The tetrodotoxin-resistant Na+ channel Na (v)1.8 reduces the potency of local anesthetics in blocking C-fiber nociceptors.

The tetrodotoxin-resistant Na+ channel Na (v)1.8 reduces the potency of local anesthetics in blocking C-fiber nociceptors.

Pflugers Arch. 2010 Apr;459(5):751-63

Authors: Kistner K, Zimmermann K, Ehnert C, Reeh PW, Leffler A

The generation of action potentials in nociceptive neurons is accomplished by the tetrodotoxin-resistant (TTXr) Na+ channel Na(v)1.8. Following nerve injury, a redistribution of Na(v)1.8 from dorsal root ganglion (DRG) neurons into peripheral axons contributes to hyperexcitability and possibly to neuropathic pain. Na(v)1.8 has been reported to display a lower sensitivity to block by Na+ channel blockers as compared to TTX-sensitive (TTXs) Na(v) subunits. Furthermore, the antinociceptive efficacy of lidocaine is increased in Na(v)1.8-knockout mice. Here, we asked if Na(v)1.8 expression can reduce the susceptibility of sensory neurons to block by lidocaine. Employing wild-type and Na(v)1.8-knockout mice, we examined C-fibers in the skin-nerve preparation and Na+ currents in DRG neurons by patch-clamp recordings. Deletion of Na(v)1.8 resulted in an enhanced tonic block of Na+ currents in DRG neurons held at -80 mV but not at -140 mV. Accordingly, lower concentrations of lidocaine were required for a conduction block of C-fibers from Na(v)1.8-knockout as compared to wild-type mice. The efficacy of lidocaine on neurons lacking Na(v)1.8 was further increased by cold temperatures, due to a synergistic hyperpolarizing shift of the slow inactivation of TTXs Na+ channels by lidocaine and cooling. Finally, the approximately 90% reduction of TTXr Na+ currents in injured neurons from mice with a peripheral nerve injury was accompanied with an enhanced tonic block by lidocaine. In conclusion, our data demonstrate that the expression of Na(v)1.8 in sensory neurons can confine the antinociceptive efficacy of lidocaine and other Na+ channel blockers employed for pain treatment.

PMID: 20174994 [PubMed – indexed for MEDLINE]

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Brain derived neurotrophic factor (BDNF) contributes to the pain hypersensitivity following surgical incision in the rats.

Brain derived neurotrophic factor (BDNF) contributes to the pain hypersensitivity following surgical incision in the rats.

Mol Pain. 2008;4:27

Authors: Li CQ, Xu JM, Liu D, Zhang JY, Dai RP

The pathogenic role of brain derived neurotrophic factor (BDNF) in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity.

PMID: 18637202 [PubMed – indexed for MEDLINE]

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Direct inhibition of Ih by analgesic loperamide in rat DRG neurons.

Direct inhibition of Ih by analgesic loperamide in rat DRG neurons.

J Neurophysiol. 2007 May;97(5):3713-21

Authors: Vasilyev DV, Shan Q, Lee Y, Mayer SC, Bowlby MR, Strassle BW, Kaftan EJ, Rogers KE, Dunlop J

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are responsible for the functional hyperpolarization-activated current (I(h)) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited I(h) channels in rat DRG neurons. Loperamide blocked I(h) in a concentration-dependent manner, with an IC(50) = 4.9 +/- 0.6 and 11.0 +/- 0.5 microM for large- and small-diameter neurons, respectively. Loperamide-induced I(h) inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V(1/2) for I(h) steady-state activation. Loperamide block of I(h) was voltage-dependent, gradually decreasing at more hyperpolarized membrane voltages from 89% at -60 mV to 4% at -120 mV in the presence of 3.7 microM loperamide. The voltage sensitivity of block can be explained by a loperamide-induced shift in the steady-state activation of I(h). Inclusion of 10 microM loperamide into the recording pipette did not affect I(h) voltage for half-maximal activation, activation kinetics, and the peak current amplitude, whereas concurrent application of equimolar external loperamide produced a rapid, reversible I(h) inhibition. The observed loperamide-induced I(h) inhibition was not caused by the activation of peripheral opioid receptors because the broad-spectrum opioid receptor antagonist naloxone did not reverse I(h) inhibition. Therefore we suggest that loperamide inhibits I(h) by direct binding to the extracellular region of the channel. Because I(h) channels are involved in pain processing, loperamide-induced inhibition of I(h) channels could provide an additional molecular mechanism for its analgesic action.

PMID: 17392420 [PubMed – indexed for MEDLINE]

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Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons.

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons.

Endocrinology. 2011 Aug 2;

Authors: Kim B, McLean LL, Philip SS, Feldman EL

Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3?. To mimic hyperinsulinemia, cells were pretreated with 20 nm insulin for 24 h and then stimulated with 20 nm insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3?. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.

PMID: 21810948 [PubMed – as supplied by publisher]

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CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy.

CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy.

Clin J Pain. 2009 Sep;25(7):570-6

Authors: Agarwal-Kozlowski K, Lorke DE, Habermann CR, Am Esch JS, Beck H

An alternate approach to the ganglion impar was chosen to minimize the risk of adverse events. Efficacy of the procedure was evaluated.

PMID: 19692797 [PubMed – indexed for MEDLINE]

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Pain relief after cervical ganglionectomy (C2 and C3) for the treatment of medically intractable occipital neuralgia.

Pain relief after cervical ganglionectomy (C2 and C3) for the treatment of medically intractable occipital neuralgia.

Stereotact Funct Neurosurg. 2008;86(2):106-12

Authors: Acar F, Miller J, Golshani KJ, Israel ZH, McCartney S, Burchiel KJ

Occipital neuralgia (ON) presents a diagnostic challenge because of the wide variety of symptoms, surgical findings, and postsurgical outcomes. Surgical removal of the second (C2) or third (C3) cervical sensory dorsal root ganglion is an option to treat ON. The goal of this study was to evaluate the short-term and the long-term efficacy of these procedures for management of cervical and occipital neuropathic pain. Twenty patients (mean age 48.7 years) were identified who had undergone C2 and/or C3 ganglionectomies for intractable occipital pain and a retrospective chart review undertaken. Patients were interviewed regarding pain relief, pain relief duration, functional status, medication usage and procedure satisfaction, preoperatively, immediately postoperative, and at follow-up (mean 42.5 months). C2, C3 and consecutive ganglionectomies at both levels were performed on 4, 5, and 11 patients, respectively. All patients reported preoperative pain relief following cervical nerve blocks. Average visual analog scale scores were 9.4 preoperatively and 2.6 immediately after procedure. Ninety-five percent of patients reported short-term pain relief (<3 months). In 13 patients (65%), pain returned after an average of 12 months (C2 ganglionectomy) and 8.4 months (C3 ganglionectomy). Long-term results were excellent, moderate and poor in 20, 40 and 40% of patients, respectively. Cervical ganglionectomy offers relief to a majority of patients, immediately after procedure, but the effect is short lived. Nerve blocks are helpful in predicting short-term success, but a positive block result does not necessarily predict long-term benefit and therefore cannot justify surgery by itself. However, since 60% of patients report excellent-moderate results, cervical ganglionectomy continues to have a role in the treatment of intractable ON.

PMID: 18216457 [PubMed – indexed for MEDLINE]

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Nonsynaptic communication through ATP release from volume-activated anion channels in axons.

Nonsynaptic communication through ATP release from volume-activated anion channels in axons.

Sci Signal. 2010;3(142):ra73

Authors: Fields RD, Ni Y

The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We identify a mechanism for nonsynaptic, nonvesicular release of adenosine triphosphate (ATP) from axons through volume-activated anion channels (VAACs) activated by microscopic axon swelling during action potential firing. We used a combination of single-photon imaging of ATP release, together with imaging for intrinsic optical signals, intracellular calcium ions (Ca(2+)), time-lapse video, and confocal microscopy, to investigate action potential-induced nonsynaptic release of this neurotransmitter. ATP release from cultured embryonic dorsal root ganglion axons persisted when bafilomycin or botulinum toxin was used to block vesicular release, whereas pharmacological inhibition of VAACs or prevention of action potential-induced axon swelling inhibited ATP release and disrupted activity-dependent signaling between axons and astrocytes. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease.

PMID: 20923934 [PubMed – indexed for MEDLINE]

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Dihydropyridine block of voltage-dependent K+ currents in rat dorsal root ganglion neurons.

Dihydropyridine block of voltage-dependent K+ currents in rat dorsal root ganglion neurons.

Neuroscience. 2009 Jun 16;161(1):184-94

Authors: Zhang XL, Gold MS

The dihydropyridines nifedipine, nimodipine and Bay K 8644 are widely used as pharmacological tools to assess the contribution of L-type voltage-gated Ca(2+) channels to a variety of neuronal processes including synaptic transmission, excitability and second messenger signaling. These compounds are still used in neuronal preparations despite evidence from cardiac tissue and heterologous expression systems that they block several voltage-dependent K(+) (Kv) channels. Both because these compounds have been used to assess the relative contribution of L-type Ca(2+) channels to several different processes in dorsal root ganglion (DRG) neurons and because a relatively wide variety of Kv channels present in other neuronal populations is present in DRG neurons, we determined the extent to which dihydropyridines block Kv currents in these neurons. Standard whole cell patch clamp techniques were used to study acutely disassociated adult rat DRG neurons. All three dihydropyridines tested blocked Kv currents in DRG neurons; IC(50) values (concentration resulting in an inhibition that is 50% of maximum) for nifedipine and nimodipine-induced block of sustained Kv currents were 14.5 and 6.6 microM, respectively. The magnitude of sustained current block was 44+/-1.6%, 60+/-2%, and 56+/-2.9% with 10 microM nifedipine, nimodipine and Bay K 8644, respectively. Current block was occluded by neither 4-aminopyridine (5 mM) nor tetraethylammonium (135 mM). Dihydropyridine-induced block of Kv currents was not associated with a shift in the voltage-dependence of current activation or inactivation, the recovery from inactivation, or voltage dependent block. However, there was a small use-dependence to the dihydropyridine-induced block. Our results suggest that several types of Kv channels in DRG neurons are blocked by mechanisms distinct from those underlying block of Kv channels in cardiac myocytes. Importantly, our results suggest that if investigators wish to explore the contribution of L-type Ca(2+) channels to neuronal function, they should consider alternative strategies for the manipulation of these channels than the use of dihydropyridines.

PMID: 19289157 [PubMed – indexed for MEDLINE]

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Anomaly with no right ventral root at the seventh cervical segment in humans: gross anatomical and neuroanatomical study.

Anomaly with no right ventral root at the seventh cervical segment in humans: gross anatomical and neuroanatomical study.

Anat Sci Int. 2007 Sep;82(3):133-8

Authors: Higo S, Koizumi M, Kawai K, Honma S, Tokiyoshi A, Tamamaki N, Kodama K

The cadaver of an 89-year-old woman who had died of cerebral apoplexy and which was dedicated to anatomy practice for medical students at Kumamoto University, was found to have complete lack of the right ventral root of the seventh cervical segment (C7). Observation of the peripheral spinal nerve indicated that the branch, which appeared to be a descending collateral of the ventral root of C6, became confluent with the dorsal root of C7 at the point just distal to the dorsal root ganglion. Following this confluence, new fiber elements ran out of the intervertebral foramen as the seventh cervical nerve. More peripherally, this fiber bundle joined the brachial plexus, its outward appearance was normal in the manner of ramification and each nerve’s supply to muscles. Additionally, the inside view of the spinal cord of C6, C7 and C8 was examined neuroanatomically. Nissl staining of transverse sections at C7 (block 2) showed that motor neurons existed in the right anterior horn and their histological features were normal. Subsequently, horizontal sections were made from the two blocks, each of which contained C6/C7 (block 1) or C7/C8 (block 3), and were treated dually with Nissl and myelin staining. These sections also had a normal picture of cells and myelinated fibers on the right side as compared with those on the left side. The results suggested that motor neurons of the right C7 had a normal supply to the targets, although the trajectory of their axons in the spinal cord was obscure.

PMID: 17867339 [PubMed – indexed for MEDLINE]

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Effects of a bupivacaine nerve block on the axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) in a rat model of carrageenan-induced inflammation.

Effects of a bupivacaine nerve block on the axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) in a rat model of carrageenan-induced inflammation.

Brain Behav Immun. 2010 May;24(4):652-9

Authors: Deruddre S, Combettes E, Estebe JP, Duranteau J, Benhamou D, Beloeil H, Mazoit JX

Many pro-inflammatory cytokines are involved in the process of inflammatory pain. Bi directional axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) occurs in case of neuropathic pain induced by nerve ligation. We used an in vivo preparation with injection of carrageenan and fluorescent TNF-alpha in the territory of the saphenous nerve of rats to study this transport. We have shown that retrograde transport of TNF-alpha occurs after an inflammatory insult caused by the injection of carrageenan. This transport was likely mediated by the TNF receptor 1. A nerve block with bupivacaine totally abolishes the expression of the receptor in the dorsal root ganglion and the retrograde transport of TNF-alpha. In addition, bupivacaine at low concentrations (1-10 microM) was able to stop the axonal transport ex vivo. Tetrodotoxin was less efficacious for inhibiting the TNF-alpha transport and the rise in receptor expression and for inhibiting the axonal transport ex vivo. This may partly explain the efficacy of nerve blocks with bupivacaine to decrease the neurogenic inflammation and in a lower extent the long-term inhibition of hyperalgesic phenomenon observed in animals and in humans.

PMID: 20144702 [PubMed – indexed for MEDLINE]

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