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The Journal of Neuroscience, May 30, 2007, 27(22):6045-6053; doi:10.1523/JNEUROSCI.1623-07.2007

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Behavioral/Systems/Cognitive
Mice Lacking Central Serotonergic Neurons Show Enhanced Inflammatory Pain and an Impaired Analgesic Response to Antidepressant Drugs

Zhong-Qiu Zhao,^1,2 * Santina Chiechio,^1,2 * Yan-Gang Sun,^1,2 Kai-Hua Zhang,^1,2 Cheng-Shui Zhao,^1,2 Michael Scott,⁶ Randy L. Johnson,⁷ Evan S. Deneris,⁶ Kenneth J. Renner,⁸ Robert W. Gereau, IV,^1,2,5 and Zhou-Feng Chen^1,2,3,4

¹Washington University Pain Center and Departments of ²Anesthesiology, ³Psychiatry, ⁴Molecular Biology and Pharmacology, and ⁵Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, ⁶Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, ⁷Department of Biochemistry and Molecular Biology, M. D. Anderson Cancer Center, University of Texas Health Science Center at Houston, Texas 77030, and ⁸Department of Biology, The University of South Dakota, Vermillion, South Dakota 57069

Correspondence should be addressed to Zhou-Feng Chen at the above address. Email: chenz{at}wustl.edu

A large body of literature has implicated serotonin [5-hydroxytryptamine (5-HT)] in descending modulation of nociceptive transmission. Here, we have studied the pain behavior of Lmx1b conditional knock-out mice (Lmx1b^f/f/p), which lack 5-HT neurons in the CNS. Lmx1b^f/f/p mutant mice showed normal thermal and visceral pain responses but were less sensitive to mechanical stimuli and exhibited enhanced inflammatory pain compared with their littermate control mice. Importantly, the analgesic effect of several antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, was either abolished or greatly attenuated in Lmx1b^f/f/p mice. Moreover, in the acute versus persistent pain settings, the analgesic actions of the SNRI duloxetine and the SSRI fluoxetine were differentially affected. Together, our results provide in vivo genetic evidence demonstrating that although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory. The findings that the analgesic effects of various antidepressant drugs are differentially dependent on the central 5-HT system should help us to understand the mechanism of the analgesic action of different classes of antidepressants in the management of persistent pain.

Key words: Lmx1b; serotonin; inflammatory pain; analgesic effect; antidepressant drugs; neurotransmitter

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Received Jan. 4, 2007; revised May 2, 2007; accepted May 4, 2007.

Correspondence should be addressed to Zhou-Feng Chen at the above address. Email: chenz{at}wustl.edu

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