Presynaptic Inhibition of Diverse Afferents to the Locus Ceruleus by  -Opiate Receptors: A Novel Mechanism for Regulating the Central Norepinephrine System

Abstract

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 -opiate receptors. Because the LC is also innervated by the endogenous -opiate receptor (-OR) ligand dynorphin and expresses -ORs, this study investigated -OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of -ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the -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 -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 -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 -ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism.

κ-Opioid Receptors in the Central Amygdala Regulate Ethanol Actions at Presynaptic GABAergic Sites

“…*P , 0.05; **P # 0.01. mediated by presynaptic mechanisms. Similar presynaptic actions of KOR activation have been recently demonstrated in the locus coeruleus (Kreibich et al, 2008) and bed nucleus of the stria terminalis (Li et al, 2012).…”

Social Stress Engages Opioid Regulation of Locus Coeruleus Norepinephrine Neurons and Induces a State of Cellular and Physical Opiate Dependence

“…Enkephalincontaining axon terminals also synapse with LC dendrites (Van Bockstaele et al, 1995) and act on m-opioid receptors (MORs) that are highly expressed by LC neurons to potently inhibit activity (Mansour et al, 1994;Williams and North, 1984). Notably, although LC neurons are also innervated by the k-opioid receptor agonist, dynorphin, k-opioid receptors are predominantly localized in axon terminals (Kreibich et al, 2008). Consistent with this presynaptic localization, k-opiate receptor agonists do not alter LC spontaneous activity (Kreibich et al, 2008).…”

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…[71][72][73][74] The LC is densely populated with adrenergic neurons 75,76 and has a substantial role in manifestation of behavioral signs of withdrawal. 77 The LC primarily receives neuronal input from the hippocampus, prefrontal cortex (PFC), and the amygdala.…”