of painful gabapentin and ultramicronized palmitoylethanolamide (umPEA), in an attempt to improve the severe symptomatology of BMS. Methods: We examined the case of a 60-year-old male, suffering from late-onset burning mouth syndrome. He found that gabapentin had a poor control of symptoms, thus we added umPEA, after administering a Visual Analog Scale (VAS), showing a score of 8-9...
2019: International Medical Case Reports Journal
J M Witkin, R Cerne, P G Davis, K B Freeman, J M do Carmo, J K Rowlett, K R Methuku, A Okun, S D Gleason, X Li, M J Krambis, M Poe, G Li, J M Schkeryantz, R Jahan, L Yang, W Guo, L K Golani, W H Anderson, J T Catlow, T M Jones, F Porreca, J L Smith, K L Knopp, J M Cook
Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects...
February 27, 2019: Pharmacology, Biochemistry, and Behavior
Florentia Kaguelidou, Enora Le Roux, Laura Mangiarini, Rebecca Lundin, Thomas G de Leeuw, Oscar Della Pasqua, Mariagrazia Felisi, Donato Bonifazi, Dick Tibboel, Adriana Ceci, Saskia N de Wildt, Corinne Alberti
INTRODUCTION: Gabapentin is currently used 'off-label' in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. OBJECTIVES: The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. METHODS AND ANALYSIS: The trial is a multicentre, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial...
February 20, 2019: BMJ Open
Víctor M López-Álvarez, Stefano Cobianchi, Xavier Navarro
OBJECTIVES: We aimed to investigate if different protocols of electrical stimulation following nerve injury might improve neuropathic pain outcomes and modify associated plastic changes at the spinal cord level. MATERIALS AND METHODS: Adult rats were subjected to sciatic nerve transection and repair, and distributed in four groups: untreated (SNTR, n = 12), repeated acute electrical stimulation (rAES, 50 Hz, one hour, n = 12), chronic electrical stimulation (CES, 50 Hz, one hour, n = 12), and increasing-frequency chronic electrical stimulation (iCES, one hour, n = 12) delivered during two weeks following the lesion...
February 20, 2019: Neuromodulation: Journal of the International Neuromodulation Society
Shahram Ala, Mina Alvandipour, Majid Saeedi, Mohaddeseh Mansourifar, Mahila Monajati, Afshin Shiva
BACKGROUND: Baclofen is an agonist for a subtype of gamma-amino butyric acid (GABA-B) receptors and traditionally been used for the systemic treatment of spasticity. Topical application of baclofen has been shown to reduce pain in patients with localized neuropathic pain. OBJECTIVES: In this study, we investigate the efficacy of baclofen cream (5%) in reducing postoperative pain and analgesic requirement after open hemorrhoidectomy. DESIGN: The patients were randomly assigned to either baclofen (5%) cream or placebo immediately after surgery and then every 12 h for 14 days...
February 19, 2019: Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract
Ken-Ichiro Hayashida, Hideaki Obata
Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord...
February 14, 2019: International Journal of Molecular Sciences
Michelino Puopolo
Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise, among others, noradrenergic, serotonergic, γ-aminobutyric acid (GABA)ergic, and dopaminergic fibers. The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated...
June 2019: Neural Regeneration Research
Lieuwe Biewenga, Thangavelu Saravanan, Andreas Kunzendorf, Jan-Ytzen van der Meer, Tjaard Pijning, Pieter G Tepper, Ronald van Merkerk, Simon J Charnock, Andy-Mark W H Thunnissen, Gerrit J Poelarends
Chiral γ-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, as antidepressants, and for the treatment of neuropathic pain. Here we report a one-pot two-step biocatalytic cascade route for synthesis of the pharmaceutically relevant enantiomers of γ-nitrobutyric acids, starting from simple precursors (acetaldehyde and nitroalkenes), using a tailor-made highly enantioselective artificial "Michaelase" (4-oxalocrotonate tautomerase mutant L8Y/M45Y/F50A), an aldehyde dehydrogenase with a broad non-natural substrate scope, and a cofactor recycling system...
February 1, 2019: ACS Catalysis
Jose Antonio Lopez Garcia
In this issue, you will find a paper by Vasović et al., entitled "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6GABAA receptors" (D. Vasović et al., 2019). Loss of GABA-mediated inhibition within pain circuits is one of the mechanisms commonly invoked to explain allodynia and hyperalgesia following injury. Intrathecal administration of picrotoxin produces pain like signs. Positive allosteric modulators of GABAA receptors like benzodiazepines are known to produce analgesia although their main effects are sedative, hypnotic and anxiolytic and therefore their use as analgesics is curtailed (Schliessbach et al...
February 8, 2019: European Journal of Pain: EJP
Li Na Qiao, Yong Sheng Yang, Jun Ling Liu, Jiang Zhu, Lian Hong Tan, Yi Nan Shi, Bing Zhu, Pei Jing Rong
Purpose: Acupuncture therapy is effective for relieving postoperative pain. Our previous study showed that electroacupuncture (EA) at Futu (LI18) and Hegu (LI4)-Neiguan (PC6) could alleviate incisional neck pain, which was related with its effect in upregulating γ-aminobutyric acid (GABA) expression in cervical (C3-6) dorsal root ganglions (DRGs); but whether its receptor subsets GABAA α2R and GABAB R1 in C3-6 DRGs are involved in EA analgesia or not, it remains unknown. Materials and methods: Seventy-five male Sprague Dawley rats were randomized to normal control, model, LI18, LI4-PC6, and Zusanli (ST36)-Yanglingquan (GB34) groups...
2019: Journal of Pain Research
Amanda C Randolph, Yu-Li Lin, Elena Volpi, Yong-Fang Kuo
BACKGROUND/OBJECTIVES: Peripheral neuropathy is a common diabetes complication that can increase fall risk. Regarding fall risk, the impact of pain management using tricyclic antidepressants (TCAs) or γ-aminobutyric acid (GABA) analogs is unclear because these medications can also cause falls. This study investigates the impact of these drugs on fall and fracture risk in older diabetic peripheral neuropathy (DPN) patients. DESIGN: Historical cohort study with 1-to-1 propensity matching of TCA/GABA-analog users and nonusers...
January 29, 2019: Journal of the American Geriatrics Society
Stacey Trzcinski, Rebecca E Rosenberg, Dennis Vasquez Montes, Akhila Sure, Peter Zhou, Jared Tishelman, Robert Mansky, Lisa McLeod, Joanna Tracy, Aaron J Buckland, Thomas J Errico
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study was to examine associations of gabapentin use with inpatient postoperative daily pain scores and opioid use in children undergoing PSF for AIS. SUMMARY OF BACKGROUND DATA: Gabapentin use in posterior spinal fusion (PSF) postoperative pain management for adolescent idiopathic scoliosis (AIS) is increasingly common in order to decrease opioid use and improve pain control, though there is conflicting data on dosing and effectiveness to support this practice in real world settings...
January 25, 2019: Clinical Spine Surgery
José Vicente Negrete-Díaz, Kirill Sumilov, M Ángeles Real, José Medina-Luque, Alejandra Valderrama-Carvajal, Gonzalo Flores, Antonio Rodríguez-Moreno, Alicia Rivera
Dopamine D4 receptor (D4 R) stimulation, in a putative D4 R/μ opioid heteroreceptor (MOR) complex, counteracts the molecular, cellular and behavioural actions of morphine which are associated with morphine addiction, without any effect on its analgesic properties. In the present work, we have evaluated the role of D4 R in modulating the effects of a continuous treatment with morphine on the GABAergic system in the basal ganglia. It has been demonstrated that the co-administration of a D4 R agonist together with morphine leads to a restoration of GABA signaling by preventing drug-induced changes in GAD65/67 expression in the caudate putamen, globus palidus and substantia nigra...
January 22, 2019: Neuropharmacology
Yingbo Zhang, Xiaomin Tang, Yuxin Pang, Luqi Huang, Dan Wang, Chao Yuan, Xuan Hu, Liping Qu
Bufadienolide-like chemicals are mostly composed of the active ingredient of Chansu and they have anti-inflammatory, tumor-suppressing, and anti-pain activities; however, their mechanism is unclear. This work used bioinformatics analysis to study this mechanism via gene expression profiles of bufadienolide-like chemicals: (1) Differentially expressed gene identification combined with gene set variation analysis, (2) similar small -molecule detection, (3) tissue-specific co-expression network construction, (4) differentially regulated sub-networks related to breast cancer phenome, (5) differentially regulated sub-networks with potential cardiotoxicity, and (6) hub gene selection and their relation to survival probability...
January 14, 2019: Cancers
Vidya Chidambaran, Xue Zhang, Kristie Geisler, Bobbie L Stubbeman, Xiaoting Chen, Matthew T Weirauch, Jarek Meller, Hong Ji
We have reported child anxiety sensitivity (CASI) predicts chronic post-surgical pain (CPSP). Here, we evaluated DNA methylation profiles to understand gene-environmental interactions underlying CPSP and CASI, in order to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI, and pain data over 12 months post-surgery were collected. DNA from peripheral blood of evaluable subjects with (n=16) and without CPSP (n=40) were analyzed using MethylationEPIC arrays...
January 9, 2019: Journal of Pain: Official Journal of the American Pain Society
Dina Vasović, Branka Divović, Marco Treven, Daniel E Knutson, Friederike Steudle, Petra Scholze, Aleksandar Obradović, Jure Fabjan, Božidar Brković, Werner Sieghart, Margot Ernst, James M Cook, Miroslav M Savić
γ-Aminobutyric acid type A (GABAA ) receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds...
January 11, 2019: European Journal of Pain: EJP
Antonela Petrovic, Priyadharishini Veeraraghavan, Dario Olivieri, Andrea Nistri, Nina Jurcic, Miranda Mladinic
The isolated spinal cord of the neonatal rat is widely employed to clarify the basic mechanisms of network development or the early phase of degeneration after injury. Nevertheless, this preparation survives in Krebs solution up to 24 h only, making it desirable to explore approaches to extend its survival for longitudinal studies. The present report shows that culturing the spinal cord in oxygenated enriched Basal Medium Eagle (BME) provided excellent preservation of neurons (including motoneurons), glia and primary afferents (including dorsal root ganglia) for up to 72 h...
December 19, 2018: Brain Research
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