Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1bf/f/p), wh...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 104; no. 36; pp. 14519 - 14524
Main Authors Zhao, Zhong-Qiu, Gao, Yong-Jing, Sun, Yan-Gang, Zhao, Cheng-Shui, Gereau, Robert W. IV, Chen, Zhou-Feng
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.09.2007
National Acad Sciences
Subjects
Analgesia
Analgesics
Analgesics, Opioid - pharmacology
Animals
Biological Sciences
Dosage
Drug Tolerance
Gene Expression Regulation
Genetics
Genotypes
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
LIM-Homeodomain Proteins
Mice
Mice, Inbred C57BL
Mice, Transgenic
Morphine
Morphine - pharmacology
Neurons
Neurons - drug effects
Neurons - metabolism
Opioid analgesics
Opioid receptors
Pain
Proteins
Reward
Rodents
Serotonin - metabolism
Serotonin receptors
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1bf/f/p), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a κ opioid receptor agonist administered at the supraspinal level was abolished in Lmx1bf/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1bf/f/p mice exhibited significantly reduced analgesic effects of μ and δ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1bf/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system.
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Author contributions: Z.-Q.Z. and Y.-J.G. contributed equally to this work; Z.-F.C. directed the project; Z.-Q.Z. maintained the mouse colony and performed analgesia and MOR experiments; Z.-Q.Z. and Y.-J.G. performed morphine reward experiments; Y.-G.S. performed tolerance experiments; Y.-G.S and C.-S.Z. contributed to analgesia experiments; Z.-Q.Z., Y.-J.G., Y.-G.S., and Z.-F.C. wrote the paper; and R.W.G. edited the paper.
On leave from: Institute of Nautical Medicine, Nantong University, Nantong 226001, China.
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 20, 2007
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0705740104