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

PW Howorth, SR Thornton, V O'Brien, WD Smith, N Nikiforova, AG Teschemacher, AE Pickering

Research output: Contribution to journalArticle (Academic Journal)

26 Citations (Scopus)

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.
Translated title of the contributionRetrograde viral vector-mediated inhibition of pontospinal noradrenergic neurons causes hyperalgesia in rats
Original languageEnglish
Pages (from-to)12855 - 12864
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number41
DOIs
Publication statusPublished - 14 Oct 2009

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