Quantitative Proteomic Analysis of the Central Amygdala in Neuropathic Pain Model Rats.

Pain and emotional distress have a reciprocal relation. The amygdala has been implicated in emotional processing. The central nucleus of the amygdala (CeA) receives nociceptive information from the dorsal horn of spinal cord and is responsible for the central plasticity in chronic pain.

VGF: a biomarker and potential target for the treatment of neuropathic pain?

Neuropathic pain (NP) remains an area of considerable unmet medical need. A persistent challenge in the management of NP is to target the specific mechanisms leading to a change from normal to abnormal sensory perception while ensuring that the defensive pain perception remains intact. Targeting VGF-derived neuropeptides may offer this opportunity.

Intracellular calcium oscillations in strongly metastatic human breast and prostate cancer cells: control by voltage-gated sodium channel activity.

The possible association of intracellular Ca with metastasis in human cancer cells is poorly understood. We have studied Ca signaling in human prostate and breast cancer cell lines of strongly versus weakly metastatic potential in a comparative approach. Intracellular free Ca was measured using a membrane-permeant fluorescent Ca-indicator dye (Fluo-4 AM) and confocal microscopy.

Identification of a receptor for neuropeptide VGF and its role in neuropathic pain.

VGF (nonacronymic) is a neuropeptide precursor that plays multiple roles in regulation of energy balance, reproduction, hippocampal synaptic plasticity, and pain. Data from a number of pain models showed significant up-regulation of VGF in sensory neurons. TLQP-21, one of the VGF-derived neuropeptides, has been shown to induce a hyperalgesic response when injected subcutaneously into the hind paw of mice.

A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy.

HIV-associated sensory neuropathy is the most frequent manifestation of HIV disease, afflicting 40-50% of patients whose HIV disease is otherwise controlled by antiretroviral therapy. It often presents with significant neuropathic pain and is consistently associated with previous exposure to nucleoside reverse transcriptase inhibitors including stavudine (d4T), which is widely used in resource-limited settings. Here we investigated complex pain-related behaviours associated with d4T treatment using ethologically relevant thigmotaxis and burrowing behaviours in adult rats.

Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability.

Voltage-gated sodium channels (VGSCs) play a key role in the initiation and propagation of action potentials in neurons. Na(V)1.8 is a tetrodotoxin (TTX) resistant VGSC expressed in nociceptors, peripheral small-diameter neurons able to detect noxious stimuli.

In vitro and intrathecal siRNA mediated K(V)1.1 knock-down in primary sensory neurons.

K(V)1.1 is a Shaker homologue K(+) channel that contributes to the juxta-paranodal membrane conductance in myelinated axons, and is blocked by fampridine (4-aminopyridine), used to treat the symptoms of multiple sclerosis. The present experiments investigate K(V)1.

Building excitable membranes: lipid rafts and multiple controls on trafficking of electrogenic molecules.

Multiple plasma membrane proteins such as ion transporters and ion channels are involved in electrogenesis by setting resting membrane potentials and triggering/propagating action potentials. Recent findings strongly suggest that some of these membrane proteins are selectively transported into membrane microdomains termed lipid rafts. There appear to be multiple mechanisms for the specific protein translocation to lipid rafts, and many of these proteins exhibit distinct properties when inserted into the raft microdomains.

The trafficking of Na(V)1.8.

The α-subunit of tetrodotoxin-resistant voltage-gated sodium channel Na(V)1.8 is selectively expressed in sensory neurons. It has been reported that Na(V)1.

A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel Na(V)1.8.

The voltage-gated sodium channel Na(V)1.8 is expressed exclusively in nociceptive sensory neurons and plays an important role in pain pathways. Na(V)1.

Protein-protein interactions involving voltage-gated sodium channels: Post-translational regulation, intracellular trafficking and functional expression.

Voltage-gated sodium channels (VGSCs), classically known to play a central role in excitability and signalling in nerves and muscles, have also been found to be expressed in a range of 'non-excitable' cells, including lymphocytes, fibroblasts and endothelia. VGSC abnormalities are associated with various diseases including epilepsy, long-QT syndrome 3, Brugada syndrome, sudden infant death syndrome and, more recently, various human cancers. Given their pivotal role in a wide range of physiological and pathophysiological processes, regulation of functional VGSC expression has been the subject of intense study.

Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.

Neuropathic pain may arise following peripheral nerve injury though the molecular mechanisms associated with this are unclear. We used proteomic profiling to examine changes in protein expression associated with the formation of hyper-excitable neuromas derived from rodent saphenous nerves. A two-dimensional difference gel electrophoresis (2D-DIGE) profiling strategy was employed to examine protein expression changes between developing neuromas and normal nerves in whole tissue lysates.

Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain.

To elucidate the mechanisms underlying peripheral neuropathic pain in the context of HIV infection and antiretroviral therapy, we measured gene expression in dorsal root ganglia (DRG) of rats subjected to systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) and concomitant delivery of HIV-gp120 to the rat sciatic nerve. L4 and L5 DRGs were collected at day 14 (time of peak behavioural change) and changes in gene expression were measured using Affymetrix whole genome rat arrays. Conventional analysis of this data set and Gene Set Enrichment Analysis (GSEA) was performed to discover biological processes altered in this model.

Alternative splicing of Nav1.5: an electrophysiological comparison of 'neonatal' and 'adult' isoforms and critical involvement of a lysine residue.

In developmentally regulated D1:S3 splicing of Nav1.5, there are 31 nucleotide differences between the 5'-exon ('neonatal') and the 3'-exon ('adult') forms, resulting in 7 amino acid differences in D1:S3-S3/S4 linker. In particular, splicing replaces a conserved negative aspartate residue in the 'adult' with a positive lysine.

Pain signalling pathways: from cytokines to ion channels.

Pain is the major reason patients seek medical care. The treatment of pain, particularly chronic pain associated with cancer and damage to the nervous system, is at present inadequate. Lack of effective analgesics is partly due to the fact that pain signalling mechanisms are still not fully understood.

Deletion of annexin 2 light chain p11 in nociceptors causes deficits in somatosensory coding and pain behavior.

The S100 family protein p11 (S100A10, annexin 2 light chain) is involved in the trafficking of the voltage-gated sodium channel Na(V)1.8, TWIK-related acid-sensitive K+ channel (TASK-1), the ligand-gated ion channels acid-sensing ion channel 1a (ASIC1a) and transient receptor potential vanilloid 5/6 (TRPV5/V6), as well as 5-hydroxytryptamine receptor 1B (5-HT1B), a G-protein-coupled receptor. To evaluate the role of p11 in peripheral pain pathways, we generated a loxP-flanked (floxed) p11 mouse and used the Cre-loxP recombinase system to delete p11 exclusively from nociceptive primary sensory neurons in mice.

Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression.

Binding to isolectin-B4 (IB4) and expression of tyrosine kinase A (trkA) (the high-affinity NGF receptor) have been used to define two different subgroups of nociceptive small dorsal root ganglion (DRG) neurons. We previously showed that only nociceptors have high trkA levels. However, information about sensory and electrophysiological properties in vivo of single identified IB4-binding neurons, and about their trkA expression levels, is lacking.

Annexin II light chain p11 promotes functional expression of acid-sensing ion channel ASIC1a.

Acid-sensing ion channels (ASICs) have been implicated in a wide variety of physiological functions. We have used a rat dorsal root ganglion cDNA library in a yeast two-hybrid assay to identify sensory neuron proteins that interact with ASICs. We found that annexin II light chain p11 physically interacts with the N terminus of ASIC1a, but not other ASIC isoforms.

trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors.

To test the hypothesis that trkA (the high-affinity NGF receptor) is selectively expressed in nociceptive dorsal root ganglion (DRG) neurons, we examined the intensity of trkA immunoreactivity in single dye-injected rat DRG neurons, the sensory receptor properties of which were identified in vivo with mechanical and thermal stimuli. We provide the first evidence in single identified neurons that strong trkA expression in DRGs is restricted to nociceptive neurons, probably accounting for the profound influence of NGF on these neurons. Furthermore, we demonstrate that trkA expression is as high in rapidly conducting (Aalpha/beta) as in more slowly conducting (Adelta and C) nociceptors.

Voltage-gated sodium channels and pain pathways.

Acute, inflammatory, and neuropathic pain can all be attenuated or abolished by local treatment with sodium channel blockers such as lidocaine. The peripheral input that drives pain perception thus depends on the presence of functional voltage-gated sodium channels. Remarkably, two voltage-gated sodium channel genes (Nav1.

Identification of binding domains in the sodium channel Na(V)1.8 intracellular N-terminal region and annexin II light chain p11.

The interaction of p11 (annexin II light chain) with the N-terminal domain of Na(V)1.8, a tetrodotoxin-resistant sodium channel, is essential for the functional expression of the channel. Here we show that p11 binds to Na(V)1.

The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons.

We have examined the distribution of the sensory neuron-specific Na+ channel Nav1.8 (SNS/PN3) in nociceptive and non-nociceptive dorsal root ganglion (DRG) neurons and whether its distribution is related to neuronal membrane properties. Nav1.

Sensory neuron proteins interact with the intracellular domains of sodium channel NaV1.8.

Voltage-gated sodium channels initiate and propagate action potentials in excitable cells. The tetrodotoxin-resistant Na(+) channel (Na(V)1.8/SNS) is expressed in damage-sensing neurons (nociceptors) and plays an important role in pain pathways.

Annexin II light chain regulates sensory neuron-specific sodium channel expression.

The tetrodotoxin-resistant sodium channel Na(V)1.8/SNS is expressed exclusively in sensory neurons and appears to have an important role in pain pathways. Unlike other sodium channels, Na(V)1.