Opioid System Research Articles

Migraine Treatment: Towards New Pharmacological Targets.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.

The role of vitamin D in the processes of nociception a narrative review

The purpose of the narrative review is to present the current knowledge on the mechanisms of action of vitaminD in the processes of nociception. The role of vitamin D in calcium homeostasis and bone metabolism is wellknown and documented, and there is a strong correlation between hypovitaminosis D and the occurrence of bonepain in humans. However, the mechanisms by which vitamin D may influence nociception processes are poorlyunderstood. The review was based on selected publications from 1973October 2022, relating to the mechanismsand analgesic efficacy of vitamin D in animal and human studies. The potential interaction between the vitamin Dpathway and nociception processes, demonstrated in the above studies, is discussed. The analysis of the results ofexperimental and clinical studies indicates a significant correlation and participation of vitamin D in the processesof nociception through its influence on receptors, numerous ion channels, modulation of the expression of pro- andanti-inflammatory cytokines, neurotrophic factors, prostaglandin levels, oxidative processes, the opioid system andthe activity of immunocompetent cells. Indirectly, vitamin D also affects the risk and course of autoimmune diseases, cardiovascular diseases and cancer, which may be associated with chronic pain in humans.

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation.

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain.

Essential oil from leaves of Croton blanchetianus Baill does not present acute oral toxicity, has antigenotoxic action and reduces neurogenic and inflammatory nociception in mice

Ethnopharmacological relevanceCroton blanchetianus Baill., popularly known as “marmeleiro preto”, is an endemic plant from Brazil, being found mainly in the Northeast region. In traditional medicine, the use of medicines based on the leaves of this plant has been reported for the treatment of inflammatory processes, pain, urethral pain, gastrointestinal disorders, rheumatism and headache.Aim of the study: The present work describes the chemical characterization, as well as toxicological evaluation and antinociceptive activity of an essential oil of C. blanchetianus leaves (EOCb). Materials and methodsThe chemical constituents of the oil were identified by gas chromatography coupled to mass spectrometry (GC-MS). In vitro hemolytic activity was tested using mouse blood. Acute toxicity in mice was assessed by the oral or intraperitoneal administration of a single dose of 2000 mg/kg b.w. EOCb (1000 and 2000 mg/kg) was also evaluated for genotoxicity and antigenotoxicity in vivo using the micronucleus test. The antinociceptive activity of EOCb (25, 50 and 100 mg/kg) was evaluated through the abdominal writhing, formalin and tail flick tests. ResultsThe chemical characterization indicated as major components α-pinene (21.23%), β-phelandrene (13.92%), terpinolene (13.01%) and germacrene D (10.89%). EOCb did not cause hemolysis and was also neither toxic nor genotoxic, while protected the animals' bone marrow cells from damage caused by cyclophosphamide in oral treatment. However, all animals died after 15 min of intraperitoneal treatment. There was a reduction in the number of abdominal contortions (69.43–89.41%) as well as in licks in the first (38.77–84.47%) and second (59.75–90.74%) phases of the formalin test. In the latter case, the effects were reduced by naloxone and glibenclamide, indicating action via the opioid system and blockage of K+ channels. The latency time in the tail flick test also increased significantly. ConclusionIn conclusion, ingestion of EOCb proved to be safe when administered orally; however, it was lethal intraperitoneally. Additionally, EOCb protected mouse blood cell DNA against the action of cyclophosphamide and showed an antinociceptive effect via the opioid system and dependent on K+ channels.

Noradrenergic projections regulate the acquisition of classically conditioned eyelid responses in wild-type and are impaired in kreisler mice

During embryonic development, heterozygous mutant kreisler mice undergo ectopic expression of the Hoxa3 gene in the rostral hindbrain, affecting the opioid and noradrenergic systems. In this model, we have investigated behavioral and cognitive processes in their adulthood. We confirmed that pontine and locus coeruleus neuronal projections are impaired, by using startle and pain tests and by analyzing immunohistochemical localization of tyrosine hydroxylase. Our results showed that, even if kreisler mice are able to generate eyelid reflex responses, there are differences with wild-types in the first component of the response (R1), modulated by the noradrenergic system. The acquisition of conditioned motor responses is impaired in kreisler mice when using the trace but not the delay paradigm, suggesting a functional impairment in the hippocampus, subsequently confirmed by reduced quantification of alpha2a receptor mRNA expression in this area but not in the cerebellum. Moreover, we demonstrate the involvement of adrenergic projection in eyelid classical conditioning, as clonidine prevents the appearance of eyelid conditioned responses in wild-type mice. In addition, hippocampal motor learning ability was restored in kreisler mice by administration of adrenergic antagonist drugs, and a synergistic effect was observed following simultaneous administration of idazoxan and naloxone.

Involvement of the Opioid Peptide Family in Cancer Progression.

Peptides mediate cancer progression favoring the mitogenesis, migration, and invasion of tumor cells, promoting metastasis and anti-apoptotic mechanisms, and facilitating angiogenesis/lymphangiogenesis. Tumor cells overexpress peptide receptors, crucial targets for developing specific treatments against cancer cells using peptide receptor antagonists and promoting apoptosis in tumor cells. Opioids exert an antitumoral effect, whereas others promote tumor growth and metastasis. This review updates the findings regarding the involvement of opioid peptides (enkephalins, endorphins, and dynorphins) in cancer development. Anticancer therapeutic strategies targeting the opioid peptidergic system and the main research lines to be developed regarding the topic reviewed are suggested. There is much to investigate about opioid peptides and cancer: basic information is scarce, incomplete, or absent in many tumors. This knowledge is crucial since promising anticancer strategies could be developed alone or in combination therapies with chemotherapy/radiotherapy.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central µ-Opioid Receptor Availability in Episodic Migraine.

The current understanding of utilizing HD-tDCS as a targeted approach to improve headache attacks and modulate endogenous opioid systems in episodic migraine is relatively limited. This study aimed to determine whether high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) can improve clinical outcomes and endogenous µ-opioid receptor (µOR) availability for episodic migraineurs. In a randomized, double-blind, and sham-controlled trial, 25 patients completed 10-daily 20-min M1 HD-tDCS, repeated Positron Emission Tomography (PET) scans with a selective agonist for µOR. Twelve age- and sex-matched healthy controls participated in the baseline PET/MRI scan without neuromodulation. The primary endpoints were moderate-to-severe (M/S) headache days and responder rate (≥50% reduction on M/S headache days from baseline), and secondary endpoints included the presence of M/S headache intensity and the use of rescue medication over 1-month after treatment. In a one-month follow-up, at initial analysis, both the active and sham groups exhibited no significant differences in their primary outcomes (M/S headache days and responder rates). Similarly, secondary outcomes (M/S headache intensity and the usage of rescue medication) also revealed no significant differences between the two groups. However, subsequent analyses showed that active M1 HD-tDCS, compared to sham, resulted in a more beneficial response predominantly in higher-frequency individuals (>3 attacks/month), as demonstrated by the interaction between treatment indicator and baseline frequency of migraine attacks on the primary outcomes. These favorable outcomes were also confirmed for the secondary endpoints in higher-frequency patients. Active treatment also resulted in increased µOR concentration compared to sham in the limbic and descending pain modulatory pathway. Our exploratory mediation analysis suggests that the observed clinical efficacy of HD-tDCS in patients with higher-frequency conditions might be potentially mediated through an increase in µOR availability. The 10-daily M1 HD-tDCS can improve clinical outcomes in episodic migraineurs with a higher baseline frequency of migraine attacks (>3 attacks/month). This improvement may be, in part, facilitated by the increase in the endogenous µOR availability. www.ClinicalTrials.gov, identifier -NCT02964741.

Examination of the Accuracy of Existing Overdose Surveillance Systems

Health departments have used a variety of methods for overdose surveillance, and the Centers for Disease Control and Prevention (CDC) is implementing a standardized case definition to improve overdose surveillance nationally. The comparative accuracy of the CDC opioid overdose case definition vs existing state opioid overdose surveillance systems is unknown. To evaluate the accuracy of the CDC opioid overdose case definition and existing Rhode Island Department of Health (RIDOH) state opioid overdose surveillance system. This cross-sectional study of ED opioid overdose visits was conducted at 2 EDs in Providence, Rhode Island, at the state's largest health system from January to May 2021. Electronic health records (EHRs) were reviewed for opioid overdoses identified by the CDC case definition and opioid overdoses reported to the RIDOH state surveillance system. Included patients were those at study EDs whose visit met the CDC case definition, was reported to the state surveillance system, or both. True overdose cases were confirmed by EHR review using a standard case definition; 61 of 460 EHRs (13.3%) were double reviewed to estimate classification accuracy. Data were analyzed from January through May 2021. Accurate identification of an opioid overdose was assessed by estimating the positive predictive value of the CDC case definition and state surveillance system using results from the EHR review. Among 460 ED visits that met the CDC opioid overdose case definition, were reported to the RIDOH opioid overdose surveillance system, or both (mean [SD] age, 39.7 [13.5] years; 313 males [68.0%]; 61 Black [13.3%], 308 White [67.0%], and 91 other race [19.8%]; and 97 Hispanic or Latinx [21.1%] among each patient visit), 359 visits (78.0%) were true opioid overdoses. For these visits, the CDC case definition and RIDOH surveillance system agreed that 169 visits (36.7%) were opioid overdoses. Of 318 visits meeting the CDC opioid overdose case definition, 289 visits (90.8%; 95% CI, 87.2%-93.8%) were true opioid overdoses. Of 311 visits reported to the RIDOH surveillance system, 235 visits (75.6%; 95% CI, 70.4%-80.2%) were true opioid overdoses. This cross-sectional study found that the CDC opioid overdose case definition more often identified true opioid overdoses compared with the Rhode Island overdose surveillance system. This finding suggests that using the CDC case definition for opioid overdose surveillance may be associated with improved data efficiency and uniformity.

Recent modifications to the US methadone treatment system are a Band-Aid-not a solution-to the nation's broken opioid use disorder treatment system.

For 5 decades, US federal regulations have segregated methadone treatment for opioid use disorder from the rest of the health care system, confining its availability to specialty treatment programs that are highly regulated. These regulations have led to severe shortages in the availability of methadone and grave underutilization of this lifesaving medication despite a worsening overdose crisis. In this commentary, we discuss current barriers to methadone in the US opioid treatment system and how recent changes to federal regulations fall short of the reforms needed to significantly expand access to this treatment. Instead, we propose the urgent need to expand methadone to mainstream health care settings by allowing for office-based prescribing and pharmacy dispensing of methadone, the norm in many other developed countries.

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms.

We and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics. Here, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension. Stimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation. These findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats.

ID: 210523 Prospective Evaluation of Washout Periods Following Dorsal Root Ganglion Stimulation Trial

Dorsal root ganglion stimulation (DRG-S) places an electrical field over the DRG to modulate neural transmission. As mechanisms underlying DRG-S have become elucidated, it is clear there are actions distinct from that of conventional spinal cord stimulation (SCS). DRG-S is efficacious when delivered as a subthreshold and paresthesia-free tonic waveform, at frequencies as low as 4 Hz, and when stimulation is delivered intermittently, none of which are possible with SCS. The endogenous opioid system may play a role in pain relief with DRG-S, which should lead to prolonged washout times based on preclinical research. This study aimed to measure the time for pain to return to baseline pain levels after subjects’ 1-week DRG-S trials ended.

A genome-wide association study of antidepressant-induced mania

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications.

Insula Dynorphin and Kappa Opioid Receptor Systems Regulate Alcohol Drinking in a Sex-Specific Manner in Mice.

Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knock-out strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased the overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPNs) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPNs. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry.SIGNIFICANCE STATEMENT The insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we use converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

Low concentrations of tricyclic antidepressants stimulate TRPC4 channel activity by acting as an opioid receptor ligand.

Traditionally prescribed for mood disorders, tricyclic antidepressants (TCAs) have shown promising therapeutic effects on chronic neuralgia and irritable bowel syndrome. However, the mechanism by which these atypical effects manifest is unclear. Among the proposed mechanisms is the well-known pain-related inhibitory G-protein coupled receptor, namely the opioid receptor (OR). Here, we confirmed that TCA indeed stimulates OR and regulates the gating of TRPC4, a downstream signaling of the Gi-pathway. In an ELISA to quantify the amount of intracellular cAMP, a downstream product of OR/Gi-pathway, treatment with amitriptyline (AMI) showed a decrease in [cAMP]i similar to that of the μOR agonist. Next, we explored the binding site of TCA by modeling the previously revealed ligand-bound structure of μOR. A conserved aspartate residue of ORs was predicted to participate in salt bridge interaction with the amine group of TCAs, and in aspartate-to-arginine mutation, AMI did not decrease the FRET-based binding efficiency between the ORs and Gαi2. As an alternative way to monitor the downstream signaling of Gi-pathway, we evaluated the functional activity of TRPC4 channel, as it is well known to be activated by Gαi. TCAs increased the TRPC4 current through ORs, and TCA-evoked TRPC4 activation was abolished by an inhibitor of Gαi2 or its dominant-negative mutant. As expected, TCA-evoked activation of TRPC4 was not observed in the aspartate mutants of OR. Taken together, OR could be proclaimed as a promising target among numerous binding partners of TCA, and TCA-evoked TRPC4 activation may help to explain the nonopioid analgesic effect of TCA.NEW & NOTEWORTHY Endogenous opioid systems modulate pain perception, but concerns about opioid-related substance misuse limit their use. This study has raised TRPC4 channel as a candidate target for alternative analgesics, tricyclic antidepressants (TCAs). TCAs have been shown to bind to and activate opioid receptors (ORs), leading to downstream signaling pathways involving TRPC4. The functional selectivity and biased agonism of TCA towards TRPC4 in dependence on OR may provide a better understanding of its efficacy or side effects.

Acupuncture in Addiction Medicine: Its History, Evidence, and Possibilities.

Substance-use disorders (SUDs) and drug addiction are not only national, but also global health concerns that have worsened during and after the COVID-19 pandemic. Acupuncture augments the endogenous opioid system and, therefore, has a theoretical basis as a treatment for opioid use disorders (OUDs). The basic science of acupuncture, its clinical research in addiction medicine, and decades of success of the National Acupuncture Detoxification Association protocol offer positive findings supporting this protocol's utility for treating SUDs. Considering the mounting opioid/substance-use concerns and deficiencies in SUD treatment availability in the United States, acupuncture can be a safe, feasible treatment option and adjunct in addiction medicine. Furthermore, large governmental agencies are lending support to acupuncture for treating acute and chronic pain, which, in turn, could translate to prevention of SUDs and addictions. This article is a narrative review of the background, the basic science and clinical research, and future direction of acupuncture in addiction medicine.

A critical review of effects on ethanol intake of the dynorphin/kappa opioid receptor system in the extended amygdala: From inhibition to stimulation.

The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol-preferring and alcohol-avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge-like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder.

Comedications with Immune Checkpoint Inhibitors: Involvement of the Microbiota, Impact on Efficacy and Practical Implications.

Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring.

The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring's cardiovascular health is understudied. We hypothesized that offspring exposed to in utero morphine exposure (IUME) would show increased CVD risk factors and endogenous opioid system dysregulation. Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5-20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring. Litter size and pups' birth weight were not different in response to IUME. Female and male IUME offspring showed reduced body length at birth (P<0.05) and body weight from weeks 1 to 3 of life (P<0.05), followed by a catch-up growth effect. By week 16, female and male IUME rats showed reduced tibia length (P<0.05) and fat mass. IUME increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) induced by IUME were abolished by a chronic treatment with an alpha-adrenergic receptor blocker (prazosin; 1 mg/kg per day, IP). Although circulating levels of angiotensin peptides were similar between groups, IUME exacerbated maximal ex vivo Ang (angiotensin) II-induced vasoconstriction (P<0.05) and induced endothelial dysfunction in a sex-specific manner (P<0.05). Proenkephalin, an endogenous opioid peptide that lowers blood pressure and sympathetic-mediated vasoconstriction, showed reduced mRNA expression in the heart, aorta, and kidneys from morphine versus vehicle group (P<0.05). Among the effects of IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.

Kappa opioid activation changes protein profiles in different regions of the brain relevant to depression

Depression is a widespread disorder with a significant burden on individuals and society. There are various available treatments for patients with depression. However, not all patients respond adequately to their treatment. Recently, the opioid system has regained interest in depression studies. Research in animals and humans suggest that blocking the kappa opioid receptor (KOR) may potentially alleviate the symptoms of depression. The mechanism behind this effect is not fully understood. Stress and alterations in hypothalamic-pituitary-adrenal axis (HPA-axis) activity are thought to play a crucial role in depression. This study aimed to characterize stress hormones and stress-related protein expression following activation of KOR using a selective agonist. The longitudinal effect was investigated 24 h after KOR activation using the selective agonist U50,488 in Sprague Dawley rats. Stress-related hormones and protein expression patterns were explored using multiplex bead-based assays and western blotting. We found that KOR activation caused an increase in both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in serum. Regarding protein assays in different brain regions, phosphorylated glucocorticoid receptors also increased significantly in thalamus (THL), hypothalamus (HTH), and striatum (STR). C-Fos increased time-dependently in THL following KOR activation, extracellular signal-regulated kinases 1/2 (ERK1/2) increased significantly in STR and amygdala (AMG), while phosphorylated ERK1/2 decreased during the first 2 h and then increased again in AMG and prefrontal cortex (PFC). This study shows that KOR activation alters the HPA axis and ERK signaling which may cause to develop mood disorders.