Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain

doi:10.1016/j.neuroscience.2009.02.023

Neuroscience

Volume 160, Issue 1, 21 April 2009, Pages 174-185

https://doi.org/10.1016/j.neuroscience.2009.02.023 Get rights and content

Abstract

Current theories of neuropathic hypersensitivity include an imbalance of supraspinal inhibition and facilitation. Our overall hypothesis is that the locus coeruleus (LC), classically interpreted as a source of pain inhibition, may paradoxically result in facilitation after tibial and common peroneal nerve transection (spared sural nerve injury—SNI). We first tested the hypothesis that non-noxious tactile hind paw stimulation of the spared sural innervation territory increases neuronal activity in the LC in male rats. We observed a bilateral increase in the stimulus-evoked expression of transcription factors Fos and phosphorylated CREB (pCREB) in LC after SNI but not sham surgery; these markers of neuronal activity correlated with the intensity of tactile allodynia. We next tested the hypothesis that noradrenergic neurons contribute to the development of neuropathic pain. To selectively destroy these neurons, we delivered antidopamine-β-hydroxylase saporin (anti-DβH-saporin) into the i.c.v. space 2 weeks before SNI. We found that anti-DβH-saporin, but not an IgG-saporin control, reduced behavioral signs of tactile allodynia, mechanical hyperalgesia, and cold allodynia from 3 to 28 days. after SNI. Our final experiment tested the hypothesis that the LC contributes to the maintenance of neuropathic pain. We performed SNI, waited 2 weeks for maximal allodynia and hyperalgesia to develop, and then administered the local anesthetic lidocaine (4%) directly into the LC parenchyma. Lidocaine reduced all behavioral signs of neuropathic pain in a reversible manner, suggesting that the LC contributes to pain facilitation. We conclude that, in addition to its well-known inhibition of acute and inflammatory pain, the LC facilitates the development and maintenance of neuropathic pain in the SNI model. Further studies are needed to determine the facilitatory pathways emanating from the LC.

Section snippets

Subjects

Male Sprague–Dawley rats (Harlan or Charles River, Houston, TX, USA) weighing 250–310 g were housed individually in plastic cages with pine-chip bedding in a temperature-controlled room (25 °C) under a 12-h light/dark cycle (6 am–6 pm) with ad libitum access to food and water. Rats were handled 5 min/day for 5 days prior to any experimental manipulation and all procedures were performed during the light cycle. All animal protocols were approved by the Institutional Animal Care and Use Committee

Results

As illustrated in Fig. 1A, SNI significantly reduced the paw withdrawal threshold to a non-noxious mechanical stimulus (von Frey hairs), and increased paw withdrawal duration to application of either a noxious mechanical (pin) or cool (acetone) stimulus, indicating the presence of tactile allodynia, mechanical hyperalgesia, and cold allodynia, respectively (P's<0.001). Hypersensitivity did not develop in the contralateral paw (P's>0.05; data not shown).

Discussion

Severe tissue injury or nerve damage triggers early neuroplastic changes in the brainstem that contribute to an endogenous feedback inhibition of pain. This serves as a beneficial, adaptive mechanism in times of stress and/or danger. With time, injury also recruits facilitatory mechanisms in the brain that ultimately sensitize pain transmission neurons in the spinal cord. Normally, such mechanisms aid in the prevention of further injury, thus promoting curative processes (Millan 1999, Millan

Conclusion

We found that SNI increased Fos and pCREB in the LC. Second, noradrenergic LC lesions inhibited the development of allodynia and hyperalgesia. And third, reversible inactivation of the LC reduced established neuropathic pain. We conclude that NE neurons in the LC participate in the development and/or maintenance of allodynia and hyperalgesia in the setting of peripheral nerve injury, and propose that the traditional view of the LC as a pain inhibitory structure be modified to account for its

Acknowledgments

The study was supported by NIH grants R01DA018732 and K02DA019656 to B.K.T. and a 2007 post-doctoral fellowship from the PhRMA foundation and NRSA FNS056889A to J.J.B. We would also like to thank Christopher L. Kreidt for his technical contributions to the lidocaine study and Heather A. Scuderi Porter (H.P.) for her contribution to the Fos analysis.

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Pain MechanismResearch PaperNoradrenergic neurons in the locus coeruleus contribute to neuropathic pain

Abstract

Section snippets

Subjects

Results

Discussion

Conclusion

Acknowledgments

Pain

Brain Res Bull

Physiol Behav

J Biol Chem

Brain Res

Pharmacol Biochem Behav

Pain

J Neurosci Methods

Prog Neurobiol

Pain

Suppl Clin Neurophysiol

Pain

J Neurosci Methods

Neuroscience

Brain Res Bull

Adv Drug Deliv Rev

Neuroscience

Cell

Pain

Brain Res

Pain

Neuron

Pain

J Neurosci Methods

Neurosci Lett

Pain

Prog Neurobiol

Prog Neurobiol

Neuroscience

Prog Neurobiol

Neurosci Lett

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Trends Neurosci

J Pain

Pain

Brain Res

Pain

Neurosci Lett

Pain Mechanism
Research Paper
Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain