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Selective Ablation of Pain-Sensing Neurons by Administration of a Vanilloid Receptor Agonist

By administering a vanilloid receptor agonist directly to the neuronal cell body in a ganglion, the method selectively ablates pain-sensing neurons, effectively addressing the limitations of current analgesic therapies in managing chronic pain and inflammatory disorders with minimal impact on other sensory functions.

Inactive Publication Date: 2013-08-15
THE GOV OF THE US REPRESENTED BY THE SEC OF THE DEPT OF HEALTH & HUMAN SERVICE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach provides effective pain relief for chronic pain conditions, including neuropathic pain, inflammatory disorders, and chronic viral infections, while minimizing impact on non-pain sensory functions, offering a targeted therapy for treatment-resistant pain without compromising acute pain responses.

Problems solved by technology

Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects.
In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method.
The conflicting results raised a number of issues such as the possibility of complications in data interpretation resulting from spinal cord damage from cannula implantation, or solvent toxicity problems.
No thermal analgesia was demonstrated and the authors concluded that intrathecal capsaicin administration is not a reliable method for producing thermal analgesia in the rat.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Administration of VR-1 Agonist to Cells Expressing VR-1

[0073]The effect of VR-1 agonist administration to cells expression VR-1 was measured using the following methodology.

[0074]A VR1 expression vector encoding a VR-1 / Green Fluorescent Protein construct was expressed in Cos7 and HEK293 cells using transient transfection. Western blot analysis showed that VR1 eGFP protein exhibited GFP-specific immunoreactivity and was not cleaved. The cells in the population that fluoresced green were voltage clamped and the holding potential adjusted to −60 mV. The first application of 10 μM capsaicin (CAP) to the cells induced a large inward current (N=5). Multiple exposures resulted in a gradual decrease, indicating receptor desensitization. The VR1eGFP-mediated current was attenuated by co-incubation of an antagonist, 10 μM capsazepine (CPZ). Current versus voltage relationships demonstrated that the VR1eGFP-mediated current was not voltage sensitive. The reversal potential was calculated to be...

example 2

VR1 Agonist Injection into the Trigeminal Ganglion Methods

[0085]Trigeminal microinjections: Male Sprague Dawley rats (300 g) were anesthetized with a combination of ketamine / xylazine and placed in a stereotaxic frame. A 26 gauge stainless steel catheter, sharpened with a bevel of ˜0.5 mm, was positioned at 2.5 mm posterior and 1.5 mm lateral to bregma. The needle was advanced till it touched the base of the skull. At this point the tip has penetrated through the trigeminal ganglion, which is ˜1.2 mm in depth. The needle was retracted 0.5 mm and RTX (200 ng) was injected in a volume of 2 microliters over 1.5 to 2 min. The RTX was diluted with 0.9% saline from a stock solution which contained 1 mg / ml of RTX, 10% ethanol, 10% Tween 80 and 80% normal saline. The vehicle that was injected was a 1:10 dilution of the RTX stock vehicle using 0.9% saline as the diluent. The needle is left in place for an additional minute, withdrawn, and the scalp incision is closed with stainless steel clip...

example 3

Intrathecal Administration of RTX

[0091]Pain sensitivity following intrathecal administration of RTX to rats was measured using a test for thermal sensitivity well known to those in the art, the paw withdrawal latency test (e.g., Hargreaves (1988) Pain 32:77-88). Sprague Dawley rats received 6 ug of RTX in a 5 microliter volume administered by lumbar puncture. The baseline sensitivity was 8.4±1.3 second. Following administration of RTX, the paw withdrawal latency was 18±1.2 seconds. No attenuation of mechanical pinch sensitivity was observed. Thus, RTX administration resulted in attenuation of thermal sensitivity.

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PUM

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Abstract

The present invention provides methods and kits for the selective ablation of pain-sensing neurons. The methods comprise administration of a vanilloid receptor agonist to a ganglion in an amount that causes death of vanilloid receptor-bearing neurons. Accordingly, the present invention provides methods of controlling pain and inflammatory disorders that involve activation of vanilloid receptor-bearing neurons.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of application Ser. No. 12 / 776,304, filed May 7, 2010, which is a continuation of U.S. patent application Ser. No. 10 / 472,784 filed Mar. 18, 2004, abandoned, which is a 371 national stage application of PCT application no. PCT / US01 / 09425 filed Mar. 22, 2001, each of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects. In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method. The sensation of pain is transduced in the periphery by pain-sensing, i.e. nociceptive, C- and A-delta primary afferent neurons. These neurons have a peripheral nerve ending in the skin or deep tissues and a central terminal that makes synaptic contact with second order neurons in the spinal cord dorsal horn. The imp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/357A61K31/167A61K31/165A61K31/16A61K36/81
CPCA61K31/16A61K31/357A61K31/167A61K31/165A61P29/00
Owner THE GOV OF THE US REPRESENTED BY THE SEC OF THE DEPT OF HEALTH & HUMAN SERVICE
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