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The Journal of Neuroscience, October 14, 2009, 29(41):12855-12864; doi:10.1523/JNEUROSCI.1699-09.2009

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Behavioral/Systems/Cognitive
Retrograde Viral Vector-Mediated Inhibition of Pontospinal Noradrenergic Neurons Causes Hyperalgesia in Rats

Patrick W. Howorth,¹ Simon R. Thornton,¹ Victoria O'Brien,¹ Wynne D. Smith,¹ Natalia Nikiforova,² Anja G. Teschemacher,¹ and Anthony E. Pickering^1,3

¹Department of Physiology & Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom, ²Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom, and ³Department of Anaesthesia, University Hospitals Bristol, Bristol BS2 8HW, United Kingdom

Correspondence should be addressed to Anthony E. Pickering, Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. Email: Tony.Pickering{at}Bristol.ac.uk

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 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.

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Received April 8, 2009; revised June 28, 2009; accepted July 6, 2009.

Correspondence should be addressed to Anthony E. Pickering, Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. Email: Tony.Pickering{at}Bristol.ac.uk

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