Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets

Munro, Gordon; Ahring, Philip K.; Mirza, Naheed

doi:10.1016/j.tips.2009.06.004

Cited by 77 publications

(58 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both animal research and clinical studies have established that perturbation of the GABA inhibitory system is involved in the pathogenesis of a variety of neurological diseases, including epilepsy, schizophrenia, depression, anxiety and chronic pain. [31][32][33] Most of these previous studies focused on the post-synaptic GABA A receptor of GABA synapses as potential therapeutic targets for the treatment of these pathological conditions. However, given the activity-dependent GAD65 function and particularly, activity-regulated Gad2 expression through epigenetic control of transcription, Gad2 might play a more important role in the chronic disease condition-induced plasticity of central GABA synapses.…”

Section: Gad2 and Gaba-related Neurological Diseasesmentioning

confidence: 99%

Transcriptional control ofGad2

Pan

2012

Transcription

View full text Add to dashboard Cite

Gad2 encodes GAD65, which is present preferentially in presynaptic terminals for synthesis of GABA for vesicle release. Gad2 is a regulatory target of cell activities in various brain functions and in GABA perturbation-related neurological diseases. However, our understanding of how Gad2 is transcriptionally regulated and how Gad2 transcription responds to changing cell environment under these conditions is still limited. This review discusses recent advances in the regulatory mechanisms for Gad2 transcription and highlights the characteristics of TATA-less Gad2 promoters and regulation of Gad2 transcription by CREB and by activity-dependent epigenetic modification of the chromatin structure in regulatory elements of the Gad2 gene.

show abstract

Section: Gad2 and Gaba-related Neurological Diseasesmentioning

confidence: 99%

Transcriptional control ofGad2

Pan

2012

Transcription

View full text Add to dashboard Cite

show abstract

“…Loss of GABAergic inhibition in pain-signaling pathways has been proposed as a primary mechanism for pain-induced maladaptive responses termed central sensitization, a key process in the development of acute pain to chronic pain (Moore et al, 2002;Knabl et al, 2008;Costigan et al, 2009;Munro et al, 2009). Coull et al (2003) demonstrated a novel mechanism for this loss of GABA inhibition in spinal dorsal horn neurons by showing that nerve injury downregulates the K 1 -Cl -cotransporter (KCC2), which controls the intracellular Cl 2 gradient in neurons, causing a depolarizing shift in the equilibrium potential of Cl 2 (E Cl ) currents such that inhibitory GABA A currents become depolarizing and excitatory.…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Zhang

Wang

et al. 2013

Mol Pharmacol

View full text Add to dashboard Cite

Chronic pain is thought to be partly caused by a loss of GABAergic inhibition and resultant neuronal hyperactivation in the central pain-modulating system, but the underlying mechanisms for pain-modulating neurons in the brain are unclear. In this study, we investigated the cellular mechanisms for activation of brainstem descending pain facilitation in rats under persistent pain conditions. In the nucleus raphe magnus (NRM), a critical relay in the brain's descending pain-modulating system, persistent inflammatory pain induced by complete Freund's adjuvant decreased the protein level of K 1 -Cl 2 cotransporter (KCC2) in both total and synaptosomal preparations. Persistent pain also shifted the equilibrium potential of GABAergic inhibitory postsynaptic current (E IPSC ) to a more positive level and increased the firing of evoked action potentials selectively in m-opioid receptor (MOR)-expressing NRM neurons, but not in MOR-lacking NRM neurons. Microinjection of brain-derived neurotrophic factor (BDNF) into the NRM inhibited the KCC2 protein level in the NRM, and both BDNF administration and KCC2 inhibition by furosemide mimicked the pain-induced effects on E IPSC and excitability in MOR-expressing neurons. Furthermore, inhibiting BDNF signaling by NRM infusion of tyrosine receptor kinase B-IgG or blocking KCC2 with furosemide prevented these pain effects in MOR-expressing neurons. These findings demonstrate a cellular mechanism by which the hyperactivity of NRM MOR-expressing neurons, presumably responsible for descending pain facilitation, contributes to pain sensitization through the signaling cascade of BDNF-KCC2-GABA impairment in the development of chronic pain.

show abstract

“…On the other hand, clonazepam is widely used in practice to treat neuropathic pain and has demonstrated efficacy in myofascial pain, temporomandibular joint dysfunction, cancer-related neuropathic pain and in stomatodynia when used topically [5][6][7][8]. However, the use of BZDs in chronic pain is rather limited by their side effects, such as sedation, memory impairment and dependence.Advances in the understanding of the molecular diversity of GABA A receptors have suggested that the therapeutic index might become improved through the development of subtypeselective or partial BDZ-site agonists [9][10][11][12].Benzodiazepine-sensitive GABA A receptors contain at least one of the following a subunits a1, a2, a3 or a5, together with two b subunits and a c2 subunit in a 2:2:1 stoichiometry [13,14]. Work in GABA A receptor point-mutated mice has shown that the sedative action of BDZs is mainly mediated by GABA A receptors containing a1 subunits [15], whereas a2-and a3-containing GABA A receptors were found to be responsible for the anxiolytic properties [16] and largely responsible for the spinal antihyperalgesic actions of classical BDZs [3,17].…”

mentioning

confidence: 99%

“…Advances in the understanding of the molecular diversity of GABA A receptors have suggested that the therapeutic index might become improved through the development of subtypeselective or partial BDZ-site agonists [9][10][11][12].…”

mentioning

confidence: 99%

Antihyperalgesic Effect of the GABA_A Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study

Besson

Daali

Lio

et al. 2012

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Facilitation of spinal GABAergic inhibition with benzodiazepines (BZDs) reverses pain sensitization in animals; however, the use of BZDs in man is limited by their sedative effect. The antihyperalgesic effects of GABA A agonists are mediated by GABA A receptors containing a2 subunits, whereas sedation is linked to a1 subunit-containing receptors. a2 and a3 selective GABA A receptor modulators have been tested in animals but are not yet available for use in human beings. Clobazam is a 1,5-BZD, which exhibits less cognitive side effects than other benzodiazepines. Here, we studied its antihyperalgesic effects in a mouse model of neuropathic pain. Clobazam showed a dose-dependent antihyperalgesic effect in the chronic constriction injury (CCI) model of neuropathic pain, peaking at 1 hr after administration and lasting for 4 hr with no relevant sedation at a dose of 3 mg/kg. At higher doses, the antihyperalgesic effect was stronger, but sedation became significant. The blood and brain kinetics of clobazam were linear over the range of doses tested with a short half-life of the parent compound and a ready penetration of the blood-brain barrier. Clobazam blood concentrations decreased rapidly, falling below the limit of detection at 120 min. after drug application. Its main metabolite, N-desmethyl-clobazam, showed more delayed and prolonged pharmacokinetics, partly explaining why antihyperalgesia persisted when clobazam was no longer detectable in the blood. Considering its therapeutic margin and its pharmacokinetic properties, clobazam would be a valuable compound to assess the role of the GABAergic pathway in pain transmission in human beings.Diminished synaptic inhibition in the spinal cord critically contributes to central sensitization, a key phenomenon in chronic inflammatory and neuropathic pain. The role of glycinergic and c-aminobutyric acid (GABA)ergic neurons in this process has been widely described [1,2]. Therefore, facilitation of the spinal GABAergic input is a rational approach to compensate for diminished inhibitory pain control. In fact, the antihyperalgesic effect of several GABA A agonists such as muscimol or of positive allosteric modulators such as diazepam has been demonstrated in animals [3].In human beings, research on the analgesic effect of BZDs is scarce and controversial. In clinical research, diazepam has been used as an active placebo in a study seeking to demonstrate the analgesic effect of fentanyl in patients with chronic non-cancer neuropathic pain [4]. On the other hand, clonazepam is widely used in practice to treat neuropathic pain and has demonstrated efficacy in myofascial pain, temporomandibular joint dysfunction, cancer-related neuropathic pain and in stomatodynia when used topically [5][6][7][8]. However, the use of BZDs in chronic pain is rather limited by their side effects, such as sedation, memory impairment and dependence.Advances in the understanding of the molecular diversity of GABA A receptors have suggested that the therapeutic index might become improved ...

show abstract

Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets

Cited by 77 publications

References 53 publications

Transcriptional control ofGad2

Transcriptional control ofGad2

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Antihyperalgesic Effect of the GABA_A Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study

Contact Info

Product

Resources

About

Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets

Cited by 77 publications

References 53 publications

Transcriptional control ofGad2

Transcriptional control ofGad2

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K+–Cl– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Antihyperalgesic Effect of the GABAA Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study

Contact Info

Product

Resources

About

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K⁺–Cl^– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Antihyperalgesic Effect of the GABA_A Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study