GABAB Receptors Do Not Mediate the Inhibitory Actions of Gabapentin on the Spinal Reflex in Rats

Shimizu, Shinobu; Honda, Motoko; Tanabe, Mitsuo; Ono, Hideki

doi:10.1254/jphs.fp0040537

Cited by 17 publications

(6 citation statements)

References 28 publications

(21 reference statements)

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“…The high EC 50 that we observed with PTZ-induced auditory cortical networks is consistent with these drugs directly antagonizing the effects of PTZ. It has been reported that gabapentin does not bind to the GABA B receptor, thus, this might perhaps account for its less potential efficacy for tinnitus patients (Shimizu et al, 2004). Anecdotal reports of patients on a regimen of pregabalin for the management of pain reported an exacerbation of their tinnitus, but some patients reported also reduced tinnitus as a result of taking pregabalin.…”

Section: Discussionmentioning

confidence: 99%

An in vitro model for testing drugs to treat tinnitus

Gopal

Gross

et al. 2011

European Journal of Pharmacology

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Pregabalin Gabapentin Drug repositioningTinnitus affects approximately 50 million people in the USA alone, with 10 million being highly debilitated. Pharmacotherapy for tinnitus is still in emerging stages due to time consuming clinical trials and/or animal experiments. We tested a new cellular model where induced rapid neuronal firing or spiking was used as a mimic for the type of aberrant activity that may occur in tinnitus. Spontaneously active auditory cortical networks growing on microelectrode arrays were exposed to pentylenetetrazol (PTZ), a proconvulsant and an antagonist of GABA A receptor, which is implicated in tinnitus. Auditory cortical networks were then exposed to experimental tinnitus drugs linopirdine (Dup966, a potassium channel blocker), L-carnitine (an antioxidant), or selective Ca 2+ channel antagonists pregabalin (Lyrica), or gabapentin (Neurontin) at various concentrations. PTZ increased spike rate by 139.6 ± 27% and burst rate by 129.7 ± 28% in auditory cortical networks with a phenotypic high firing of excitable neurons. Reductions of increased activity were observed to varying degrees using the experimental tinnitus drugs. The potency of the drugs was linopirdine (EC 50 : 176±7.0 μM) N L-carnitine (EC 50 : 1569± 41 μM)N pregabalin (EC 50 : 8360± 340 μM), Ngabapentin, with 34.2± 7.5% efficacy (EC 50 : 2092± 980 μM). These studies provide proof of principle for the use of auditory cortical networks on microelectrode array as a feasible platform for semi-high throughput application for screening of drugs that might be used for the treatment of tinnitus.

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Section: Discussionmentioning

confidence: 99%

An in vitro model for testing drugs to treat tinnitus

Gopal

Gross

et al. 2011

European Journal of Pharmacology

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“…However, the induced pancreatic tumors were derived from pancreatic acinar cells and not pancreatic duct epithelial cells (105). In addition, more recent publications revealed that Gabapentin does not act via the GABA-B- receptor (106) that was found to mediate the inhibitory actions of GABA in PDAC cells (92), and even activates the noradrenergic system (107). Another seemingly contradictory finding was the observation that GABA selectively stimulated the growth of PDAC cell lines that over-expressed the GABA-A receptor pi subunit (108).…”

Section: Beta-adrenergic Signaling In Pancreatic Ductal Adenocarcinommentioning

confidence: 99%

Beta-adrenergic Signaling in the Development and Progression of Pulmonary and Pancreatic Adenocarcinoma

Schüller¹,

Al-Wadei²

2012

CCTR

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Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the α7nicotinic acetylcholine receptor (α7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate β-adrenergic receptor (β-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter γ-aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta-blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful.

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“…The method used for microinjection of drugs into the spinal cord was modified from Bell et al (28) and Shimizu et al (29). Two-barreled glass pipettes (1.5-mm outside diameter, GD-1.5; Narishige, Tokyo) were pulled using an electrode puller (PE-2, Narishige) and the tips were adjusted to 40 -50 μm with the aid of a microscope.…”

Section: Electrophysiology Protocolsmentioning

confidence: 99%

N- and L-Type Voltage-Dependent Ca<SUP>2+</SUP> Channels Contribute to the Generation of After-Discharges in the Spinal Ventral Root After Cessation of Noxious Mechanical Stimulation

2012

Self Cite

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Abstract. Voltage-dependent Ca2+ channels (VDCCs) play a crucial role in the spinal pain transduction. We previously reported that nociceptive mechanical stimuli to the rat hindpaw evoked two types of ventral root discharges that increased during stimulation (during-discharges) and after cessation of stimulation (after-discharges). To explore the involvement of VDCCs in these ventral root discharges, several VDCC blockers were applied directly to the surface of the spinal cord. Spinalized rats were laminectomized. The fifth lumbar ventral root was sectioned and used for multi-unit efferent discharges recording. An agar pool was constructed on the first lumbar vertebra for drug application. Ethosuximide (a T-type VDCC blocker) had no effect on ventral root discharges. ω-Conotoxin GVIA (an N-type VDCC blocker) preferentially suppressed after-discharges. ω-Agatoxin IVA (a P/Q-type VDCC blocker), diltiazem, and verapamil (L-type VDCC blockers) nonselectively depressed both during-and after-discharges. The more selective L-type VDCC blocker nicardipine depressed only after-discharges and the depression was exhibited when nicardipine was microinjected into the dorsal horn, but not into the ventral horn. These findings suggested that N-and L-type VDCCs in the dorsal horn were involved in the generation of afterdischarges and these blockers might be useful for treatment of persistent pain that involves the spinal pathway.

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GABAB Receptors Do Not Mediate the Inhibitory Actions of Gabapentin on the Spinal Reflex in Rats

Cited by 17 publications

References 28 publications

An in vitro model for testing drugs to treat tinnitus

An in vitro model for testing drugs to treat tinnitus

Beta-adrenergic Signaling in the Development and Progression of Pulmonary and Pancreatic Adenocarcinoma

N- and L-Type Voltage-Dependent Ca<SUP>2+</SUP> Channels Contribute to the Generation of After-Discharges in the Spinal Ventral Root After Cessation of Noxious Mechanical Stimulation

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