Research article summary (published 12 Oct 2009):

Retrograde viral vector-mediated inhibition of pontospinal noradrenergic neurons causes hyperalgesia in rats.

Full Abstract

Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir(2.1)) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir(2.1)). Expression of hKir(2.1) in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. LC neurons transduced by AVV-PRS-hKir(2.1) in slice cultures also showed barium-sensitive inward rectification and reduced spontaneous firing rate (median 0.2 Hz; n = 19 vs control 1.0 Hz; n = 18, p < 0.05). Pontospinal noradrenergic neurons were retrogradely transduced in vivo by injection of AVV into the lumbar dorsal horn (L4-5). Rats transduced with AVV-PRS-hKir(2.1) showed thermal but not mechanical hyperalgesia. Similar selective augmentation of thermal hyperalgesia was seen in the CFA-inflammatory pain model after AVV-PRS-hKir(2.1). In the formalin test, rats transduced with hKir(2.1) showed enhanced nocifensive behaviors (both Phase I and II, p < 0.05, n = 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir(2.1) before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of approximately 150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.

Author information

Author/s: Howorth, Patrick W (PW); Thornton, Simon R (SR); O'Brien, Victoria (V); Smith, Wynne D (WD); Nikiforova, Natalia (N); Teschemacher, Anja G (AG); Pickering, Anthony E (AE);

Affiliation: Department of Physiology & Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.

Journal and publication information

Publication Type: In Vitro; Journal Article

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 29 (issue 41) : pp 12855-64

Dates: Created 2009/10/15; Completed 2009/10/30;

PMID: 19828800, status: MEDLINE (last retrieval date: 10/30/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adenoviridae - genetics Animals Animals, Newborn Catecholamines - genetics Cell Count - methods Disease Models, Animal Dopamine beta-Hydroxylase - metabolism Genetic Vectors - genetics Green Fluorescent Proteins - genetics Hyperalgesia - etiology; pathology Laminectomy - methods Male Membrane Potentials - genetics; physiology Motor Activity - genetics

Neurons - metabolism Norepinephrine - metabolism PC12 Cells Pain Measurement - methods Pain Threshold - physiology Patch-Clamp Techniques - methods Peripheral Nervous System Diseases - physiopathology Pons - pathology Potassium Channels, Inwardly Rectifying - genetics Promoter Regions, Genetic - genetics Proto-Oncogene Proteins c-fos - metabolism Rats Rats, Wistar Transfection - methods

Associated Chemicals: Catecholamines (0) ; Kir2.1 channel (0) ; Potassium Channels, Inwardly Rectifying (0) ; Proto-Oncogene Proteins c-fos (0) ; enhanced green fluorescent protein (0) ; Green Fluorescent Proteins (147336-22-9) ; Norepinephrine (51-41-2) ; Dopamine beta-Hydroxylase (EC 1.14.17.1)

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