| Title | Retrograde viral vector-mediated inhibition of pontospinal noradrenergic neurons causes hyperalgesia in rats. | | Author(s) | Howorth PW, Thornton SR, O'Brien V, Smith WD, Nikiforova N, Teschemacher AG, Pickering AE | | Institution | Department of Physiology & Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom. | | Source | J Neurosci 2009 Oct 14; 29(41):12855-64. | | MeSH | Adenoviridae
Animals
Animals, Newborn
Catecholamines
Cell Count
Disease Models, Animal
Dopamine beta-Hydroxylase
Genetic Vectors
Green Fluorescent Proteins
Hyperalgesia
Laminectomy
Male
Membrane Potentials
Motor Activity
Neurons
Norepinephrine
PC12 Cells
Pain Measurement
Pain Threshold
Patch-Clamp Techniques
Peripheral Nervous System Diseases
Pons
Potassium Channels, Inwardly Rectifying
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos
Rats
Rats, Wistar
Transfection
| | 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. | | Language | eng | | Pub Type(s) | In Vitro
Journal Article
| | PubMed ID | 19828800 |
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