Localization of mu-opioid receptors to locus coeruleus-projecting neurons in the rostral medulla: Morphological substrates and synaptic organization

Abstract

The increase in discharge activity of locus coeruleus (LC) neurons following precipitated opiate withdrawal has been reported to be caused, in part, by excitatory amino acid release most likely originating from the nucleus paragigantocellularis lateralis (PGCl) in the rostral ventral medulla. Activation of glutamate-containing neurons in the PGCl may depend on changes in the occupancy of opioid receptive sites located on LC-projecting neurons which subsequently effect excitatory amino acid release in the LC during opiate withdrawal. To determine whether the mu-opioid receptor (MOR) is localized to plasmalemmal sites of LC-projecting neurons in the PGCl, we combined retrograde transport of the protein-gold tracer, wheat germ agglutinin-conjugated to inactive horseradish peroxidase (WGA-AU-apoHRP), from the LC with immunocytochemical detection of MOR in the same section of tissue throughout the rostral medulla. Light microscopic analysis indicated that neurons containing either the retrograde tracer or immunoperoxidase labeling for the MOR were numerous throughout the ventral medulla and that individual PGCl neurons contained both WGA-Au-apoHRP as well as MOR. By electron microscopy, WGA-Au-apoHRP was commonly identified in lysosomes within somata and large proximal dendrites. The somata contained either spherical or invaginated nuclei and were often surrounded by numerous myelinated axons. Gold deposits could also be identified in the cytoplasm of smaller dendritic processes in the PGCl, although these were not necessarily associated with lysosomes. The smaller dendritic processes were often the target of afferent input by axon terminals containing heterogeneous types of synaptic vesicles. Of 150 cellular profiles exhibiting WGA-Au-apoHRP retrograde labeling, 31% contained immunoperoxidase labeling for MOR. These results indicate that the MOR is distributed along plasmalemmal sites of morphologically diverse neurons in the PGCl which project to the LC.

Paternal exposure to morphine during adolescence potentiates morphine withdrawal in male offspring: Involvement of the lateral paragigantocellularis nucleus

“…In addition, morphine-dependent rats, which were administered with discrete microinjections of naloxone into the LPGi nucleus, exhibited prominent withdrawal-like behaviors (Sinchaisuk et al, 2002). Opiates can produce effects on LPGi neurons and their opioid sensitive connections through MORs (Van Bockstaele et al, 1999). MORs appear not to be evenly distributed throughout all LPGi neurons or their afferents (Aicher et al, 2001).…”

“…Although earlier studies suggest that C1 neurons produce inhibition by releasing catecholamines (Aston-Jones et al, 1992), a more recent study uncovered that these actually form excitatory synapses (Abbott et al, 2012) and thus may amplify LPGi mediated LC excitation during opiate withdrawal (Baraban et al, 1995). Beyond that, LPGi afferents in the LC co-express neuromodulators such as corticotropin releasing factor, leucine, methionine, and enkephalin that may enhance glutamatergic neurotransmission at the LPGi-LC synapse during opioid withdrawal (Van Bockstaele et al, 1999). Further assays are required to unveil the precise mechanisms governing such adaptive responses.…”

Locus coeruleus is a central chemoreceptive site in toads

“…Our results fit the first criterion since lesions of the LC resulted in an attenuation of the hypercarbiainduced hyperventilation, and local tissue acidosis increased the ventilation of the toads. Regarding the second criterion, it is well known that the LC of mammals projects to respiratory neurons, such as ventral medullary and solitary tract nuclei (52,53). There is neuroanatomical evidence suggesting that the LC of amphibians is homologous to the LC of mammals primarily on the basis of its position, noradrenergic content, and projections to brain stem structures (17,18,32).…”

The (Un)Conscious Mouse as a Model for Human Brain Functions: Key Principles of Anesthesia and Their Impact on Translational Neuroimaging

“…α2AR Agonists Induce a Sleep-Like State by Suppressing General Arousal Sympatholytics or α2AR agonists such as xylazine, medetomidine, or its potent dextro enantiomer dexmedetomidine exert their sedating and antinociceptive effects primarily by acting on presynaptic α2 A adrenergic receptors of noradrenergic cells that project from the locus coeruleus. This results in a hyperpolarization of the affected neurons and a reduction in the release of noradrenaline to their target sites (Correa-Sales et al, 1992;Jorm and Stamford, 1993;Chiu et al, 1995;Van Bockstaele et al, 1999). The locus coeruleus is a major arousal nucleus that projects to the basal forebrain (a subcortical arousal structure, which regulates cortical states by cholinergic efferents; Nelson et al, 2005;Hoover and Vertes, 2007;Pal et al, 2018), intralaminar nucleus of the thalamus, thalamic reticular nucleus, preoptic area of the hypothalamus, and diffusely into the cortex (Figure 1C; Asanuma, 1992;Nelson et al, 2003;Samuels and Szabadi, 2008a;Saper et al, 2010;Zhang et al, 2015;Fu et al, 2017;Brown et al, 2018a).…”