Delayed estrogen actions diminish food consumption without changing food approach, motor activity, or hypothalamic activation elicited by corticostriatal µ-opioid signaling.

Mu-opioid receptor (μ-OR) signaling in forebrain sites including nucleus accumbens (Acb) and ventromedial prefrontal cortex (vmPFC) modulates reward-driven feeding and may play a role in the pathophysiology of disordered eating. In preclinical models, intra-Acb or intra-vmPFC μ-OR stimulation causes overeating and vigorous responding for food rewards. These effects have been studied mainly in male animals, despite demonstrated sex differences and estrogen modulation of central reward systems.

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered.

MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2- and IgE/FcεRI-mediated events.

MRGPRX2, a novel G -coupled human mast cell receptor, mediates non-immune adverse reactions without the involvement of antibody priming. Constitutively expressed by human skin mast cells, MRGPRX2 modulates cell degranulation producing pseudoallergies manifesting as itch, inflammation and pain. The term pseudoallergy is defined in relation to adverse drug reactions in general and immune/non-immune-mediated reactions in particular.

Opioid toxicity: histamine, hypersensitivity, and MRGPRX2.

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation.

Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome.

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind to mu (µ)-opioid receptors (MORs) encoded by the MOR gene widely expressed in the central and peripheral nervous systems including centers that modulate breathing. Respiratory centers are located throughout the brainstem.

Mechanisms of opioid-induced respiratory depression.

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g.

Delayed but not immediate effects of estrogen curtail gamma-aminobutyric acid-mediated feeding responses elicited from the nucleus accumbens shell.

The present study investigated immediate versus delayed effects of estrogen replacement in ovariectomized (OVX) rats on hyperphagia elicited by gamma-aminobutyric acid (GABA)-A-agonist (muscimol) infusions into the nucleus accumbens shell (AcbSh). First, because intra-AcbSh muscimol-induced feeding has never been explored in OVX rats, a dose-effect curve was generated and compared to sham-operated males, the current point of reference in the literature. Muscimol (5, 10, 25, and 50 ng) increased food intake in both sexes, and both sexes reached the same asymptotic level of intake.

Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies.

Identification of new disease-associated biomarkers; specific targeting of such markers by monoclonal antibodies (mAbs); and application of advances in recombinant technology, including the production of humanized and fully human antibodies, has enabled many improved treatment outcomes and successful new biological treatments of some diseases previously neglected or with poor prognoses. Of the 110 mAbs preparations currently approved by the FDA and/or EMA, 46 (including 13 antibody-drug conjugates) recognizing 29 different targets are indicated for the treatment of cancers, and 66, recognizing 48 different targets, are indicated for non-cancer disorders. Despite their specific targeting with the expected accompanying reduced collateral damage for normal healthy non-involved cells, mAbs, may cause types I (anaphylaxis, urticaria), II (e.

Eating driven by the gustatory insula: contrasting regulation by infralimbic vs. prelimbic cortices.

Subregions within insular cortex and medial prefrontal cortex (mPFC) have been implicated in eating disorders; however, the way these brain regions interact to produce dysfunctional eating is poorly understood. The present study explored how two mPFC subregions, the infralimbic (IL) and prelimbic (PRL) cortices, regulate sucrose hyperphagia elicited specifically by a neurochemical manipulation of the agranular/dysgranular region of gustatory insula (AI/DI). Using intra-AI/DI infusion of the mu-opioid receptor (µ-OR) agonist, DAMGO (1 µg), sucrose hyperphagia was generated in ad-libitum-maintained rats, while in the same rat, either the IL or prelimbic (PRL) subregion of mPFC was inactivated bilaterally with muscimol (30 ng).

Inhibition of platelet-activating factor (PAF)-induced platelet aggregation by fatty acids from human saliva.

Experiments were undertaken to identify the nature of a previously identified inhibitor of PAF-induced platelet aggregation (PA) in human saliva. Human saliva fractionated by preparative thin layer chromatography (TLC) yielded a fraction that co-migrated with fatty acids (FAs) and inhibited PAF-induced aggregation of platelets. Synthetic FAs tested for their capacities to inhibit 0.

Dissociable control of μ-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex.

This study explored potentially dissociable functions of mu-opioid receptor (µ-OR) signaling across different cortical territories in the control of anticipatory activity directed toward palatable food, consumption, and impulsive food-seeking behavior in male rats. The µ-OR agonist, DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin), was infused into infralimbic cortex (ILC), prelimbic cortex (PrL), medial and lateral ventral orbitofrontal cortices (VMO, VLO), and agranular/dysgranular insular (AI/DI) cortex of rats. Intra-ILC DAMGO markedly enhanced contact with a see-through screen behind which sucrose pellets were sequestered; in addition, rats having received intra-ILC and intra-VMO DAMGO exhibited locomotor hyperactivity while the screen was in place.

Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity.

Opioid-induced respiratory depression is potentially life-threatening and often regarded as the main hazard of opioid use. Main cause of death is cardiorespiratory arrest with hypoxia and hypercapnia. Respiratory depression is mediated by opioid μ receptors expressed on respiratory neurons in the CNS.

The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review.

Most cases of serotonin toxicity are provoked by therapeutic doses of a combination of two or more serotonergic drugs, defined as drugs affecting the serotonin neurotransmitter system. Common serotonergic drugs include many antidepressants, antipsychotics, and opioid analgesics, particularly fentanyl, tramadol, meperidine (pethidine), and methadone, but rarely morphine and other related phenanthrenes. Symptoms of serotonin toxicity are attributable to an effect on monoaminergic transmission caused by an increased synaptic concentration of serotonin.

Early life stress alters opioid receptor mRNA levels within the nucleus accumbens in a sex-dependent manner.

Early life stress (ELS) strongly impacts mental health, but little is known about its interaction with biological sex and postnatal development to influence risk and resilience to psychopathologies. A number of psychiatric disorders, such as social anhedonia and drug addiction, involve dysfunctional opioid signaling; moreover, there is evidence for differential central opioid function in males vs. females.

Modulation of appetitive motivation by prefrontal cortical mu-opioid receptors is dependent upon local dopamine D1 receptor signaling.

Opioid neurotransmission has been implicated in psychiatric disorders featuring impaired control over appetitive motivation, such as addiction and binge-eating disorder. We have previously shown that infusions of the μ-opioid receptor (μOR) agonist DAMGO into the ventromedial prefrontal cortex (vmPFC) induced hyperphagia, increased motor activity, and augmented sucrose-reinforced responding in the task progressive ratio (PR) task, which assesses the motivational value of an incentive. These effects were not reproduced by intra-PFC infusion of a variety of dopamine (DA) agonists and antagonists, suggesting that manipulation of intra-PFC DA systems alone is not sufficient to reproduce μOR-like effects.

Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.

Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity.