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Ken-Ichiro Hayashida, James C Eisenach
Gabapentinoids are effective in a wide range of animal pain models and in patients with neuropathic pain and has become one of first-line treatments for neuropathic pain. Because spinal plasticity and sensitization have been intensely studied in neuropathic pain, most laboratory studies have focused on actions of gabapentinoids in the spinal cord, where they reduce primary afferent traffic and excitation of spinal nociceptive neurons, via interaction with α2δ subunits of voltage-gated Ca2+ channels. However, a recent clinical study questioned the relevance of this in vitro and in vivo rodent studies by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain...
2018: Advances in Experimental Medicine and Biology
Yaeko Yokoshima, Masahiko Sumitani, Daisuke Nishizawa, Makoto Nagashima, Kazutaka Ikeda, Ryoji Kato, Jun Hozumi, Hiroaki Abe, Kenji Azuma, Rikuhei Tsuchida, Yoshitsugu Yamada
AIM: Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health-related quality of life of patients with cancer pain deteriorates. Opioid analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness...
September 14, 2018: Neuropsychopharmacology reports
Kun Lv, Wenwen Song, Rui Tang, Zhiyong Pan, Yong Zhang, Yi Xu, Bin Lv, Yihong Fan, Maosheng Xu
PURPOSE: Crohn's disease (CD) has been known to cause both abdominal pain alongside functional and structural alterations in the central nervous system (CNS) in affected patients. This study seeks to determine the alternations of metabolites in the bilateral anterior cingulate cortex (ACC) of CD patients with abdominal pain by using proton magnetic resonance spectroscopy (1 H-MRS) to further explore the neural mechanism. METHODS: Sixteen CD patients with abdominal pain and 13 CD patients without abdominal pain, were recruited alongside 20 healthy controls (HCs) for this study...
September 18, 2018: NeuroImage: Clinical
Sampurna Chakrabarti, Luke A Pattison, Kaajal Singhal, James R F Hockley, Gerard Callejo, Ewan St John Smith
Ongoing, spontaneous pain is characteristic of inflammatory joint pain and reduces an individual's quality of life. To understand the neural basis of inflammatory joint pain, we made a unilateral knee injection of complete Freund's adjuvant (CFA) in mice, which reduced their natural digging behavior. We hypothesized that sensitization of knee-innervating dorsal root ganglion (DRG) neurons underlies this altered behavior. To test this hypothesis, we performed electrophysiological recordings on retrograde labeled knee-innervating primary DRG neuron cultures and measured their responses to a number of electrical and chemical stimuli...
September 18, 2018: Neuropharmacology
Tobias Schmidt, Nikoo Ghaffarian, Camille Philippot, Gerald Seifert, Christian Steinhäuser, Hans-Christian Pape, Peter Blaesse
The thalamus is important for sensory integration with the ventrobasal thalamus (VB) as relay controlled by GABAergic projections from the nucleus reticularis thalami (NRT). Depending on the [Cl- ]i primarily set by cation-chloride-cotransporters, GABA is inhibitory or excitatory. There is evidence that VB and NRT differ in terms of GABA action, with classical hyperpolarization in VB due to the expression of the Cl- extruder KCC2 and depolarizing/excitatory GABA action in the NRT, where KCC2 expression is low and Cl- accumulation by the Cl- inward transporter NKCC1 has been postulated...
September 17, 2018: Scientific Reports
Min Xu, David L H Bennett, Luis Antonio Querol, Long-Jun Wu, Sarosh R Irani, James C Watson, Sean J Pittock, Christopher J Klein
The immune system has long been recognised important in pain regulation through inflammatory cytokine modulation of peripheral nociceptive fibres. Recently, cytokine interactions in brain and spinal cord glia as well as dorsal root ganglia satellite glia have been identified important- in pain modulation. The result of these interactions is central and peripheral sensitisation of nociceptive processing. Additionally, new insights and the term 'autoimmune pain' have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability...
September 17, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Alicja Nowaczyk, Łukasz Fijałkowski, Magdalena Kowalska, Adrian Podkowa, Kinga Sałat
In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17 GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and psychiatric diseases (e...
September 28, 2018: ACS Chemical Neuroscience
Alicja Nowaczyk, Łukasz Fijałkowski, Paula Zaręba, Kinga Sałat
Inhibition of 4-aminobutanoic acid (GABA) uptake is a strategy for enhancing GABA transmission. The utility of this approach is demonstrated by the successful development of such agents for the treatment of epilepsy and pain. Existing reports on acute brain slice preparations indicate the intersecting of complementary channels and receptors sets between astrocytes and neurons cells. Thorough analysis of astroglial cells by means of molecular and functional studies demonstrated their active modulatory role in intercellular communication...
September 8, 2018: Journal of Molecular Graphics & Modelling
Timothy J Ness, Cary DeWitte, Jamie McNaught, Buffie Clodfelder-Miller, Xin Su
Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models of bladder pain and anecdotally reduces pain in humans with pelvic pain of urologic origin. The spinal neurochemical mechanisms of this antinociception are unknown. In the present study, bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Visceromotor responses (VMRs; abdominal muscle contractions) to urinary bladder distension (UBD) were used as a nociceptive endpoint under urethane-isoflurane anesthesia...
September 12, 2018: Neuroscience Letters
P Balaram, T A Hackett, D B Polley
Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx)...
September 1, 2018: Neuroscience
Xiuling Deng, Dong Wang, Shenyuan Wang, Haisheng Wang, Huanmin Zhou
PURPOSE: This aim of this study was to investigate the key genes and pathways involved in the response to pain in goat and sheep by transcriptome sequencing. METHODS: Chronic pain was induced with the injection of the complete Freund's adjuvant (CFA) in sheep and goats. The animals were divided into four groups: CFA-treated sheep, control sheep, CFA-treated goat, and control goat groups (n = 3 in each group). The dorsal root ganglions of these animals were isolated and used for the construction of a cDNA library and transcriptome sequencing...
August 17, 2018: Biological Research
David Kang, James H McAuley, Mustafa S Kassem, Justine M Gatt, Sylvia M Gustin
BACKGROUND AND OBJECTIVE: Alterations in the grey matter volume of several brain regions have been reported in people with chronic pain. The most consistent observation is a decrease in grey matter volume in the medial prefrontal cortex. These findings are important as the medial prefrontal cortex plays a critical role in emotional and cognitive processing in chronic pain. Although a logical cause of grey matter volume decrease may be neurodegeneration, this is not supported by the current evidence...
August 12, 2018: European Journal of Pain: EJP
Rose Cairns, Andrea L Schaffer, Nicole Ryan, Sallie-Anne Pearson, Nicholas A Buckley
BACKGROUND AND AIMS: Pregabalin is a gamma-aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in 2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse. DESIGN AND SETTING: Population-based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012-February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004-2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005-2016)...
August 11, 2018: Addiction
Lakshmi Rajagopal, Mei Huang, Eric Michael, Sunoh Kwon, Herbert Y Meltzer
GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABAA α2,3 subtype-selective GABAA partial agonist and α1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABAA antagonist, may improve CIAS in pilot clinical trials...
November 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Mohammed Zacky Ariffin, Khairunisa Mohamad Ibrahim, Andy Thiam-Huat Lee, Rui Zhi Lee, Shou Yu Poon, Hwai Kit Thong, Eugene Hern Choon Liu, Chian-Ming Low, Sanjay Khanna
The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception...
August 8, 2018: Scientific Reports
Keisuke Migita, Yu Matsuzaki, Kohei Koga, Taichi Matsumoto, Kenichi Mishima, Shuji Hara, Kenji Honda
The role of the GABAB receptor in the anterior cingulate cortex (ACC) of neuropathic pain is unclear. Injection of a GABAB receptor antagonist CGP35348 into the ACC induced mechanical hypersensitivity in normal rats. Activation of the GABAB receptor injected by a GABAB receptor agonist baclofen into the ACC attenuated mechanical hypersensitivity in partial sciatic nerve ligation (PSNL) rats. Co-microinjection of CGP35348 with a muscarinic M1 receptor agonist McN-A-343 into the ACC significantly inhibited McN-A-343-induced antihypersensitivity in PSNL rats...
June 2018: Journal of Pharmacological Sciences
Abigail L Brewer, Shulin Liu, Amber V K Buhler, Donald Y Shirachi, Raymond M Quock
New pain treatments are in demand due to the pervasive nature of pain conditions. Hyperbaric oxygen (HBO2 ) has shown potential in treating pain in both clinical and preclinical settings, although the mechanism of this effect is still unknown. The aim of this study was to investigate whether the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in HBO2 -induced antinociception in the central nervous system. To accomplish this goal, pharmacological interactions between GABA drugs and HBO2 were investigated using the behavioral acetic acid abdominal constriction test...
August 2, 2018: Brain Research
Pablo Andrade, Erwin M J Cornips, Claudia Sommer, Marc A Daemen, Veerle Visser-Vandewalle, Govert Hoogland
BACKGROUND: The pathophysiology of pain in patients with symptomatic thoracic disc herniation (TDH) remains poorly understood. Mere mechanical compression of the spinal cord and/or the exiting nerve root by a prolapsed disc cannot explain the pathogenesis of pain in all cases. Previous studies report a direct correlation between the levels of proinflammatory cytokines in disc biopsies and the severity of leg pain in patients with lumbar disc herniation. A similar correlation in patients with TDH has not been investigated...
August 2, 2018: Spine Journal: Official Journal of the North American Spine Society
Diana M Roccaro-Waldmeyer, Franck Girard, Daniele Milani, Elisabetta Vannoni, Laurent Prétôt, David P Wolfer, Marco R Celio
The calcium-binding protein parvalbumin (PV) is a recognized marker of short-axon GABA-ergic neurons in the cortex and the hippocampus. However in addition, PV is expressed by excitatory, glutamatergic neurons in various areas of the brain and spinal cord. Depending on the location of these neurons, loading of their synaptic vesicles with glutamate is mediated by either of three vesicular glutamate transporters (VGlut): VGlut1, VGlut2, or VGlut3. Driven by our interest in one of these glutamatergic/PV-expressing cell clusters-the lateral hypothalamic parvafox nucleus-we investigated the functions of this population of neurons by the selective deletion of VGlut2 expression in PV-expressing cells according to the Cre/Lox-approach...
2018: Frontiers in Behavioral Neuroscience
Wuping Sun, Qian Zhou, Xiyuan Ba, Xiaojin Feng, Xuexue Hu, Xiaoe Cheng, Tao Liu, Jing Guo, Lizu Xiao, Jin Jiang, Donglin Xiong, Yue Hao, Zixian Chen, Changyu Jiang
Objective: Oxytocin (OT) is synthesized within the paraventricular nucleus and supraoptic nucleus of the hypothalamus. In addition to its role in uterine contraction, OT plays an important antinociceptive role; however, the underlying molecular mechanisms of antinociceptive role of OT remain elusive. We hypothesized that the antinociceptive effect of OT on neuropathic pain may occur via inhibition of TRPV1 activation in the spinal cord. The present study explores the antinociceptive role of OT and its mechanisms in neuropathic pain...
2018: Frontiers in Molecular Neuroscience
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