RT Journal Article
SR Electronic
T1 Retrograde Viral Vector-Mediated Inhibition of Pontospinal Noradrenergic Neurons Causes Hyperalgesia in Rats
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12855
OP 12864
DO 10.1523/JNEUROSCI.1699-09.2009
VO 29
IS 41
A1 Patrick W. Howorth
A1 Simon R. Thornton
A1 Victoria O'Brien
A1 Wynne D. Smith
A1 Natalia Nikiforova
A1 Anja G. Teschemacher
A1 Anthony E. Pickering
YR 2009
UL http://www.jneurosci.org/content/29/41/12855.abstract
AB 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-hKir2.1) 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 (hKir2.1). Expression of hKir2.1 in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. LC neurons transduced by AVV-PRS-hKir2.1 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-hKir2.1 showed thermal but not mechanical hyperalgesia. Similar selective augmentation of thermal hyperalgesia was seen in the CFA-inflammatory pain model after AVV-PRS-hKir2.1. In the formalin test, rats transduced with hKir2.1 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-hKir2.1 before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of ∼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.