Category: Spinal Injections

Intractable pruritus after traumatic spinal cord injury.

Intractable pruritus after traumatic spinal cord injury.

J Spinal Cord Med. 2009;32(4):436-9

Authors: Crane DA, Jaffee KM, Kundu A

This report describes a young woman with incomplete traumatic cervical spinal cord injury and intractable pruritus involving her dorsal forearm.

PMID: 19777867 [PubMed – indexed for MEDLINE]

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Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.

Pain. 2009 Apr;142(3):225-35

Authors: Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, George AL, Camerino DC

Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson’s disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.

PMID: 19217209 [PubMed – indexed for MEDLINE]

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A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium.

A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium.

Eur J Neurosci. 2007 Jul;26(1):12-22

Authors: Leffler A, Linte RM, Nau C, Reeh P, Babes A

Heat-activated ion channels from the vanilloid-type TRP group (TRPV1-4) seem to be central for heat-sensitivity of nociceptive sensory neurons. Displaying a high-threshold (> 52 degrees C) for activation, TRPV2 was proposed to act as a sensor for intense noxious heat in mammalian sensory neurons. However, although TRPV2 is expressed in a distinct population of thinly myelinated primary afferents, a widespread expression in a variety of neuronal and non-neuronal tissues suggests a more diverse physiological role of TRPV2. In its role as a heat-sensor, TRPV2 has not been thoroughly characterized in terms of biophysical and pharmacological properties. In the present study, we demonstrate that the features of heterologously expressed rat TRPV2 closely resemble those of high-threshold heat-evoked currents in medium- and large-sized capsaicin-insensitive rat dorsal root ganglion (DRG) neurons. Both in TRPV2-expressing human embryonic kidney (HEK)293t cells and in DRGs, high-threshold heat-currents were sensitized by repeated activation and by the TRPV1-3 agonist, 2-aminoethoxydiphenyl borate (2-APB). In addition to a previously described block by ruthenium red, we identified the trivalent cations, lanthanum (La(3+)) and gadolinium (Gd(3+)) as potent blockers of TRPV2. Thus, we present a new pharmacological tool to distinguish between heat responses of TRPV2 and the closely related capsaicin-receptor, TRPV1, which is strongly sensitized by trivalent cations. We demonstrate that self-sensitization of heat-evoked currents through TRPV2 does not require extracellular calcium and that TRPV2 can be activated in cell-free membrane patches in the outside-out configuration. Taken together our results provide new evidence for a role of TRPV2 in mediating high-threshold heat responses in a subpopulation of mammalian sensory neurons.

PMID: 17596195 [PubMed – indexed for MEDLINE]

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Two Nedd4-binding motifs underlie modulation of sodium channel Nav1.6 by p38 MAPK.

Two Nedd4-binding motifs underlie modulation of sodium channel Nav1.6 by p38 MAPK.

J Biol Chem. 2010 Aug 20;285(34):26149-61

Authors: Gasser A, Cheng X, Gilmore ES, Tyrrell L, Waxman SG, Dib-Hajj SD

Sodium channel Na(v)1.6 is essential for neuronal excitability in central and peripheral nervous systems. Loss-of-function mutations in Na(v)1.6 underlie motor disorders, with homozygous-null mutations causing juvenile lethality. Phosphorylation of Na(v)1.6 by the stress-induced p38 MAPK at a Pro-Gly-Ser(553)-Pro motif in its intracellular loop L1 reduces Na(v)1.6 current density in a dorsal root ganglion-derived cell line, without changing its gating properties. Phosphorylated Pro-Gly-Ser(553)-Pro motif is a putative binding site to Nedd4 ubiquitin ligases, and we hypothesized that Nedd4-like ubiquitin ligases may contribute to channel ubiquitination and internalization. We report here that p38 activation in hippocampal neurons from wild-type mice, but not from Scn8a(medtg) mice that lack Na(v)1.6, reduces tetrodotoxin-S sodium currents, suggesting isoform-specific modulation of Na(v)1.6 by p38 in these neurons. Pharmacological block of endocytosis completely abolishes p38-mediated Na(v)1.6 current reduction, supporting our hypothesis that channel internalization underlies current reduction. We also report that the ubiquitin ligase Nedd4-2 interacts with Na(v)1.6 via a Pro-Ser-Tyr(1945) motif in the C terminus of the channel and reduces Na(v)1.6 current density, and we show that this regulation requires both the Pro-Gly-Ser-Pro motif in L1 and the Pro-Ser-Tyr motif in the C terminus. Similarly, both motifs are necessary for p38-mediated reduction of Na(v)1.6 current, whereas abrogating binding of the ubiquitin ligase Nedd4-2 to the Pro-Ser-Tyr motif results in stress-mediated increase in Na(v)1.6 current density. Thus, phosphorylation of the Pro-Gly-Ser-Pro motif within L1 of Na(v)1.6 is necessary for stress-induced current modulation, with positive or negative regulation depending upon the availability of the C-terminal Pro-Ser-Tyr motif to bind Nedd4-2.

PMID: 20530479 [PubMed – indexed for MEDLINE]

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Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

PLoS One. 2009;4(9):e7021

Authors: Jeffry JA, Yu SQ, Sikand P, Parihar A, Evans MS, Premkumar LS

Chronic pain is a major clinical problem and opiates are often the only treatment, but they cause significant problems ranging from sedation to deadly respiratory depression. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), causes a slow, sustained and irreversible activation of TRPV1 and increases the frequency of spontaneous excitatory postsynaptic currents, but causes significant depression of evoked EPSCs due to nerve terminal depolarization block. Intrathecal administration of RTX to rats in the short-term inhibits nociceptive synaptic transmission, and in the long-term causes a localized, selective ablation of TRPV1-expressing central sensory nerve terminals leading to long lasting analgesia in behavioral models. Since RTX actions are selective for central sensory nerve terminals, other efferent functions of dorsal root ganglion neurons can be preserved. Preventing nociceptive transmission at the level of the spinal cord can be a useful strategy to treat chronic, debilitating and intractable pain.

PMID: 19753113 [PubMed – indexed for MEDLINE]

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[Case of painful muscle spasm induced by thoracic vertebral fracture: successful treatment with lumbar sympathetic ganglia block].

[Case of painful muscle spasm induced by thoracic vertebral fracture: successful treatment with lumbar sympathetic ganglia block].

Rinsho Shinkeigaku. 2008 Oct;48(10):733-6

Authors: Shimizu F, Kawai M, Koga M, Ogasawara J, Negoro K, Kanda T

We report a 70-year-old man, who developed painful involuntary muscle contraction of the left leg after the lumbar discectomy, which exacerbated after a vertebral fracture of Th12. This involuntary movement was accompanied with the abnormal position of left leg simulating triple flexion response, and was induced by active or passive movement of his left knee and foot joints. Several drugs including benzodiazepines and dantrolene were ineffective, although treatment with baclofen or carbamazepine was effective. These findings suggest that hyperexcitability of the anterior horn cells following the disturbance of spinal inhibitory interneurons was involved. Electophysiological studies suggested the disturbance of left lumber nerve roots. The spinal root blocks from L3 to S1 were performed, after which the painful involuntary muscle spasm was resolved. The lumbar sympathetic ganglia block was also effective; suggesting that abnormal afferent neuronal input to spinal cord was caused by the nerve root trauma which triggered the formation of secondary abnormal network in the spine. Lumbar sympathetic ganglia block should be recommended to a therapeutic option for the refractory painful muscle spasm of the leg.

PMID: 19086429 [PubMed – indexed for MEDLINE]

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Inhibition of insect calcium channels by huwentoxin-V, a neurotoxin from Chinese tarantula Ornithoctonus huwena venom.

Inhibition of insect calcium channels by huwentoxin-V, a neurotoxin from Chinese tarantula Ornithoctonus huwena venom.

Eur J Pharmacol. 2008 Mar 17;582(1-3):12-6

Authors: Deng M, Luo X, Meng E, Xiao Y, Liang S

The effects of huwentoxin-V, an insect neurotoxic peptide from Chinese tarantula Ornithoctonus huwena venom, were studied on neuronal voltage-gated ion channels. Whole-cell patch-clamp configuration indicated that huwentoxin-V specifically inhibited high-voltage-activated calcium channels in adult cockroach dorsal unpaired median neurons (IC(50) approximately 219 nM) while having no evident effect on voltage-gated potassium and sodium channels. Omega-conotoxin GVIA is a well-known neuronal N-type calcium channel blocker from the venom of the sea snail Conus geographus and it also can partially block calcium currents in cockroach dorsal unpaired median neurons. In our study, huwentoxin-V inhibited omega-conotoxin GVIA-sensitive, diltiazem-sensitive and partial omega-conotoxin GVIA and diltiazem-resistant calcium currents elicited from insect neurons. Based on the sensitivity of calcium currents to these toxins, insect neuronal HVA calcium channels might be classified into four types: Type I, omega-conotoxin GVIA-sensitive and huwentoxin-V-sensitive; type II, diltiazem-sensitive and huwentoxin-V-sensitive; type III, huwentoxin-V-sensitive but omega-conotoxin GVIA and diltiazem-resistant; type IV, omega-conotoxin GVIA and diltiazem-resistant and huwentoxin-V-resistant. Its specificity, incomplete inhibition and insect-toxic effects make it an interesting tool for investigating insect voltage-gated calcium channels and development of new insecticidal compounds.

PMID: 18234186 [PubMed – indexed for MEDLINE]

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[Writer's cramp].

[Writer’s cramp].

Brain Nerve. 2007 Jun;59(6):569-79

Authors: Murase N

Writer’s cramp is classified as a focal dystonia. Abnormal sensory-motor integration is characteristic and loss of inhibition is seen in many levels, including cortex, spinal cord, and peripheral nerves. Altered, irregular firing pattern of the basal ganglia, as well as push-pull system of the motor loop, probably play an important role in the pathophysiology of dystonia. First therapeutic step is providing the information of pathophysiology to the patients and advicing them to reduce the amount of writing. According to severity, local lidocaine block or medication is used in Japan.

PMID: 17585588 [PubMed – indexed for MEDLINE]

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