The placenta as a target of opioid drugs

Opioid drugs are analgesics increasingly being prescribed to control pain associated with a wide range of causes. Usage of pregnant women has dramatically increased in the past decades. Neonates born to these women are at risk for neonatal abstinence syndrome (NAS, also referred termed neonatal opioid withdrawal syndrome, NOWS). Negative birth outcomes linked with maternal opioid use disorder include compromised fetal growth, premature birth, reduced birthweight, and congenital defects. Such infants require lengthier hospital stays necessitating rising health care costs, and they are at greater risk for neurobehavioral and other diseases. Thus, it is essential to understand the genesis of such disorders. As the primary communication organ between mother and conceptus, the placenta itself is susceptible to opioid effects but may be key to understanding how these drugs affect long-term offspring health and how poor health outcomes may be ameliorated in utero. In this review, we will consider the evidence that placental responses are regulated through an endogenous opioid system. However, maternal consumption of opioid drugs can also bind and act through opioid receptors express by trophoblast (TB) cells of the placenta. Thus, we will also discuss the current human and rodent studies that have examined the effects of opioids on the placenta. These drugs might affect placental hormones associated with maternal recognition of pregnancy, including placental lactogens and human chorionic gonadotropin (hCG) in rodents and humans, respectively. A further understanding of how such drugs affect the placenta may open up new avenues for early diagnosis and remediation approaches.

Investigation of THz Absorptive Signatures in Opioids

We investigate the possibility of sensing opioid drugs, such as fentanyl, by their THz electromagnetic signatures. The methods include both computer modeling and experiments. Molecular dynamics simulations predict that fentanyl should display THz resonances, with several of them occurring below 1.0 THz; the lowest one is at around 0.337 THz (337 GHz). Spectroscopy measurements were conducted on oxycodone, which was used as a surrogate for fentanyl. They display vibrational absorption resonances between ∼1.4 and 1.6 THz.

Morphometric characteristics of the mucous membrane and the cartilaginous component of the larynx are normal at different times during the experimental opioid effect and during withdrawal

Background. The problem of uncontrolled use of opioid drugs is extremely relevant based on the data of domestic and world statistics which are covered in the scientific literature. That is why the study of indicators of morphometric characteristics of the laryngeal mucosa under opioid exposure under experimental opioid exposure will be of interest to both morphologists and practical otorhinolaryngologists. Objective: To study the morphometric parameters of the laryngeal mucosa in normal at different times of the experimental opioid effect and its cancellation. Methods. The material of the study were sexually mature, outbred rats - males in the amount of 61 animals, weighing 80 - 135 g, aged 4.5 - 7.5 months. Histological specimens were prepared according to conventional methods. All morphometric studies were performed using primary (unedited) photographs taken on a Meiji MT4300 LE microscope, Canon EOS 550D x100 lens. All statistical calculations were performed using RStudio v. 1.2.5042. Results. Throughout the experiment, the change of morphometric parameters of the laryngeal mucosa with signs of wavy growth and decline was clearly observed at all times. More positive was the dynamics of morphometric parameters after the abolition of the opioid analgesic, which hypothetically suggests the process of recovery of the mucosa, even after prolonged administration of the opioid.

Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs

Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.

BODY IMMUNOLOGICAL REACTIVITY IN OPIOMANIA

Due to the general trend of changes in reactivity in many exogenous and endogenous diseases, more and more attention is currently being paid to changes in immunological reactivity in drug addiction. The expediency of assessing the state of immune mechanisms in opioid addiction is determined by the need to predict their course and outcome. The aim of the study was to study the immunological reactivity of the body in patients with opium addiction in a stage of abstinence. For this purpose, clinical and immunological studies were conducted in 80 patients who use opioid drugs. The duration of the disease ranged from 0.5-19 years. Of these, the disease duration is up to 3 years – 28 patients (group I), and over 3 years – 52 patients (group II). The number of subjects in the control group was n = 50. Authors carried out the assessment of the mental, narcological, somatic, and neurological status. In addition, they have studied the general clinical, biochemical and immunological parameters As a result of this study, it was found, that patients of group I had more pronounced T-lymphocytopenia. A persistent increase in the value of serum IgM was revealed both in the dynamics of abstinence and depending on the duration of the disease, which may indicate a strain on the humoral link of immunity in opium addiction. In addition, as the duration of chronic narcotization increases, there is a tendency to increase the relative number of B-lymphocytes. Thus, at the patients with opium addiction in a state of abstinence develop T-lymphocytopenia. Moreover, with an increase in the duration of the disease, an increase in the level of IgM by 2-2.6 times. The revealed changes in the immunological reactivity of the organism suggest the need to include immunocorrective therapy in the complex of therapeutic measures for opium addiction.

Prolonged morphine exposure during adolescence alters the responses of lateral paragigantocellularis neurons to naloxone in adult morphine dependent rats

Introduction Adolescence is a critical period in brain development, and it is characterized by persistent maturational alterations in the function of central nervous system. In this respect, many studies show the non-medical use of opioid drugs by adolescents. Although this issue has rather widely been addressed during the last decade, cellular mechanisms through which adolescent opioid exposure may induce long-lasting effects are not duly understood. The present study examined the effect of adolescent morphine exposure on neuronal responses of lateral paragigantocellularis nucleus to naloxone in adult morphine-dependent rats. Methods Adolescent male Wistar rats (31 days old) received increasing doses of morphine (from 2.5 to 25 mg/kg, twice daily, s.c.) for 10 days. Control subjects were injected saline with the same protocol. After a drug-free interval (20 days), animals were rendered dependent on morphine during 10 days (10 mg/kg, s.c., twice daily). Then, extracellular single-unit recording was performed to investigate neural response of LPGi to naloxone in adult morphine-dependent rats. Results Results indicated that adolescent morphine treatment increases the number of excitatory responses to naloxone, enhances the baseline activity and alters the pattern of firing in neurons with excitatory responses in adult morphine-dependent rats. Moreover, the intensity of excitatory responses is reduced following the early life drug intake. Conclusion It seems that prolonged opioid exposure during adolescence induces long-lasting neurobiological changes in LPGi responsiveness to future opioid withdrawal challenges.

Transcriptomes of Electrophysiologically Recorded Dbx1-derived Inspiratory Neurons of the preBötzinger Complex in Neonatal Mice

Breathing depends on interneurons in the preBötzinger complex (preBötC) derived from Dbx1-expressing precursors. Here we investigate whether rhythm- and pattern-generating functions reside in discrete classes of Dbx1 preBötC neurons. In a slice model of breathing with ~5 s cycle period, putatively rhythmogenic Type-1 Dbx1 preBötC neurons activate 100-300 ms prior to Type-2 neurons, putatively specialized for output pattern, and 300-500 ms prior to the inspiratory motor output. We sequenced Type-1 and Type-2 transcriptomes and identified differential expression of 123 genes including ionotropic receptors (Gria3 and Gabra1) that may explain their preinspiratory activation profiles and Ca2+ signaling (Cracr2a, Sgk1) involved in inspiratory and sigh bursts. Surprisingly, neuropeptide receptors that influence breathing (e.g., μ-opioid and bombesin-like peptide receptors) were only sparsely expressed, which suggests that cognate peptides and opioid drugs exert their profound effects on a small fraction of the preBötC core. These data in the public domain help explain the neural origins of breathing.