Abstract
Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Behavior, Animal / physiology
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Brain-Derived Neurotrophic Factor / deficiency
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Brain-Derived Neurotrophic Factor / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Cell Count
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Colforsin / pharmacology
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Cyclic AMP / metabolism
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Gene Deletion
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Genes, Reporter
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Genotype
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In Situ Hybridization
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In Vitro Techniques
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Integrases / genetics
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Locus Coeruleus / cytology
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Locus Coeruleus / drug effects
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Locus Coeruleus / physiology
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Mice
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Mice, Mutant Strains
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Mice, Transgenic
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Narcotics / adverse effects
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Narcotics / pharmacology*
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Neuronal Plasticity / drug effects*
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Neuronal Plasticity / physiology
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / physiology*
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Norepinephrine / metabolism
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Receptors, Opioid, mu / agonists
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Recombination, Genetic
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Severity of Illness Index
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Substance Withdrawal Syndrome
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Transgenes
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Tyrosine 3-Monooxygenase / metabolism
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Viral Proteins / genetics
Substances
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Brain-Derived Neurotrophic Factor
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Narcotics
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Receptors, Opioid, mu
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Viral Proteins
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Colforsin
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Cyclic AMP
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Tyrosine 3-Monooxygenase
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Cre recombinase
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Integrases
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Norepinephrine