Agonist-Specific Regulation of G Protein-Coupled Receptors after Chronic Opioid Treatment.

Chronic treatment of animals with morphine results in a long lasting cellular tolerance in the locus coeruleus and alters the kinase dependent desensitization of opioid and nonopioid G protein-coupled receptors (GPCRs). This study examined the development of tolerance and altered regulation of kinase activity after chronic treatment of animals with clinically relevant opioids that differ in efficacy at the -opioid receptors (MOR). In slices from oxycodone treated animals, no tolerance to opioids was observed when measuring the MOR induced increase in potassium conductance, but the G protein receptor kinase 2/3 blocker, compound 101, no longer inhibited desensitization of somatostatin (SST) receptors.

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding.

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLM) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLM neurons orchestrate glucoprivation-induced food seeking behavior.

Separation of Acute Desensitization and Long-Term Tolerance of -Opioid Receptors Is Determined by the Degree of C-Terminal Phosphorylation.

Phosphorylation of sites on the C terminus of the -opioid receptor (MOR) results in the induction of acute desensitization that is thought to be a precursor for the development of long-term tolerance. Alanine mutations of all 11 phosphorylation sites on the C terminus of MORs almost completely abolished desensitization and one measure of tolerance in locus coeruleus neurons when these phosphorylation-deficient MORs were virally expressed in MOR knockout rats. In the present work, we identified specific residues that underlie acute desensitization, receptor internalization, and tolerance and examined four MOR variants with different alanine or glutamate mutations in the C terminus.

The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism.

The paraventricular nucleus of the thalamus (PVT) is increasingly being recognized as a critical node linking stress detection to the emergence of adaptive behavioral responses to stress. However, despite growing evidence implicating the PVT in stress processing, the neural mechanisms by which stress impacts PVT neurocircuitry and promotes stressed states remain unknown. Here we show that stress exposure drives a rapid and persistent reduction of inhibitory transmission onto projection neurons of the posterior PVT (pPVT).