RT Journal Article
SR Electronic
T1 Presynaptic Inhibition of Diverse Afferents to the Locus Ceruleus by κ-Opiate Receptors: A Novel Mechanism for Regulating the Central Norepinephrine System
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6516
OP 6525
DO 10.1523/JNEUROSCI.0390-08.2008
VO 28
IS 25
A1 Arati Kreibich
A1 Beverly A. S. Reyes
A1 Andre L. Curtis
A1 Laurel Ecke
A1 Charles Chavkin
A1 Elisabeth J. Van Bockstaele
A1 Rita J. Valentino
YR 2008
UL http://www.jneurosci.org/content/28/25/6516.abstract
AB The norepinephrine nucleus, locus ceruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAAs), corticotropin-releasing factor (CRF), and endogenous opioids acting at μ-opiate receptors. Because the LC is also innervated by the endogenous κ-opiate receptor (κ-OR) ligand dynorphin and expresses κ-ORs, this study investigated κ-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of κ-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the κ-OR agonist (trans)-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)-cyclo-hexyl] benzeneacetamide (U50488) into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the κ-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that κ-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC–norepinephrine system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate κ-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism.