Effect of Drugs Used for Neuropathic Pain Management on Tetrodotoxin-resistant Na+Currents in Rat Sensory Neurons

Bräu, Michael E.; Dreimann, Marc; Olschewski, Andrea; Vogel, Werner; Hempelmann, G.

doi:10.1097/00000542-200101000-00024

Cited by 127 publications

(62 citation statements)

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“…Pharmalogical studies show that amitriptyline acts at Na ϩ Ch, diazepam and midazolam at BDZ-Rs, gabapentin at GABA A -R and L-Ca 2ϩ Ch ␣2␦-1 (42), and carbamazepine at Na ϩ Ch (43). Our present findings show that these receptors and ion channels are strongly up-regulated.…”

Section: Identification Of Differentially Expressed Genes and Verificsupporting

confidence: 62%

Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain

Xiao

Huang²,

Zhang³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

467

324

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Phenotypic modification of dorsal root ganglion (DRG) neuronsrepresents an important mechanism underlying neuropathic pain. However, the nerve injury-induced molecular changes are not fully identified. To determine the molecular alterations in a broader way, we have carried out cDNA array on the genes mainly made from the cDNA libraries of lumbar DRGs of normal rats and of rats 14 days after peripheral axotomy. Of the 7,523 examined genes and expressed sequence tags (ESTs), the expression of 122 genes and 51 expressed sequence tags is strongly changed. These genes encompass a large number of members of distinct families, including neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, and others. Of particular interest is the up-regulation of ␥-aminobutyric acidA receptor ␣5 subunit, peripheral benzodiazepine receptor, nicotinic acetylcholine receptor ␣7 subunit, P2Y1 purinoceptor, Na ؉ channel ␤2 subunit, and L-type Ca 2؉ channel ␣2␦-1 subunit. Our findings therefore reveal dynamic and complex changes in molecular diversity among DRG neurons after axotomy. N europathic pain is caused by nervous system lesions, persists long after the initiating event has healed, and may result from a pathological operation of the nervous system. Available therapies are often inadequate. Therefore, it is essential to identify the molecular changes that may lead to neuropathic pain, both for understanding underlying mechanisms and developing new therapies.The peripherally axotomized animal represents one model to study the mechanisms of neuropathic pain (1). After the finding that vasoactive intestinal polypeptide is up-regulated after axotomy (2), many subsequent studies have reported dramatic changes in individual molecules in dorsal root ganglion (DRG) after nerve injury, and some molecules are implicated in generation and maintenance of pain (3-5). For example, downregulation of -opioid receptor and up-regulation of cholecystokinin B receptor (6, 7) may contribute to the attenuated analgesic effect of opioids in neuropathic pain. Up-regulation of adrenoreceptor ␣2A (A-R␣2A) and neuropeptide Y (NPY) Y2-R enhances sympathetically maintained pain (8, 9). The increase in Na ϩ channel (Ch) III mediates ectopic activity in injured neurons (10). Moreover, hyperalgesia appearing during the course of nerve regeneration suggests a correlation between regeneration and pain. Neurotrophins play important roles in both nerve regeneration and regulation of the expression of some neuropeptides and ion channels (11,12). Taken together, current knowledge suggests that changes in gene expression in DRGs may contribute to the generation and development of neuropathic pain. However, although in situ hybridization and other methods have been extensively used to study the changes of individual genes in DRG, a limiting factor with these methods is the lack of a comprehensive overview of the alteration of gene expression. Here, we took a broader approach, a cDNA array (13), to gain a global view of the chang...

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Section: Identification Of Differentially Expressed Genes and Verificsupporting

confidence: 62%

Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain

Xiao

Huang²,

Zhang³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

467

324

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“…This concentration was specifically chosen, because it has been demonstrated that the half-maximum inhibitory concentration values for lidocaine to block tetrodotoxin-resistant (TTX-R) Na ϩ channels, and thereby inhibiting nerve conduction in rat sensory neurons, were 73 mol/L and 128 mol/L, respectively. 17,18 Lidocaine completely reversed the HFES-induced increase of GAP-43 levels and neurite outgrowth ( Figure 2B and 2C).…”

Section: Hfes Of Nigp Induced Neuronal Growthmentioning

confidence: 88%

Chronic Electrical Neuronal Stimulation Increases Cardiac Parasympathetic Tone by Eliciting Neurotrophic Effects

Rana

Saygili

Gemein

et al. 2011

Circulation Research

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Rationale: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off.Objective: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. Methods and Results:In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ␤-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. Key Words: atrial fibrillation Ⅲ tachyarrhythmias Ⅲ acetylcholine Ⅲ nervous system D uring the last 10 years, techniques have been developed to directly and selectively interfere with the intrinsic cardiac neural system via electric stimulation catheters or leads in animals and patients. [1][2][3][4][5] The baseline observation for these applications was that depolarization of intracardiac neural fibers by high-frequency electric stimulation (HFES) delivers neurotransmitters that subsequently act locally on cardiac structures (eg, stimulation of sympathetic fibers along the coronary sinus selectively increases left ventricle inotropy). 5 Furthermore, acute, short-term endocardial HFES of the right inferior ganglionated plexus (RIGP) elicits selective negative dromotropic effects in awake patients and slows atrioventricular (AV) conduction during atrial fibrillation. 3 The RIGP is located between the inferior caval vein, the left atrium and the ostium of the coronary sinus. It contains abundant parasympathetic fibers that affect AV node conduction. 6,7 After proof of concept in humans, we and others developed a technique for chronic endocardial 8,9 and epicardial 10 neurostimulation of the RIGP for ventricular rate control during atrial fibrillation (AF) in dogs. Of note, the negative dromotropic effect during endocardial HFES could be maintained throughout the entire neurostimulation period of 2 year...

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“…Although epinephrine and norepinephrine have previously been shown to sensitize nociceptors located on small diameter primary afferents in the periphery (Hu and Zhu 1989;Khasar et al 1999b;Shyu et al 1989), elevated levels of central catecholamines are generally associated with descending inhibition of pain via actions at α 2 ARs or D 2 DARs in the spinal dorsal horn (Millan 2002). Antidepressants used extensively in the treatment of persistent pain conditions, are thought to inhibit pain transmission at the spinal level by increasing synaptic levels of norepinephrine and serotonin (Sanchez and Hyttel 1999) as well as by blocking tetrodotoxin-resistant sodium channels (Brau et al 2001). Furthermore, catecholamine-induced elevations in blood pressure have been shown to produce analgesia through the stimulation of arterial baroreceptors Randich and Maixner 1984;Zamir and Maixner 1986).…”

Section: Comt Inhibition Increases Pain Behavior Via β 2 and β 3 Adrementioning

confidence: 99%

Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

Nackley

Tan

Fecho

et al. 2007

Pain

256

200

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Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Our group demonstrated that human genetic variants of COMT are predictive for the development of Temporomandibular Joint Disorder (TMJD) and are associated with heightened experimental pain sensitivity (Diatchenko et al. 2005). Variants associated with heightened pain sensitivity produce lower COMT activity. Here we report the mechanisms underlying COMT-dependent pain sensitivity. To characterize the means whereby elevated catecholamine levels, resulting from reduced COMT activity, modulate heightened pain sensitivity, we administered a COMT inhibitor to rats and measured behavioral responsiveness to mechanical and thermal stimuli. We show that depressed COMT activity results in enhanced mechanical and thermal pain sensitivity. This phenomenon is completely blocked by the nonselective β-adrenergic antagonist propranolol or by the combined administration of selective β 2 -and β 3 -adrenergic antagonists, while administration of β 1 -adrenergic, α-adrenergic, or dopaminergic receptor antagonists fail to alter COMT-dependent pain sensitivity. These data provide the first direct evidence that low COMT activity leads to increased pain sensitivity via a β 2/3 -adrenergic mechanism. These findings are of considerable clinical importance, suggesting that pain conditions resulting from low COMT activity and/or elevated catecholamine levels can be treated with pharmacological agents that block both β 2 -and β 3 -adrenergic receptors. Keywords epinephrine; norepinephrine; catecholamines; allodynia; hyperalgesia; carrageenan Catecholamines and enzymatic pathways that regulate the bioavailability of catecholamines influence persistent pain. Adrenergic systems contribute to the pathogenesis of rheumatoid Corresponding Author: Andrea G Neely, Center for Neurosensory Disorders, School of Dentistry, CB 7450, University of North Carolina, Chapel Hill, NC 27599-7450, Phone: (919) 966-2953, Fax: (919) Email: andrea_nackley@dentistry.unc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPain. Author manuscript; available in PMC 2007 July 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript arthritis in animals, as denervation of sympathetic noradrenergic fibers (Levine et al. 1986a) and depletion of peripheral epinephrine (Coderre et al. 1990) attenuate arthritic responses. Additionally, chronic administration of β-adrenergic receptor (βAR) agonists produces a painful arthritis-like s...

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Effect of Drugs Used for Neuropathic Pain Management on Tetrodotoxin-resistant Na+Currents in Rat Sensory Neurons

Cited by 127 publications

References 0 publications

Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain

Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain

Chronic Electrical Neuronal Stimulation Increases Cardiac Parasympathetic Tone by Eliciting Neurotrophic Effects

Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

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