Thermochemical Study of the Interaction of Cytosine and Uracil with Peptides in a Buffered Saline: Complex Formation with beta-Endorphin 30-31 (Human), L-Glutathion (Reduced) and α-L-Alanyl-L-Tyrosine.

The complex formation of uracil and cytosine with glycyl-L-glutamic acid (ß-endorphin 30-31), γ-L-glutamyl-L-cysteinyl-glycine (glutathione reduced), α-L-alanyl-L-tyrosine, and α-L-alanyl-α-L-alanine in a buffered saline has been studied using dissolution calorimetry. The values of the reaction constant, the change in Gibbs energy, enthalpy, and entropy were obtained. It is shown that the ratio of the enthalpy and entropy factors depends on the charge of the peptide ion, and the number of H-bond acceptors in the peptide structure. The contributions of interaction between charged groups and polar fragments, hydrogen bonding, and stacking interaction are discussed, taking into account the effect of solvent reorganization around the reactant molecules.

αN-Acetyl ß-Endorphin Is an Endogenous Ligand of σ1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for σ2Rs in σ1R Oligomers.

The opioid peptide ß-endorphin coexists in the pituitary and brain in its αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (σ1R) displayed positive effects. Thus, αN-acetyl ß-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, αN-acetyl ß-Endorphin reduced the analgesia of morphine, ß-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by ß-Endorphin and absent in σ1R-/- mice. We observed that σ1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, ß-Endorphin promoted the exchange of σ2Rs by G proteins at σ1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the αN-acetyl derivative, as σ1R oligomerization decreased and σ2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological ß-Endorphin-specific epsilon receptor is a σ1R-regulated MOR and that ß-Endorphin and αN-acetyl ß-Endorphin are endogenous ligands of σ1R.

Between Pleasure and Pain: A Pilot Study on the Biological Mechanisms Associated With BDSM Interactions in Dominants and Submissives.

BACKGROUND: BDSM is an abbreviation used to reference the concepts of bondage and discipline, dominance and submission, sadism, and masochism, enacted by power exchanges between consensual partners. AIM: To shed light upon the rewarding biological mechanisms associated with BDSM interactions. METHODS: A group of 35 BDSM couples (dominant and submissive counterparts) were recruited and tested during a BDSM interaction, with an additional control group of 27 non-BDSM interested people tested in a normal social interaction. OUTCOMES: We compared the evolution of the stress and reward hormone levels of cortisol, beta-endorphins, and endocannabinoids (2AG and anandamide) in a group of BDSM practitioners before and after an active BDSM interaction with the levels in control individuals. RESULTS: We showed that submissives showed increases in cortisol and endocannabinoid levels due to the BDSM interaction, with dominants only showing increased endocannabinoid levels when the BDSM interaction was associated with power play. CLINICAL IMPLICATIONS: This study effectively provides a link between behavior that many think of as aberrant on one hand, and biological pleasure experience on the other, in the hope that it may relieve some of the stigma these practitioners still endure. STRENGTHS & LIMITATIONS: It is one of the first and largest studies of its kind, but is still limited in sample size and only represents a specific population of Flemish BDSM practitioners. CONCLUSION: Even though this is one of the first studies of its kind, we can conclude that there is a clear indication for increased pleasure in submissives when looking at biological effects of a BDSM interaction, which was related to the increases in experienced stress. Wuyts E, De Neef N, Coppens V, et al. Between Pleasure and Pain: A Pilot Study on the Biological Mechanisms Associated With BDSM Interactions in Dominants and Submissives. J Sex Med 2020;17:784-792.

Spermatogenesis and regulatory factors in the wall lizard Podarcis sicula.

Spermatogenesis is an extraordinarily complex process, regulated by several factors, which leads to the differentiation of spermatogonia into spermatozoa. Among vertebrates, several reports have been focused on the lizard Podarcis sicula, a seasonal breeder and a good model for the study of reproductive processes. The goal of this review is to resume all the available data about systemic and above all local control factors involved in the control of P. sicula testicular activity. During the seasonal reproductive cycle, the variation of the expression levels of these factors determines significant variations that induce the activation or blocking of spermatogenesis. The data supplied in this review, in addition to analyze the current literature regarding the main actors of Podarcis sicula spermatogenesis, will hopefully provide a basic model that can be used for further studies on the intratesticular interaction between molecular factors that control spermatogenesis.

Effects of Tai Chi on beta endorphin and inflammatory markers in older adults with chronic pain: an exploratory study.

The purpose of this exploratory study was to examine the effects of Tai Chi on blood levels of beta endorphin (ß-endorphin) and inflammatory markers in older adults with chronic pain. Forty community-dwelling older adults with chronic pain were randomized to Tai Chi or light physical exercise, and each offered twice weekly for 12 weeks. Following the 12-week intervention, neither Tai Chi nor light physical exercise changed levels of ß-endorphin and inflammatory markers. However, in older adults who completed 70% or more classes, Tai Chi significantly lowered levels of ß-endorphin (p < 0.05), whereas light physical exercise did not change levels of ß-endorphin. The results suggest that Tai Chi may reduce levels of ß-endorphin in older adults with chronic pain. Future studies are needed to better understand the role of the opioid analgesic system and immune system in regulating pain with aging and the long-term effects of Tai Chi on pain-related biomarkers.

Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and ß-Endorphin Concentrations in the Periaqueductal Gray Area in Rats.

Ghrelin is an endogenous ligand for orphan growth hormone secretagogue receptors. Ghrelin receptors have been found in central nervous system (CNS) areas responsible for pain modulation and transmission. This study investigated the effects of intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin on pain behavioral responses and levels of ß-endorphin (ß-EP) and met-enkephalin (MENK) in the periaqueductal gray area (PAG) during the formalin test in rats. Thirty-five male rats were studied in five groups. Ghrelin was injected into the left lateral ventricle (ICV, 5 µL) or into the ARC (1 µL). After 15 min, formalin (2.5%) was subcutaneously injected into the left hind paw. Behavioral nociceptive scores were recorded for 60 min. MENK and ß-EP were collected by microdialysis in the PAG and determined by high-performance liquid chromatography (HPLC). ICV and ARC injection of ghrelin significantly reduced pain in all phases of the formalin test (p < 0.001). Dialysate concentrations of MENK and ß-EP in the PAG increased in all the phases (p < 0.01). In conclusion, the present study shows that the ARC nucleus and the endogenous opioid system are involved in ghrelin-induced pain modulation.

Lithium reverses mechanical allodynia through a mu opioid-dependent mechanism.

Background Lithium is widely used to treat bipolar disorders and displays mood stabilizing properties. In addition, lithium relieves painful cluster headaches and has a strong analgesic effect in neuropathic pain rat models. Objectives To investigate the analgesic effect of lithium on the cuff model of neuropathic pain. Methods We used behavioral and pharmacological approaches to study the analgesic effect of a single injection of lithium in wild-type and mu opioid receptor (MOR) null cuffed neuropathic mice. Mass spectrometry and enzyme-linked immunosorbent assay allowed to measure the levels of endogenous MOR agonist beta-endorphin as well as monoamines in brain and plasma samples 4 h after lithium administration. Results A single injection of lithium chloride (100 mg/kg, ip) alleviated mechanical allodynia for 24 h, and this effect was absent in MOR null neuropathic mice. Biochemical analyses highlight a significant increase in beta-endorphin levels by 30% in the brain of lithium-treated mice compared to controls. No variation of beta-endorphin was detected in the blood. Conclusions Together, our results provide evidence that lithium induces a long-lasting analgesia in neuropathic mice presumably through elevated brain levels of beta-endorphin and the activation of MORs.

A Novel Paradigm for Sacubitril/Valsartan: Beta-Endorphin Elevation as a Contributor to Exercise Tolerance Improvement in Rats With Preexisting Heart Failure Induced by Pressure Overload.

BACKGROUND: Simultaneous angiotensin receptor (AT1) blockade and neprilysin inhibition with the use of sacubitril/valsartan has been recently approved to treat patients with heart failure (HF). Therapeutic benefits of this therapy have been attributed to natriuretic peptide elevation and AT1 receptor blockade. However, that pharmacologic picture may not be complete. The aims of this study were to investigate the pharmacology of sacubitril/valsartan compared with sacubitril and valsartan alone and to examine their impact on peptides up-regulated by neprilysin inhibition, such as beta-endorphin. METHODS AND RESULTS: An HF model was induced by pressure overload via constriction of the suprarenal abdominal aorta in rats. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or placebo was administered by daily oral gavage (starting 4 weeks after pressure overload onset and continued for 4 additional weeks; n = 8 in each group). Exercise tolerance testing was conducted using a rodent treadmill and hemodynamic assessments were conducted under anesthesia with the use of Millar left ventricular (LV) conductance technology. Pressure overload led to exercise intolerance by 4 weeks and to hypertension and LV dysfunction and remodeling by 8 weeks. Both sacubitril/valsartan and sacubitril elevated beta-endorphin levels, by 40% and 54%, respectively, and improved exercise tolerance, by 93% and 112%, whereas valsartan did not. Indices of LV dysfunction persisted with the use of sacubitril/valsartan and valsartan therapies and even deteriorated in sacubitril group. CONCLUSIONS: When added to valsartan, sacubitril increases beta-endorphin concentrations and improves exercise tolerance. These data suggest beta-endorphin elevation as a potential mechanism of action leading to improvement in exercise tolerance that is seen with sacubitril/valsartan. This therapeutic benefit is potentially independent from LV function.

Beta endorphin in serum and follicular fluid of PCOS- and non-PCOS women.

PURPOSE: To compare the concentrations of beta endorphin in serum and follicular fluid (FF) of PCOS- and non-PCOS women. Secondarily, to investigate associations between beta endorphin and other parameters. METHODS: Fifty-nine women undergoing in vitro fertilization (IVF) were included in the study. Sixteen were stratified to the PCOS group using the Rotterdam criteria. The remaining 43 women served as controls. Follicular fluid was collected during oocyte retrieval and peripheral blood sampling was performed on the same day. Beta endorphin concentrations in serum and follicular fluid, serum levels of insulin, glucose, LH, estradiol and progesterone were measured. Additionally, testosterone was measured before starting the stimulation protocol. RESULTS: There was no difference in beta endorphin levels between PCOS- and non-PCOS women. The concentration of the peptide was higher in serum than in FF, likely due to collection of FF after ovulation induction and corresponding to the early luteal phase. We found a significant correlation between the number of mature Metaphase II (MII) oocytes retrieved and beta endorphin concentration in FF. In women with biochemical hyperandrogenemia, beta endorphin levels in FF correlated with testosterone levels. CONCLUSION: Beta Endorphin concentrations in serum and FF do not differ between PCOS- and non PCOS-women undergoing IVF. However, together with sex hormones, beta endorphin might play a key role in oocyte maturation.

Non-pharmacological interventions during childbirth for pain relief, anxiety, and neuroendocrine stress parameters: A randomized controlled trial.

AIM: This study aimed to investigate the effect of warm shower hydrotherapy and perineal exercises with a ball on pain, anxiety, and neuroendocrine stress parameters during childbirth. METHODS: This randomized controlled trial was conducted with 128 women during childbirth, admitted for hospital birth in São Paulo, Brazil, from June 2013 to February 2014. The participants were randomly assigned into one of the following intervention groups: received warm shower hydrotherapy (GA); performed perineal exercises with a ball (GB); and combined intervention group, which received warm shower hydrotherapy and perineal exercises with a ball (GC) (n = 39). Pre-and post-intervention parameters were evaluated using visual analogue scales for pain and anxiety, and salivary samples were collected for the stress hormones analysis. RESULTS: Pain, anxiety, and epinephrine release decreased in the group performing perineal exercises with a ball (GB). ß-endorphin levels increased in this group (GB) after the intervention and showed significant difference in capacity to cause this effect (P = .007). However, no significant differences were observed in cortisol, epinephrine, and norepinephrine levels. CONCLUSIONS: Warm showers and perineal exercises could be considered as adjunct therapy for women suffering from pain, anxiety, and stress during childbirth. Clinical Trial Registry RBR-84xprt.

Immediate Effects of Core Stabilization Exercise on ß-Endorphin and Cortisol Levels Among Patients With Chronic Nonspecific Low Back Pain: A Randomized Crossover Design.

OBJECTIVE: The main objective of the study was to measure the levels of plasma ß-endorphin (PB) and plasma cortisol (PC) under lumbar core stabilization exercise (LCSE), placebo and control conditions in patients with chronic nonspecific low back pain. METHODS: Twenty-four participants with chronic nonspecific low back pain participated in a randomized, placebo-controlled, crossover design study. There were 3 experimental exercise conditions: control condition (positioning in crook lying and rest), placebo condition (passive cycling in crook lying using automatic cycler), and LCSE on a Pilates device tested with a 48-hour interval between sessions by concealed randomization. A blood sample was collected before and after the exercise conditions. Plasma ß-endorphin and PC were measured through enzyme-linked immunosorbent assay and electrochemiluminescence in a Cobas E411 auto analyzer. RESULTS: A significant difference in PB level was identified before and after the LCSE condition (P < .05), whereas no significant differences were noted in control and placebo exercise conditions. Also, the trend of elevation of PB under the LCSE was significantly different compared with the placebo and control conditions (P < .01). In contrast, the PC level remained unchanged in all 3 conditions. CONCLUSION: The findings of this study indicate that LCSE could possibly influence PB but not PC level among patients with chronic nonspecific low back pain. The mechanism of action of the pain-relieving effect of LCSE might be related to an endogenous opioid mechanism as part of its effects and might not be involved with a stress-induced analgesia mechanism.

[The application of combining low dose naloxone with ropivacaine in supraclavicular brachial plexus block].

Objective: To observe the effect of low dose naloxone combinewith ropivacaine for supraclavicular brachial plexus block. Methods: Seventy patients undergoing elective upper limb surgery were randomly divided into two groups, ropivacaine group (Group R, n=35) and naloxone group (Group N, n=35). An ultrasound guided technique was used in both two groups.The onset and duration time of sensory and motor blockade, visual analog score(VAS)of 3, 6, 12, 18, 24 h postoperatively, time of first request fordezocine, total amount of dezocine needed, incidence of nausea and vomiting postoperatively(PONV) and patients' satisfaction score for analgesia in 24 h after surgery were measured.At the same time, blood samples were taken before anesthesia, 6 h, 24 h after operation for inspecting the concentration of ß-endorphin(ß-EP)in plasma. Results: The duration of sensory and motor blockade, time of first request for dezocine in Group N were 736.0(713.5, 836.5), 514.5(491.3, 572.8), 708.5(683.2, 877.0)min, which were all prolonged compared to Group R(522.0(469.5, 606.5), 401.0(370.0, 458.5), 570.0(435.0, 618.5)min)(Z=-6.844, -6.758, -6.700, all P<0.01). The 6, 12, 18 h postoperatively VAS of Group N were 0, 5.0(3.0, 5.8), 5.0(5.0, 6.0)point. Among which the 6, 12 h postoperatively VAS of Group N were lower than that of Group R(1.0(1.0, 3.5), 6.0(6.0, 7.0)point)(Z=-6.596, -4.864, all P<0.01), while the 18 h postoperatively VAS was higher than that of Group R (5.0(4.0, 5.0)point)(Z=-2.603, P<0.01). Total amount of dezocine needed in Group N in 24 h after surgery was 7.5(5.0, 10.0)mg, which was lower than that of Group R(10.0(10.0, 15.0)mg)(Z=-3.449, P<0.01). The incidence of PONV after surgery in Group N was 21.9%, which was lower than that of Group R(45.5%)(χ(2)=4.034, P<0.05). Ptients' satisfaction score for analgesia in 24 h after surgery in Group N was 8.0(7.0, 8.0)point, which was higher than that of Group R(7.0(6.0, 7.0)point)(Z=-3.509, P<0.01). At 6 h postoperatively , the concentration of plasma ß-EP in Group N was(113.34±12.36)µg/L, lower than that of Group R((147.14±11.65)µg/L)(t=-7.694, P<0.01). Conclusion: Low dose naloxone combine with ropivacaine for supraclavicular brachial plexus block, prolong the duration of sensory and motor blockade without affecting the onset time.

Affiliation, reward, and immune biomarkers coalesce to support social synchrony during periods of bond formation in humans.

Social bonds are critical for survival and adaptation and periods of bond formation involve reorganization of neurobiological systems as mediated by social behavior. Theoretical accounts and animal studies suggest similarity between parent-infant and pair bonding, a hypothesis not yet directly tested in humans. In this study, we recruited three groups of human adults (N=189); parents who had their firstborn child in the last 4-6months, new lovers who began a romantic relationship within the past 4months, and non-attached singles. We measured plasma oxytocin (OT), beta endorphin (ß-End), and interlukin-6 (IL-6), biomarkers of the affiliation, reward, and stress-response systems, and micro-coded gaze and affect synchrony between parents and infants and among new lovers during social interaction. OT significantly increased during periods of parental and romantic bonding and was highest in new lovers. In contrast, IL-6 and ß-End were highest in new parents and lowest in singles. Biomarkers became more tightly coupled during periods of bond formation and inter-correlation among hormones was highest during romantic bonding. Structural equation modeling indicated that the effects of IL-6 and ß-End on behavioral synchrony were mediated by their impact on OT, highlighting the integrative role of the oxytocinergic system in supporting human social affiliation. Findings suggest that periods of bond formation are accompanied by increased activity, as well as tighter cross-talk among systems underpinning affiliation, reward, and stress management and that research on the multidimensional process of bonding may shed further light on the effects of attachment on health.

Inhibition of Mammary Cancer Progression in Fetal Alcohol Exposed Rats by ß-Endorphin Neurons.

BACKGROUND: Fetal alcohol exposure (FAE) increases the susceptibility to carcinogen-induced mammary cancer progression in rodent models. FAE also decreases ß-endorphin (ß-EP) level and causes hyperstress response, which leads to inhibition of immune function against cancer. Previous studies have shown that injection of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) into the third ventricle increases the number of ß-EP neurons in the hypothalamus. In this study, we assessed the therapeutic potential of stress regulation using methods to increase hypothalamic levels of ß-EP, a neuropeptide that inhibits stress axis activity, in treatment of carcinogen-induced mammary cancer in fetal alcohol exposed rats. METHODS: Fetal alcohol exposed and control Sprague Dawley rats were given a dose of N-Nitroso-N-methylurea (MNU) at postnatal day 50 to induce mammary cancer growth. Upon detection of mammary tumors, the animals were either transplanted with ß-EP neurons or injected with dbcAMP-delivering nanospheres into the hypothalamus to increase ß-EP peptide production. Spleen cytokines were detected using reverse transcription polymerase chain reaction assays. Metastasis study was done by injecting mammary cancer cells MADB106 into jugular vein of ß-EP-activated or control fetal alcohol exposed animals. RESULTS: Both transplantation of ß-EP neurons and injection of dbcAMP-delivering nanospheres inhibited MNU-induced mammary cancer growth in control rats, and reversed the effect of FAE on the susceptibility to mammary cancer. Similar to the previously reported immune-enhancing and stress-suppressive effects of ß-EP transplantation, injection of dbcAMP-delivering nanospheres increased the levels of interferon-γ and granzyme B and decreased the levels of epinephrine and norepinephrine in fetal alcohol exposed rats. Mammary cancer cell metastasis study also showed that FAE increased incidence of lung tumor retention, while ß-EP transplantation inhibited lung tumor growth in both normal and fetal alcohol exposed rats. CONCLUSIONS: Our results suggest that increase of ß-EP production in the hypothalamus may serve as a potential therapeutic strategy for treating the cancer growth in patients with chronic stress and compromised immune function, such as the patients with FAE.

ß-Endorphin neuronal transplantation into the hypothalamus alters anxiety-like behaviors in prenatal alcohol-exposed rats and alcohol-non-preferring and alcohol-preferring rats.

BACKGROUND: Alcohol exposure has adverse effects on stress physiology and behavioral reactivity. This is suggested to be due, in part, to the effect of alcohol on ß-endorphin (ß-EP)-producing neurons in the hypothalamus. In response to stress, ß-EP normally provides negative feedback to the hypothalamic-pituitary-adrenal axis and interacts with other neurotransmitter systems in the amygdala to regulate behavior. We examined whether ß-EP neuronal function in the hypothalamus reduces the corticosterone response to acute stress, attenuates anxiety-like behaviors, and modulates alcohol drinking in rats. METHODS: To determine whether ß-EP neuronal transplants modulate the stress response, anxiety behavior, and alcohol drinking, we implanted differentiated ß-EP neurons into the paraventricular nucleus (PVN) of the hypothalamus of normal, prenatal alcohol-exposed, and alcohol-preferring (P) and alcohol-non-preferring (NP) rats. We then assessed corticosterone levels in response to acute restraint stress and other markers of stress response in the brain and anxiety-like behaviors in the elevated plus maze and open-field assays. RESULTS: We showed that ß-EP neuronal transplants into the PVN reduced the peripheral corticosterone response to acute stress and attenuated anxiety-like behaviors. Similar transplants completely reduced the hypercorticosterone response and elevated anxiety behaviors in prenatal alcohol-exposed adult rats. Moreover, we showed that ß-EP reduced anxiety behavior in P rats with minimal effects on alcohol drinking during and following restraint stress. CONCLUSIONS: These data further establish a role of ß-EP neurons in the hypothalamus for regulating physiological stress response and anxiety behavior and resemble a potential novel therapy for treating stress-related psychiatric disorders in prenatal alcohol-exposed children and those genetically predisposed to increased alcohol consumption.

Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.

OBJECTIVE: Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF). DESIGN: Cross-sectional, comparative, observational study. SUBJECTS: Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included. METHODS: Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit. RESULTS: We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs. rs = 0.574, P = 0.032). CONCLUSIONS: Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

Interactions Between Endocannabinoid and Endogenous Opioid Systems Prospectively Influence Postoperative Opioid Use in Pregnant Patients Undergoing Cesarean Delivery.

Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin (BE) concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol and plasma anandamide) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for BE and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, body mass index at time of delivery, and race revealed significant multiplicative interactions between EC and BE concentrations on number of opioid tablets used (based on pill count), days of opioid use, and total milligram morphine equivalents used in the 2-week follow-up period. Elevated preoperative plasma and CSF 2-arachidonoylglycerol predicted reduced outpatient opioid analgesic use, particularly for patients low in CSF BE. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (P < .02) characterized by higher preoperative BE concentrations being associated with lower subsequent pain only for individuals with low preoperative plasma anandamide concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide the development of precision pain management approaches. PERSPECTIVE: In the postoperative setting of patients undergoing cesarean delivery, elevated ECs were linked to reduced outpatient opioid analgesic use in individuals who had low endogenous opioid concentrations in CSF. Further exploration of interactions between these 2 inhibitory systems as they impact responses to pain management interventions appears warranted.

Analysis of Salivary Neuropeptides in Anxiety and Depression Using the Luminex MAGPIX® System.

BACKGROUND: Anxiety and depressive disorders are highly prevalent mental health conditions, affecting millions worldwide. Advancements in neurobiology have identified the effects of various neuropeptides in modulating mood and stress responses. Some of the well-researched neuropeptides in plasma are oxytocin (OXT), alpha-melanocyte-stimulating hormone (alpha-MSH), beta-endorphin, neurotensin, and substance P. In this study, we used methods of liquid biopsy to acquire saliva samples to analyze the concentrations of neuropeptides associated with depression. METHODS: The study was conducted in Bratislava, Slovakia, from January to June 2022. Participants were 20 subjects treated for depression and anxiety without medication; the control group consisted of 20 healthy individuals with no personal history of depression or anxiety. Salivary samples were collected using buccal swabs to measure the concentrations of the examined neuropeptides. Laboratory analysis was based on detecting fluorescent signals performed on the Luminex MAGPIX® System (Luminex Corporation, Austin, Texas). Means and standard deviations were calculated for individual neuropeptide levels. To determine if there are statistically significant differences in neuropeptide levels between individuals with and without depression, independent t-tests and a one-way ANOVA were conducted. RESULTS: Our findings indicate a significant decrease in all studied neuropeptides in subjects compared to healthy controls. Reductions in mean levels were observed for OXT (7.3), alpha-MSH (3.9), beta-endorphin (2.9), neurotensin (15.1), and a 6.9-fold decrease for substance P. Alpha-MSH and beta-endorphin showed higher variability in measured levels within both groups. CONCLUSION: The results of this study indicate that the levels of the studied salivary neuropeptides, OXT, alpha-MSH, beta-endorphin, neurotensin, and substance P, are statistically significantly reduced in individuals with depression compared to healthy controls.

Longitudinal associations between beta-endorphin, nonsuicidal self-injury and comorbid psychopathology.

Homeostasis models posit that nonsuicidal self-injury (NSSI) serves, in part, to upregulate the endogenous opioid system in order to compensate for an opioid deficiency. A few studies have demonstrated lower basal levels of beta-endorphin (BE), an endogenous opioid, in individuals with NSSI. However, longitudinal studies are missing. Hence, the present study aimed to investigate the longitudinal associations between NSSI, comorbid psychopathology (i.e., borderline personality disorder and depressive symptoms), pain sensitivity and basal BE levels in adolescents with NSSI. N = 53 adolescents with NSSI disorder undergoing specialized treatment participated in baseline and one-year follow-up assessments. BE was measured in plasma; pain sensitivity was assessed with a heat pain stimulation paradigm. Associations between BE and change in NSSI, borderline personality disorder and depressive symptoms as well as pain sensitivity were examined using negative binomial and linear regression analyses. We found that an increase in basal BE was significantly associated with a decrease in depressive symptoms. No associations between BE and NSSI, borderline personality disorder symptoms or pain sensitivity were observed. Our findings may confirm a role of plasma BE in the etiology of depressive symptoms but challenge current models of endogenous opioid homeostasis in NSSI.

Hemostatic mechanism of Jianpi Yiqi Shexue decoction in treatment of immune thrombocytopenia.

OBJECTIVE: To explore the early hemostatic mechanism of Jianpi Yiqi Shexue decoction (, JYSD) in treating immune thrombocytopathy (ITP), based on the functional homeostasis of brain-intestine axis and blood neurotransmitter METHODS: Non-drug treatment cases: Healthy volunteers were selected as normal control group and compared with patients with dysfunctional uterine bleeding, gastrointestinal tumors with bleeding and ITP, to detect the changes of blood 5-hydroxytryptamine (5-HT), ß-endorphin (ß-EP), vasoactive intestinal peptide (VIP) and compare the changes of blood neuro-transmitters in patients with different disease symptoms. Drug treatment cases: According to the randomized controlled multicenter clinical trial, 272 ITP patients were randomly divided into three groups: treatment group (JYSD) combined group (JYSD + Prednisone) control group (Prednisone). The changes of blood neuro-transmitter (5-HT, ß-EP, VIP) before and after treatment were detected on the basis of peripheral blood platelet (PLT) and grade score. RESULTS: Non-drug treatment cases: compared with the normal control group, the 5-HT level was higher, and the VIP and ß-EP levels were both lower in the ITP group (P < 0.001), and the 5-HT, VIP and ß-EP levels in the Gastrointestinal tumors with bleeding group were also lower compared with the normal control group (P < 0.05, 0.001). Drug treatment cases: The PLT grading scores of the combination group and the control group after treatment were lower than that before treatment (P < 0.05, 0.001). The PLT grading score of the 3 groups were compared in pairs after treatment: the combination group was the lowest among the 3 groups, which was better than the treatment group, but no better than the control group (vs the treatment group, P = 0.005, vs the control group, P = 0.709). The statistical results of full analysis set (FAS) and per protocol set (PPS) were consistent. The bleeding symptom scores of the treatment and combination groups began to drop 7 d after treatment, and kept dropping 14 d after treatment until the end of the study (P < 0.05). On the other hand, the control group started to show favorable results 14 d after treatment (P < 0.05). The FAS and PPS analysis results were consistent. In the control group, the 5-HT level was higher and VIP level was lower after treatment, compared with those before treatment (P < 0.05, 0.001). The ß-EP levels were both increased in the treatment and combination group after treatment, compared with those before treatment (P < 0.05). After treatment, the ß-EP levels in the treatment and control groups were significantly lower compared with the combination groups (P < 0.05). After treatment, compared with the control group, the VIP levels in the treatment and combination groups were up-regulated, and the differences were statistically significant by rank sum test (P < 0.01), and by t-test (P = 0.0002, 0.0001). CONCLUSIONS: The prednisone tablet is better than the JYSD in increasing the level of PLT, while prednisone tablet combined with JYSD has more advantages in improving patients' peripheral blood PLT levels. However, in improving the bleeding time of ITP patients, the combination of the two drugs was significantly delayed compared with the single usage, showing the characteristics and advantages of traditional Chinese medicine. JYSD can regulate the neurotransmitter level of ITP patients through the function of the brain-gut axis, mobilize 5-HT in the blood of ITP patients to promote the contraction of blood vessels and smooth muscles, and activate the coagulation mechanism are the early hemostatic mechanisms of JYSD. Up-regulate the levels of ß-EP and balancing VIP levels may be an important part of the immune mechanism of JYSD for regulating ITP patients.