The locus coeruleus: A key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse

Abstract

The interaction between the stress axis and endogenous opioid systems has gained substantial clinical attention as it is increasingly recognized that stress predisposes to opiate abuse. For example, stress has been implicated as a risk factor in vulnerability to the initiation and maintenance of opiate abuse and is thought to play an important role in relapse in subjects with a history of abuse. Numerous reports indicating that stress alters individual sensitivity to opiates suggest that prior stress can influence the pharmacodynamics of opiates that are used in clinical settings. Conversely, the effects of opiates on different components of the stress axis can impact on individual responsivity to stressors and potentially predispose individuals to stress-related psychiatric disorders. One site at which opiates and stress substrates may interact to have global effects on behavior is within the locus coeruleus (LC), the major brain norepinephrine (NE)-containing nucleus. This review summarizes our current knowledge regarding the anatomical and neurochemical afferent regulation of the LC. It then presents physiological studies demonstrating opposing interactions between opioids and stress-related neuropeptides in the LC and summarizes results showing that chronic morphine exposure sensitizes the LC-NE system to corticotropin releasing factor and stress. Finally, new evidence for novel presynaptic actions of kappa-opioids on LC afferents is provided that adds another dimension to our model of how this central NE system is co-regulated by opioids and stress-related peptides.

Figure 1

Our previous studies indicate that NE activity is regulated via distinct CRF and ENK afferents targeting postsynaptically distributed CRF and μ-opioid receptors (μ-OR). The circuitry that links DYN to the LC-NE system and the conditions that engage this circuitry are steadily emerging (see text). Our working model now includes presynaptic modulation of NE activity via dynorphin-κ-OR regulation of afferent inputs that is posited to differentially affect behavior. Left schematic: Schematic diagram of an LC neuron containing μ-OR (symbol: fleur de lis), CRF-R (symbol: ink spot) and glutamate receptors (Glu-R, symbol: circle) targeted by axon terminals containing CRF, ENK, Glu or GABA. Anatomical studies support the localization of κ-OR on terminals containing glutamate, CRF and dynorphin. Right schematic: Schematic depicting selected afferents to the LC that are known to differentially modulate LC activity. CRF afferents from the amygdala are engaged to increase LC neuronal activity following hypotensive stress. Upon termination of the stress, opioid modulation of LC neurons (most likely arising from medullary sources) results in inhibition for a period of time, an effect that is completely blocked by microinfusion of naloxone. Glutamatergic afferents from the nucleus paragigantocellularis (PGi) convey sciatic nerve stimulation that is completely abolished by excitatory amino acid antagonists. Both stimuli are temporally correlated with, and necessary for, cortical EEG activation via LC efferent projections to forebrain structures. Table summarizing percentages of co-transmitters in LC afferents. Percentages are shown with respect to total number of profiles for neurotransmitters in the vertical column (e.g., ENK/total CRF sampled = 12%). Abbreviations: nc: not counted; ne: not examined

Figure 2

A. Darkfield photomicrograph showing immunoperoxidase labeling of DYN in the core of the LC (straight black arrow) and peri-LC area (arrowheads). Cb: cerebellum; IV: 4^th ventricle; scp: superior cerebellar peduncle. B-F. Processes exhibiting DYN (red), CRF (green) or both DYN/CRF (yellow) overlap TH neurons (blue) in the LC. White arrows indicate DYN/CRF processes in close proximity to TH somatodendritic profiles. Panels D and E are taken through the core of the LC while panels B, C and F are in the peri-LC. Scale bar = 250 μm.

Figure 3

A. Immunoperoxidase labeled DYN axon terminal (DYN-t) forms an asymmetric-type (excitatory) synapse with a dendrite containing TH (TH-d). B. Immunoperoxidase labeling for DYN (that is particularly enriched in dense core vesicles, dcv) in an axon terminal (DYN-t) that forms a synapse (curved arrow) with an unlabeled dendrite (ud) that receives convergent input from an axon terminal containing gold-silver labeling for ENK. C. An axon terminal contains immunogold-silver labeling for CRF (arrowheads) and immunoperoxidase labeling for DYN. CRF-DYN-t contains several dense core vesicles (dcv) and forms a synapse (black arrow) with an unlabeled dendrite (ud). D. An axon terminal containing immunoperoxidase labeling for VGLUT also exhibits immunogold-silver labeling for κ-OR in the LC. Scale bars: 0.5 μm.