Search

The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, 2 members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in this study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-melanocyte-stimulating hormone, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased proopiomelanocortin immunoreactivity per cell. These results indicate that protein tyrosine phosphatase receptor type N contributes to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of electroacupuncture in conjunction with additional medications in providing analgesia and stabilizing hemodynamic parameters during total thyroidectomy. Methods: This randomized controlled trial included 100 patients who underwent a total thyroidectomy between October 2022 and October 2023 at the Vietnam National Hospital of Acupuncture. The patients were randomized into two groups. The electroacupuncture analgesia (EA) group received EA stimulation at five acupuncture points: Hegu (LI 4), Neiguan (PC 6), Shuitu (ST 10), Quepen (ST 12), and Yifeng (SJ 17), while the control group received a bilateral superficial cervical plexus block. Primary outcomes included the level of analgesia and perioperative vital signs in both groups. Additionally, pain thresholds and serum β-endorphin levels were measured before and after electroacupuncture in the EA group. Results: Complete analgesia (Level A) was attained in 86% and 76% of the patients in the EA and control groups, respectively, with no significant difference between the two groups (P = 1.00). In the EA group, the mean pain threshold after receiving EA doubled (648.7 (77.4) g/s vs. 305.3 (45.3) g/s, P

It has been widely recognized that electroacupuncture (EA) inducing the release of β-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of β-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2 Hz EA at the Zusanli (ST36) increased the level of β-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2 Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2 Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2 Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2 Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the β-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2 Hz EA promoted the neural projection from ARC to PAG compared to 100 Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of β-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of β-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2 Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of β-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism. [ABSTRACT FROM AUTHOR]

Once thought of as an immune-privileged site, we now know that the nervous system communicates in a bidirectional manner with the immune system via the neuroimmune axis. Neuropeptides constitute a component of this axis, playing critical roles in the brain and periphery. The function of salivary neuropeptides in the acute stress response is not well understood. The purpose of this study is to investigate salivary neuropeptide levels during acute stress. Salivary samples were collected from fire recruits engaged in a stress training exercise previously shown to induce acute stress, at three separate timepoints during the exercise and levels of oxytocin, neurotensin, Substance P, α-MSH, and β-Endorphin were measured using the Human Neuropeptide 5-Plex Custom Assay Eve Technologies. All neuropeptides increased throughout the acute stress simulation and during the recovery phase. Exploratory factor analysis (EFA) identified one factor contributing to baseline values across five neuropeptides and Pairwise Pearson Correlation Coefficient analysis showed positive correlations >0.9 for almost all neuropeptide combinations at the pre-stress timepoint. Further analysis identified negative and positive correlations between past-life trauma and self-assessed hardiness, respectively. Calculated neuropeptide scores showed an overall positive correlation to self-assessed hardiness. Altogether, our results suggest that salivary neuropeptides increase synchronously during acute stress and higher levels correlate with an increase in self-assessed hardiness. Further study is required to determine if interventions designed to enhance neuropeptide activity can increase stress resilience, especially in high-stress occupations such as firefighting. [ABSTRACT FROM AUTHOR]

Although the involvement of β-endorphin (β-ERP) in vertebrate reproduction has been suggested, its role in testicular activity is not clear in fish. We describe the influence of β-ERP on spermatogenesis in a cichlid fish in the present paper. In comparison to the control group, the administration of β-ERP (3 µg) caused a significant increase in the number of spermatogonia-A and spermatids. Following treatment with β-ERP (6 µg), a significant increase in the number of spermatogonia-A was observed, whereas the numbers of all the other germ cells, excluding spermatogonia-B, significantly decreased in comparison to those in the control group. In addition, treatment of fish with 6 µg β-ERP resulted in a significant reduction in the dimensions of the lumen and seminiferous lobules, the level of immunopositive androgen receptor (AR) expression in Sertoli cells, and the percentage of luteinizing hormone (LH) immunolabeled in the pituitary compared to those in the control group or the group treated with 3 µg β-ERP. In contrast, the intensity of AR immunoreactivity and the percentage of LH immunolabeling were substantially increased in fish treated with 3 µg β-ERP compared to those in the control group. These findings reveal for the first time that a low dose of β-ERP stimulates the recruitment of spermatogonia as well as spermateleosis, whereas a high concentration affects the recruitment of germ cells prior to meiotic division in tilapia. These results suggest that β-ERP exerts modulatory effects at the testicular and hypophysial levels through alterations in AR expression and LH secretory activity, respectively, in teleosts. [ABSTRACT FROM AUTHOR]

Substance use disorder, and particularly cocaine use disorder, is a complex disease that affects societal, economic, and psychological factors. Endogenous β-endorphin released after prolonged cocaine withdrawal has been reported to activate the accumbal delta-opioid receptor (DOR), leading to attenuated cocaine seeking. However, using DOR β-endorphin activation to treat cocaine use disorder is impractical since β-endorphin does not cross the blood-brain barrier. Also, only activation of the sub-group DOR1 efficiently attenuates craving, as activation of DOR2 yields an opposite effect. Here, we isolated a specific peptide, PEP1, from a phage display peptide library with similar biological properties to β–endorphin, demonstrating specificity for DOR1 and functioning as full receptor agonists. Our pharmacodynamic results showed fast trafficking incorporation of DOR into the cell membrane, interpreted as superior rehabilitation of the receptor and its bioavailability compared to commercial agonists. We administered PEP1, either intrabrain or intranasal, to rats trained to self-administer cocaine. PEP1 induced a significant decrease in cocaine-craving behavior and reinstatement in three different animal models of addiction. Also, PEP1 did not exhibit rewarding properties and did not interfere with the natural reward system. ICP-OES analysis revealed that at least one hour post-administration, PEP1 was retained in the brain rather than in peripheral organs. These findings render PEP1 a potential novel regulator of cocaine craving, especially for being non-addictive. Hence, PEP1 should be further examined as a possible new therapy for substance use disorder.

Objective To observe the clinical effects of auricular point therapy on burning mouth syndrome (BMS) and its effect on the psychological state of patients and plasma β-endorphin. Methods A total of 105 patients diagnosed with BMS were randomly divided into an auricular acupoint application group (50 cases) and a drug treatment group (55 cases). The treatment course lasted one month. The patients in the auricular acupoint application group selected 3 points on their tongue, heart and Shenmen through traditional Chinese medical dialectics used for patients with BMS. Wangbuliu seeds were applied, two ears were pressed alternately and one ear was applied each time. The patient was instructed to press the treatment site three times a day, 1-2 min each time, until the auricle skin became reddish and hot. The patients in the drug treatment group took vitamin E 100 mg+oryzanol 10 mg+vitamin B2 10 mg orally three times a day. Before and after treatment, the pain intensity and mental and psychological state of the patients were evaluated. The patient's plasma was detected before and after β-endorphin treatment. Results The pain sensation intensity of the two groups decreased after treatment (P

A 15-yr-old, male, captive red-tailed boa (Boa constrictor constrictor) was submitted for postmortem examination after it was euthanized after becoming nonresponsive and laterally recumbent. The snake had a history of respiratory disease, coelomic swelling, leukocyte intracytoplasmic inclusion bodies, and an antemortem negative Reptarenavirus PCR. At necropsy, there were solid white masses in the lungs and throughout the alimentary tract, and firm, smooth yellow masses in the pericardium and adventitia of heart base vessels. Histopathology revealed an anaplastic large-cell lymphoma that infiltrated multiple tissue types, most severely the lungs and esophagus. Neoplastic lymphocytes were negative for CD3 and positive for Pax5, consistent with a B-cell lymphoma. The yellow pericardial masses were composed of neoplastic neuroendocrine cells with moderate amounts of vacuolated cytoplasm and small, ovoid nuclei with finely stippled chromatin arranged in packets separated by fine fibrovascular stroma. Neoplastic cells were positive for β-endorphin consistent with a diagnosis of paraganglioma. Additionally, many cell types, including neoplastic lymphocytes and neuroendocrine cells, contained cytoplasmic viral eosinophilic inclusions, and Reptarenavirus PCR on spleen detected a virus in the species Reptarenavirus giessenae. This snake was diagnosed with concurrent paraganglioma, inclusion body disease, and anaplastic lymphoma, morphologically represented as a diffuse lymphoma of B-cell phenotype. Whether Reptarenavirus predisposes to neoplasia in snakes is debated. This case describes multiple neoplasms in a snake with a concurrent Reptarenavirus infection. [ABSTRACT FROM AUTHOR]

We examined the association between endogenous opioid β-endorphin, cancer progression and pain in a transgenic mouse model of breast cancer, with a rat C3(1) simian virus 40 large tumor antigen fusion gene (C3TAg). C3TAg mice develop ductal epithelial atypia at 8 weeks, progression to intra-epithelial neoplasia at 12 weeks, and invasive carcinoma with palpable tumors at 16 weeks. Consistent with invasive carcinoma at 4 months of age, C3TAg mice demonstrate a significant increase in hyperalgesia compared to younger C3TAg or control FVBN mice without tumors. Our data show that the growing tumor contributes to circulating β-endorphin. As an endogenous ligand of mu opioid receptor, β-endorphin has analgesic activity. Paradoxically, we observed an increase in pain in transgenic breast cancer mice with significantly high circulating and tumor-associated β-endorphin. Increased circulating β-endorphin correlates with increasing tumor burden. β-endorphin induced the activation of mitogenic and survival-promoting signaling pathways, MAPK/ERK 1/2, STAT3 and Akt, observed by us in human MDA-MB-231 cells suggesting a role for β-endorphin in breast cancer progression and associated pain.

Once thought of as an immune-privileged site, we now know that the nervous system communicates in a bidirectional manner with the immune system via the neuroimmune axis. Neuropeptides constitute a component of this axis, playing critical roles in the brain and periphery. The function of salivary neuropeptides in the acute stress response is not well understood. The purpose of this study is to investigate salivary neuropeptide levels during acute stress. Salivary samples were collected from fire recruits engaged in a stress training exercise previously shown to induce acute stress, at three separate timepoints during the exercise and levels of oxytocin, neurotensin, Substance P, α-MSH, and β-Endorphin were measured using the Human Neuropeptide 5-Plex Custom Assay Eve Technologies. All neuropeptides increased throughout the acute stress simulation and during the recovery phase. Exploratory factor analysis (EFA) identified one factor contributing to baseline values across five neuropeptides and Pairwise Pearson Correlation Coefficient analysis showed positive correlations >0.9 for almost all neuropeptide combinations at the pre-stress timepoint. Further analysis identified negative and positive correlations between past-life trauma and self-assessed hardiness, respectively. Calculated neuropeptide scores showed an overall positive correlation to self-assessed hardiness. Altogether, our results suggest that salivary neuropeptides increase synchronously during acute stress and higher levels correlate with an increase in self-assessed hardiness. Further study is required to determine if interventions designed to enhance neuropeptide activity can increase stress resilience, especially in high-stress occupations such as firefighting.

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia–ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10 week old male db/db and db/ + mice, collected tissue at 24 and 72 h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1 mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48 h post HI, and collected brain tissue and blood at 72 h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN. [ABSTRACT FROM AUTHOR]

Estrogen and progesterone (P4) act in neural circuits to elicit lordosis, the stereotypical female sexual receptivity behavior. Estradiol acts through membrane receptors to rapidly activate a limbic-hypothalamic circuit consisting of the arcuate (ARH), medial preoptic (MPN), and ventromedial (VMH) nuclei of the hypothalamus. This initial activation results in a transient but necessary inhibition of lordosis, which appears to be a result of the release of β-endorphin (β-End) from proopiomelanocortin (POMC) terminals onto cells containing the µ-opioid receptor (MOR) in the MPN. To functionally examine the role of the MOR in the hypothalamic lordosis circuit, we transfected a channelrhodopsin (ChR2) adeno-associated virus into POMC cell bodies in the ARH and photostimulated POMC/β-End axon terminals in the MPN in sexually receptive female Pomc-cre mice. Following estrogen and P4 priming, sexual receptivity was assessed by measuring the lordosis quotient (LQ). Following an initial trial for sexual receptivity, mice were photostimulated during behavioral testing, and brains were processed for MOR immunohistochemistry (IHC). Photostimulation decreased the LQ only in ChR2-expressing Pomc-cre mice. Furthermore, photostimulation of ChR2 in POMC/β-End axon terminals in the MPN resulted in the internalization of MOR, indicating activation of the receptor. Our results suggest that the activation of the MOR in the MPN is sufficient to attenuate lordosis behavior in a hormone-primed, sexually receptive female mouse. These data support a central role of MOR in female sexual behavior, and provide further insight into the hypothalamus control of sexual receptivity.

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV. [ABSTRACT FROM AUTHOR]

Background: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. Methods: A cross‐sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case–control study was then conducted to determine the biomarker for pruritus. Arsenite‐treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double‐blind, placebo‐controlled trial was conducted to test the efficacy of naloxone in arsenic‐exposed patients with pruritus in Shimen. Results: Hair arsenic (μg/g) showed a dose–response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate‐to‐severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β‐endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β‐endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic‐exposed participants in 2 weeks (β = −0.98, p = 0.04). Conclusion: Arsenic exposure is associated with pruritus, and β‐endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammatory lameness is a common painful condition in dairy cows that affects animal welfare and produces significant yield losses. Bovine chronic lameness can lead to a chronic pain condition due to the participation of pro- and anti-nociceptive mediators and reactive oxygen species. The results of this study revealed increased concentrations of substance P and β-endorphin in lame dairy cows, indicating chronic pain development and sustained endogenous analgesics release. Moreover, the results revealed decreased disulfide levels and α-tocopherol concentrations in the lame group, suggesting an overproduction of reactive oxygen species, which may indicate their involvement in the development of chronic pain in bovine lameness. Initial lameness inflammation leads to chronic lameness and development of chronic pain due to the release of pro-inflammatory mediators such as reactive oxygen species (ROS), which are implicated in the transition from acute to chronic pain, and free radical scavengers countering thiol, substance P (SP), and β-endorphin (BE). The present study aimed to evaluate the dynamic thiol–disulfide homeostasis, α-tocopherol concentrations and SP and BE concentrations in the spinal cord of chronically lame dairy cows. Ten lame and 10 non-lame cows with a parity range of 2–6 were selected for the study. Lame cows had a history of up to 3 months of lameness. Spinal cord samples were obtained from the L2 to L4 lumbar vertebrae aspect of each animal. A thiol–disulfide homeostasis assay was performed using absorbance, and the α-tocopherol concentration was determined by HPLC. SP and BE concentrations were measured using ELISA kits. The results indicated that SP and BE were significantly higher in the spinal cord of lame cows. In contrast, disulfide levels and α-tocopherol concentrations were significantly lower in the spinal cord of lame cows. In conclusion, disulfide levels and α-tocopherol concentrations indicated a defective antioxidant response in cows with chronic lameness. The results of SP and BE concentrations suggested chronic pain and a defective endogenous analgesic response. [ABSTRACT FROM AUTHOR]

Microglia are glial cells centrally related to pathophysiology and neuroimmunological regulation of pain through microglia–neuron crosstalk mechanisms. In contrast, anti-inflammatory mechanisms guided by immunological effectors such as IL-10 trigger the secretion of analgesic substances, culminating in the differential expression of genes encoding endogenous opioid peptides, especially β-endorphin. Thus, when β-endorphin binds to the µ-opioid receptor, it generates neuronal hyperpolarization, inhibiting nociceptive stimuli. This review aimed to summarize the recent advances in understanding the mechanism by which IL-10/β-endorphin can reduce pain. For this, databases were searched for articles from their inception up until November 2022. Two independent reviewers extracted the data and assessed the methodological quality of the included studies, and seventeen studies were considered eligible for this review. Several studies have demonstrated the impact of IL-10/β-endorphin in reducing pain, where IL-10 can stimulate GLP-1R, GRP40, and α7nAChR receptors, as well as intracellular signaling pathways, such as STAT3, resulting in increased β-endorphin expression and secretion. In addition, molecules such as gabapentinoids, thalidomide, cynandione A, morroniside, lemairamin, and cinobufagin, as well as non-pharmacological treatments such as electroacupuncture, reduce pain through IL-10 mediated mechanisms, reflecting a microglia-dependent β-endorphin differential increase. This process represents a cornerstone in pain neuroimmunology knowledge, and the results obtained by different studies about the theme are presented in this review. [ABSTRACT FROM AUTHOR]

Abstract: The nucleus of the solitary tract (NTS) contains pro-opiomelanocortin (POMC) neurons that are 1 of the 2 major sources of β-endorphin in the brain. The functional role of these NTSPOMC neurons in nociceptive and cardiorespiratory function is debated. We have shown that NTSPOMC optogenetic activation produces bradycardia and transient apnoea in a working heart-brainstem preparation and chemogenetic activation with an engineered ion channel (PSAM) produced opioidergic analgesia in vivo. To better define the role of the NTSPOMC neurons in behaving animals, we adopted in vivo optogenetics (ChrimsonR) and excitatory/inhibitory chemogenetic DREADD (hM3Dq/hM4Di) strategies in POMC-Cre mice. We show that optogenetic activation of NTSPOMC neurons produces time-locked, graded, transient bradycardia and bradypnoea in anaesthetised mice that is naloxone sensitive (1 mg/kg, i.p.), suggesting a role of β-endorphin. Both optogenetic and chemogenetic activation of NTSPOMC neurons produces sustained thermal analgesia in behaving mice that can be blocked by naloxone. It also produced analgesia in an inflammatory pain model (carrageenan) but not in a neuropathic pain model (tibial nerve transection). Inhibiting NTSPOMC neurons does not produce any effect on basal nociception but inhibits stress-induced analgesia (unlike inhibition of arcuate POMC neurons). Activation of NTSPOMC neuronal populations in conscious mice did not cause respiratory depression, anxiety, or locomotor deficit (in open field) or affective preference. These findings indicate that NTSPOMC neurons play a key role in the generation of endorphinergic endogenous analgesia and can also regulate cardiorespiratory function. [ABSTRACT FROM AUTHOR]

Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1β in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased β-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic β-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic β-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain. [ABSTRACT FROM AUTHOR]

Since the recent coronavirus disease 2019 pandemic and the lifestyle changes it necessitated, the demand for mental health treatment has skyrocketed, with long wait lists for both psychological and psychiatric care. Over-the-counter supplements and home remedies are increasingly sought. In this study, we screened natural materials and blended supplements from Asia that may improve the mood and mental health of humans by testing cell viability and expression of the proopiomelanocortin gene as a marker of β-endorphin production in rat hypothalamus neuron cells. Among 23 tested samples, 3 samples produced significantly higher cell viability in R-HTH-507 cells than the control treatment. In a real-time-polymerase chain reaction (RT-PCR) experiment, 7 samples showed significant β-endorphin synthesis activity. This is the first report that the Asian natural materials Areca catechu, Moringa oleifera, Lignosis rhinocerus, and Aegle marmelos promote β-endorphin synthesis; further investigation will identify the active ingredients in the blended samples. These results suggested that these Asian natural materials have great potential to expand the range of treatments for mental health. [ABSTRACT FROM AUTHOR]

Tobacco smoking is considered to be one of the main risk factors in the development of chronic pain. Long-term chronic exposure to nicotine and other forms of tobacco have been shown to be associated with an increased incidence of pain. Studies have shown that acupuncture can help smokers to reduce their desire to smoke, reduce their withdrawal symptoms, and avoid a relapse after treatment. However, little has been reported about the effects of acupuncture on pain sensitivity caused by long-term smoking. Models of hyperalgesia were established in rats exposed to nicotine for 6 weeks. After 6 weeks of continuous nicotine exposure, electroacupuncture at bilateral acupoints Zusanli (ST36) and Taichong (LR3) was performed 20 minutes per day for 6 days at a continuous wave with a frequency of 2 Hz and a stimulus intensity of 1 mA. The results revealed that electroacupuncture treatment increased the mechanical response threshold of hind paw of nicotine-dependent rats with hyperalgesia and up-regulated the protein expression of pain-related factors μ-opioid receptor, β-endorphin and glutamic acid decarboxylase 65 in the spinal cord and midbrain periaqueductal gray and the protein expression of glutamic acid decarboxylase 67 in the spinal cord. These findings suggest that electroacupuncture treatment has positive analgesic effects on pain sensitivity caused by long-term chronic nicotine exposure. One possible mechanism for the improved analgesia is that electroacupuncture increases the expression of pain-related factors in the spinal cord and midbrain periaqueductal gray. This study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Miami (#18-167) on December 12, 2018.

Preterm infants are a special cohort of newborns that require long-term treatment in the neonatal intensive care unit (NICU). NICU stay, accompanied by numerous excessive stimuli, painful procedures, and separation from parents leads to a high risk of chronic pain and stress. The aim of research was to study the level of chronic pain and pain-related stress markers in preterm infants with a gestational age of less than 34 weeks, and their associations with various factors. Materials and methods. The study involved 104 preterm infants with gestational age (GA) less than 34 weeks who were treated in the NICU. The level of chronic pain and pain-related stress markers (dopamine, β-endorphin, serotonin) in urine samples was determined by an enzyme-linked immunosorbent assay using kits for the quantitative determination of dopamine (Dopamine Elisa kit, Elabscience, Wuhan, China), β-endorphin (β-endorphin Elisa kit, Elabscience, Wuhan, China), serotonin (Serotonin Elisa kit, Elabscience, Wuhan, China). Samples were analyzed in duplicate, and assays were performed using provided controls according to the manufacturer’s instructions. Ethics approval was obtained from the appropriate local ethics committee and research was conducted under the World Medical Association’s Helsinki Declaration. Informed consent was obtained from all the participants who took part in the study. All computations were performed using StatSoft STATISTICA Version 13 (Tulsa, OK). Quantitative data are presented as the median and interquartile range (IQR; 25th to 75th percentiles). For qualitative parameters, absolute and relative frequencies are presented. The Mann-Whitney U-test (for two independent groups) and Kruskal-Wallis test (for three groups) were used to compare numerical data. Significance was assumed at p

Circadian sleep/wake rhythms are synchronized to environmental light/dark cycles in a process known as photoentrainment. We have previously shown that activation of β-endorphin-preferring μ-opioid receptors (MORs) inhibits the light-evoked firing of intrinsically photosensitive retinal ganglion cells (ipRGCs), the sole conduits of photoentrainment. Although we have shown that β-endorphin is expressed in the adult mouse retina, the conditions under which β-endorphin is expressed are unknown. Moreover, it is unclear whether endogenous activation of the MORs expressed by ipRGCs modulates the photoentrainment of sleep/wake cycles. To elucidate this, we first measured the mRNA expression of β-endorphin's precursor, proopiomelanocortin (POMC), at various times of day by quantitative reverse-transcription PCR. POMC mRNA appears to have cyclic expression in the mouse retina. We then studied β-endorphin expression with immunohistochemistry and found that retinal β-endorphin is more highly expressed in the dark/at night. Finally, we used telemetry to measure activity, EEG and EMG in freely moving animals to compare sleep/wake cycles in wild-type and transgenic mice in which only ipRGCs lack functional MORs. Results from these experiments suggest that the MORs expressed by ipRGCs contribute to the induction and maintenance of activity in the dark phase in nocturnal mice, via the promotion of wakefulness and inhibition of slow-wave sleep. Together, these data suggest that endogenous β-endorphin activates MORs expressed by ipRGCs to modulate sleep/wake activity via the photoentrainment pathway.

Objective: This study was performed to determine the impact of different acupressure procedures, performed on women's hands during labor, on β-endorphin plasma levels and labor pain perception.Design: Randomized controlled experimental trial SETTING AND PARTICIPANTS: This study was conducted with 140 pregnant women in the delivery rooms of a university research and training hospital and a state hospital in a province in the Black Sea Region of Turkey.Methods: This study was conducted with three experimental groups (who had conventional, warm and cold acupressure on their LI4 acupressure point) and one control group (no acupressure). Each group included 35 pregnant women. The data were collected using a personal information form, the Labor Intervention Follow-up Form, the Visual Analog Scale (VAS) and the Verbal Category Scale (VCS). Its main outcomes were the women's labor pain perceptions and β-endorphin plasma levels.Results: The experimental and control groups had homogeneous introductory characteristics. The experimental groups had significantly higher mean VAS and VCS posttest scores than the control group (p<0.001). The experimental groups' mean posttest β-endorphin plasma levels were also significantly higher (p<0.05).Conclusion: In this study, conventional, warm and cold acupressure reduced the women's labor pain and increased their β-endorphin plasma levels. Midwives can use acupressure to reduce labor pain. [ABSTRACT FROM AUTHOR]

Self-injurious behavior (SIB) (either non-suicidal self-injury, NSSI; or suicide attempts, SA) is a common reason for adolescent psychiatric emergency hospitalizations. Altered basal serum β-endorphin (BE) levels have been reported in adults with a history of SIB, but information is lacking in adolescents. We analyzed the psychoclinical profile and serum BE level of 39 adolescents admitted to the acute unit at a hospital in Spain due to SIB. TheMean (SD) serum BE level was high (190.53 ± 74.83). Regarding time sequence, the onset age of NSSI and SA were related (p < 0.001). The older the onset age of NSSI, the shorter the transition between NSSI and the onset of SA behavior (p = 0.05), but this difference does not lead the variation of BE (p = 0.81). Patients diagnosed with depression had lower serum BE levels than adolescents with other diagnoses (p = 0.03). Although adolescents who seem to be addicted to SIB had higher levels of BE, this finding was not statistically significant. The relationship between serum BE levels and SIB in adolescents requires further investigation. [ABSTRACT FROM AUTHOR]

Purpose of Review: We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels. Recent Findings: This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid β-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma β-endorphin levels. Summary: Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use. [ABSTRACT FROM AUTHOR]

Endorphins are endogenous peptides that play a role in the regulation of pain, behavior, neuroendocrine and autonomic functions. In our study, we aimed to investigate the role of β endorphins in these effects of midazolam and dexmedetomidine. In this experimental study, 36 rats were divided into 6 groups. Group 1: (control) (n=6): An average of 100-150μl CSF samples were obtained after general anesthesia was achieved. An intracardiac 3-4ml blood sample was then taken. Group 2: (sham) (n=6): intraperitoneal 1 mL saline was administered. For all other groups after general anesthesia; Group 3: (midazolam-1) (n=6): intraperitoneal 4mg/kg midazolam was administered. Group 4: (midazolam-2) (n=6): 12mg/kg midazolam was administered intraperitoneally. Group 5: (Dexmedetomidine-1) (n=6): Dexmedetomidine 50µg/kg was administered intraperitoneally. Group 6: (Dexmedetomidine-2) (n=6): Dexmedetomidine 150 µg/kg was administered intraperitoneally.CSF and plasma samples were taken with the same method. All samples were stored at -80 °C. No statistically significant difference was found between the levels of rat CSF β-endorphin. However, when the plasma ß-endorphin levels of rats were evaluated, there was a statistically significant difference between the groups. No difference was found between the levels of plasma ß-endorphin in the patients who received midazolam, while plasma ß-endorphin levels of 50 µg/kg with dexmedetomidine were found to be lower than the control group. However, the values of the 150 µg/kg dexmedetomidine group did not support this result. Different findings from both this study and in vitro and human studies; the number of subjects, the use of different drug doses, the differences in measurement times, the absence of control groups may be due to methodological differences, and more research is needed. [Med-Science 2021; 10(3.000): 737-40]

The hypothalamus is most often associated with innate behaviors such as is hunger, thirst and sex. While the expression of these behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive behavior, i.e., lordosis behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating β-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity-the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of lordosis behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory behavior and vice versa. While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual behavior and other innate behaviors in humans.

Endogenous opioid peptides have attracted attention as critical neuropeptides in the central mechanism regulating female reproduction ever since the discovery that arcuate dynorphin neurons that coexpress kisspeptin and neurokinin B (NKB), which are also known as kisspeptin/neurokinin B/dynorphin (KNDy) neurons, play a role as a master regulator of pulsatile gonadotropin-releasing hormone (GnRH) release in mammals. In this study, we first focus on the role of dynorphin released by KNDy neurons in the GnRH pulse generation. Second, we provide a historical overview of studies on endogenous opioid peptides. Third, we discuss how endogenous opioid peptides modulate tonic GnRH/gonadotropin release in female mammals as a mediator of inhibitory internal and external cues, such as ovarian steroids, nutritional status, or stress, on reproduction. Then, we discuss the role of endogenous opioid peptides in GnRH surge generation in female mammals.

Although blunted sensitivity to reward is thought to play a key role in promoting risk for depression, most research on this topic has utilized monetary reward paradigms and focused on currently depressed adults. To address this issue, we analyzed neural reward and β-endorphin data from the Psychobiology of Stress and Adolescent Depression (PSY SAD) Study, which recruited a well-characterized sample of adolescent girls at high vs. low risk for major depressive disorder (MDD) (N = 52, Mage = 14.90, SD = 1.35) based on their mothers’ lifetime history of MDD. As hypothesized, greater striatal activity while receiving positive (vs. neutral) social evaluation was associated with lower depression symptom severity as independently assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). This association was present for girls at high but not low risk for MDD, suggesting that this neural response may represent a pre-clinical marker of risk for depression. Consistent with these results, higher post-social evaluation levels of a peripheral marker of reward sensitivity, β-endorphin, were related to lower clinician-rated depression symptom severity. Together, these results indicate that neural and peripheral markers of responsivity to social reward are both related to depression severity, which may have implications for understanding the pathophysiology of depression.

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.

Initial lameness inflammation leads to chronic lameness and development of chronic pain due to the release of pro-inflammatory mediators such as reactive oxygen species (ROS), which are implicated in the transition from acute to chronic pain, and free radical scavengers countering thiol, substance P (SP), and β-endorphin (BE). The present study aimed to evaluate the dynamic thiol–disulfide homeostasis, α-tocopherol concentrations and SP and BE concentrations in the spinal cord of chronically lame dairy cows. Ten lame and 10 non-lame cows with a parity range of 2–6 were selected for the study. Lame cows had a history of up to 3 months of lameness. Spinal cord samples were obtained from the L2 to L4 lumbar vertebrae aspect of each animal. A thiol–disulfide homeostasis assay was performed using absorbance, and the α-tocopherol concentration was determined by HPLC. SP and BE concentrations were measured using ELISA kits. The results indicated that SP and BE were significantly higher in the spinal cord of lame cows. In contrast, disulfide levels and α-tocopherol concentrations were significantly lower in the spinal cord of lame cows. In conclusion, disulfide levels and α-tocopherol concentrations indicated a defective antioxidant response in cows with chronic lameness. The results of SP and BE concentrations suggested chronic pain and a defective endogenous analgesic response.

Microglia are glial cells centrally related to pathophysiology and neuroimmunological regulation of pain through microglia–neuron crosstalk mechanisms. In contrast, anti-inflammatory mechanisms guided by immunological effectors such as IL-10 trigger the secretion of analgesic substances, culminating in the differential expression of genes encoding endogenous opioid peptides, especially β-endorphin. Thus, when β-endorphin binds to the µ-opioid receptor, it generates neuronal hyperpolarization, inhibiting nociceptive stimuli. This review aimed to summarize the recent advances in understanding the mechanism by which IL-10/β-endorphin can reduce pain. For this, databases were searched for articles from their inception up until November 2022. Two independent reviewers extracted the data and assessed the methodological quality of the included studies, and seventeen studies were considered eligible for this review. Several studies have demonstrated the impact of IL-10/β-endorphin in reducing pain, where IL-10 can stimulate GLP-1R, GRP40, and α7nAChR receptors, as well as intracellular signaling pathways, such as STAT3, resulting in increased β-endorphin expression and secretion. In addition, molecules such as gabapentinoids, thalidomide, cynandione A, morroniside, lemairamin, and cinobufagin, as well as non-pharmacological treatments such as electroacupuncture, reduce pain through IL-10 mediated mechanisms, reflecting a microglia-dependent β-endorphin differential increase. This process represents a cornerstone in pain neuroimmunology knowledge, and the results obtained by different studies about the theme are presented in this review.

Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer. [Display omitted] • FAO senses circadian disruption underlying SD-enhanced tumorigenesis • ACSL1 drives ZDHHC5-mediated CLOCK-Cys194 palmitoylation to stabilize CLOCK protein • Timed β-endorphin resets CLOCK/ACSL1 rhythm to reverse SD-enhanced tumorigenesis • Sleep quality, β-endorphin, and ACSL1 predict prognosis of lung cancer Peng et al. show that fatty acid oxidation senses circadian disruption underlying sleep-deficiency (SD)-enhanced tumorigenesis. SD-induced circadian disruption dysregulates CLOCK to hyper-transactivate ACSL1, increasing palmitoyl-CoA. CLOCK S-palmitoylation prevents CLOCK proteasomal degradation, therefore forming a transcription-palmitoylation feedback loop to facilitate cancer stemness. Chronotherapy with β-endorphin resets circadian rhythm ameliorating tumorigenesis. [ABSTRACT FROM AUTHOR]

Objective: Adrenocorticotropic hormone (ACTH) and ß-endorphin are pituitary neuro-peptides released by acute stress. We determined why the prognosis of patients with subarachnoid hemorrhages (SAH) due to aneurysmal rupture is not always dependent on the Hunt-Hess grading system (HHS) and delta-National Institutes of Health Stroke Scale (NIHSS), while studying endogenous neuropeptides, including ACTH and ß-endorphin. Methods: We analyzed blood samples collected from patients with SAH (SAH group; n=37) and those with unruptured intracranial aneurysms (control group; n=37). Blood sampling was performed before any procedure or chemical agents administration. The results of ACTH and ß-endorphin measurements were compared using the delta-NIHSS and HHS. The data were analyzed using descriptive statistics, independent samples t-tests, and Pearson's correlations. Results: Of the 18 patients with low-grade HHS, 13 had low delta-NIHSS and five showed high delta-NIHSS. Of the 19 patients with high-grade HHS, the delta-NIHSS was =14 in the other five patients. ACTH concentration was high (497.3 pg/mL) in five patients with high-grade HHS and high delta-NIHSS. ß-endorphin concentration was high (159.7 pg/mL) in 13 patients with low-grade HHS and low delta-NIHSS. Conclusions: High ACTH levels in patients with massive bleeding and poor neurological status suggests increasing ACTH secretion in response to bleeding stress, which may aggravate neurological status. Contrary to ACTH, high ß-endorphin levels in patients with low-grade HHS implied the involvement of additional factors in predicting fair outcomes related to low delta-NIHSS. These results may provide insight into the varying prognostic potential of HHS in SAH patients. [ABSTRACT FROM AUTHOR]

Morphological and pharmacological studies indicate that hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons communicate with each other in rats and regulate a variety of hypothalamic and extrahypothalamic functions. Indeed, electron microscopic studies revealed NPY-immunoreactive (NPI-IR) synapses on β-endorphin-IR neurons in the hypothalamus. However, no such connections have been reported in humans. Here, we studied the putative NPY–β-endorphin associations with high-resolution light microscopic double-label immunocytochemistry in the human hypothalamus. The majority of β-endorphin-IR perikarya appear to be innervated by abutting NPY-IR fibers in the infundibulum/median eminence, receiving more than 6 contacts (38% of the counted neurons) or three to six contacts (42% of the counted neurons). The rest of the β-endorphin-IR neurons are lightly innervated by NPY fibers (14%, one–three contacts) or do not receive any detectable NPY-IR axon varicosities (6% of the counted neurons). Since β-endorphin is cleaved from the proopiomelanocortin (POMC) precursor, the NPY–β-endorphin connections also provide the foundation for NPY–α-MSH and NPY–ACTH connections and their subsequent physiology. The close anatomical connections between NPY-IR nerve terminals and β-endorphin-IR neurons reported herein may represent functional synapses and provide the foundation for NPY-stimulated β-endorphin release. By interacting with β-endorphin, NPY may have a more widespread regulatory capacity than acting alone on different neurotransmitter systems. [ABSTRACT FROM AUTHOR]

Wei-Hong Qi,1,* Wei-Juan Miao,2,* Yu-Zhi Ji,1 Chao Li,1 Jun-Huan Wang1 1Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Obstetrics, Ri-Zhao People’s Hospital, Ri Zhao, 276800, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei-Hong QiDepartment of Obstetrics, Affiliated Hospital of Qingdao University, No. 59 of Haier Road, LaoShan District, Qingdao, Shandong, 266000, People’s Republic of ChinaTel +86 532-82913296Fax +86 532-82913018Email qiweihong45@163.comObjective: This study aimed to investigate the analgesic effect of transcutaneous electrical acupoint stimulation (TEAS) on labor.Methods: Primiparas with single birth and head presentation were enrolled in this study and randomly divided into three groups: TEAS group (n = 76), patient-controlled epidural analgesia (PCEA) group (n = 75), and control group without any analgesic measures (n = 78).Results: Compared with the control group, the visual analog scores of the TEAS group and the PCEA group at each time point decreased (P < 0.01). The decrease was greater in the PCEA group than that in the TEAS group (P < 0.01). At 120 minutes after analgesia, there were significant differences in plasma β-endorphin content between the TEAS group, PCEA group, and control group (P < 0.01). The difference between the PCEA group and the control group was statistically significant (P < 0.01). Among the parturients having a vaginal delivery, the duration of the first stage of labor was significantly shorter in the TEAS group and control group than in the PCEA group (P < 0.01). The duration of the second stage of labor was significantly shorter in the TEAS group than in the PCEA group (P < 0.01). Oxytocin usage rate during labor was significantly lower in the TEAS group and control group than in the PCEA group (P < 0.01), and adverse reactions were significantly fewer in the TEAS group and control group than in the PCEA group (P < 0.01).Conclusion: The duration of the first and second stage of labor is significantly shorter in the TEAS group than in the PCEA group. TEAS does not increase the use rate of oxytocin or the rate of cesarean section and will not bring about obvious maternal or fetal adverse reactions.Keywords: labor analgesia, transcutaneous electrical acupoint stimulation, patient-controlled epidural analgesia, visual analog score of pain, β-endorphin

Background : Pain is a major complaint in cancer patients and a global problem that requires medical attention, including pain in cervical cancer. Although pharmacotherapy has been used for the treatment of cancer pain, there are still around 40% cannot be treated only with pharmacotherapy. Objectives: To determine the effects of electroacupuncture (EA) on pain in stage III cervical cancer patients. Methods : Twenty-eight stage III cervical cancer patients were divided into two groups (14 treatments and 14 controls) with randomized control trial design. The treatment group received EA with a frequency of 2/20-25 Hz at points of ST36, SP6, LI4 and LR3 for 30 minutes, while the control group did not receive EA. Both groups were given paracetamol and codeine at the same dose. Assessment was carried out by measuring pain scale (VAS), plasma β-endorphin levels, and quality of life/QoL (EORTC QLQ-C30) before and after therapy. Results : The average reduction in VAS in the treatment group (2.71 ± 1.14) compared to the control group (0.71 ± 1.33; p < 0.001), average increase in plasma β-endorphin levels in the treatment group (88.57 ± 52.46 pg/ml) compared to the control group (12.86 ± 56.76 pg/ml; p = 0.001), and in QoL, there were significant differences in symptom improvement between the treatment and control groups in the domain of fatigue, pain, insomnia and overall QoL (p < 0.05). Conclusion : Medical therapy combined with EA decreased pain scale, increased plasma β-endorphin levels, and improved the QoL for stage III cervical cancer patients.

The endogenous opioid peptide system, comprised of enkephalins, endorphins, dynorphins, and nociceptin, is a highly complex neurobiological system. Opioid peptides are derived from four precursor molecules and undergo several processing events yielding over 20 unique opioid peptides. This diversity together with low in vivo concentration and complex processing and release dynamics has challenged research into each peptide's unique function. Despite the subsequent challenges in detecting and quantifying opioid peptides in vivo, researchers have pioneered several techniques to directly or indirectly assay the roles of opioid peptides during behavioral manipulations. In this review, we describe the limitations of the traditional techniques used to study the role of endogenous opioid peptides in food and drug reward and bring focus to the wealth of new techniques to measure endogenous opioid peptides in reward processing.

Małgorzata Urban-Kowalczyk,1 Magdalena Kotlicka-Antczak,1 Dominik Strzelecki,1 Ewa Rudecka,2,3 Janusz Śmigielski4 1Department of Affective and Psychotic Disorders, Medical University of Łódź, Łódź, Poland; 2Babiński Memorial Hospital in Łódź, Łódź, Poland; 3Faculty of Human Nutrition and Consumer Sciences, Warsaw University of Life Sciences SGGW, Warsaw, Poland; 4State High Vocational School in Konin, Konin, PolandCorrespondence: Małgorzata Urban-KowalczykDepartment of Affective and Psychotic Disorders, Medical University of Łódź, Czechosłowacka 8/10, Lodz 92-216, PolandTel +48 42 675 73 71Fax +48 42 675 74 03Email malgorzata.urban1@wp.plObjective: Extensive investigations have been conducted into predictors of schizophrenia outcome. The heterogeneity of the illness implies that many factors should be taken into account. Some studies have reported the relationship between increased β-endorphin concentration and predominant negative symptoms.Methods: We included 77 outpatients with schizophrenia and 74 healthy controls. Data referring to duration and course of illness, hospitalization number and treatment were collected on the basis of clinical interviews and medical documentation analysis. The β-endorphin concentrations were assessed once in all participants, at the onset of the study.Results: A chronic course of illness was found in 44 of the 77 schizophrenics. Patients with schizophrenia, especially those with a chronic course of illness, revealed significantly higher β-endorphin concentrations than those with an episodic course and controls (mean 29.70 vs 19.86 pmol/L; p=0.0001). Increased levels of β-endorphin were related to longer duration of illness (R=0.294, p=0.009) and frequent psychiatric hospitalization (R=0.346, p=–0.002).Conclusion: Endorphins may be potential biological predictors of persistent negative symptoms and final outcome in schizophrenia.Keywords: β-endorphin, dopamine, opioid peptides, schizophrenia

Background: Polycystic Ovary Syndrome (PCOS), the ubiquitous reproductive disorder, has been documented as highly prevalent (6-9%) in India. 10% of women globally are predicted to have the disease. The highly mutable endocrinopathy, with differential clinical criteria for each diagnosis of PCOS, can mask the severity of the syndrome by influencing the incidence and occurrence of PCOS., Area Covered: When there is a solid theoretical hypothesis between the neuroendocrine origin and ovarian origin of PCOS, recent evidence supports the neuroendocrine derivation of the pathology. It is considered of neuroendocrine basis - as it controls the ovarian axis and acts as a delicate target because it possesses receptors for various gonadal hormones, neurotransmitters & neuropeptides. Can these neuroendocrine alterations, variations in central brain circuits, and neuropeptide dysregulation be the tie that would link the pathophysiology of the disorder, the occurrence of all the 1˚ and 2˚ symptoms like polycystic ovaries, hyperandrogenism, obesity, insulin resistance, etc., in PCOS?, Conclusion: This review anticipates providing a comprehensive overview of how neuropeptides such as Kisspeptin, Neurokinin B, Dynorphin A, β-Endorphin, Nesfatin, Neuropeptide Y, Phoenixin, Leptin, Ghrelin, Orexin, and Neudesin influence PCOS, the understanding of which may help to establish potential drug candidates against precise targets in these central circuits., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this study, circulating β-endorphin, ACTH and cortisol concentrations were chosen as physiological markers of the hypothalamic-pituitary-adrenal (HPA) stress-related response in Therapeutic Riding Horses (TRHs). The aim of this research was to investigate HPA axis hormonal response in TRHs and check the effects of different kind of riders (mentally-impaired and able-minded riders). The main hypothesis was that, in TRHs, the HPA axis reaction would be less responsive to mentally-impaired than to able-minded riders, due to increasing levels of horse control by the able-minded riders. 6 TRHs were randomly ridden in the same setting by 2 groups of riders, adult mentally-impaired riders (Treatment Group A) and able-minded adult riders (Treatment Group B). Both groups consisted of inexperienced riders. Each rider rode 2 times a week for 6 consecutive weeks. The horses performed the same gaits and exercises at all sessions, with both Treatment Group A and Treatment Group B riders. All hormones' concentrations were determined on a resting day (baseline, T0), before the session (T1), and at 5 min (T2) and 30 min (T3) after each session. Statistical analysis showed significant effects of the different Treatment Groups on the cortisol concentrations only, with lower cortisol concentrations both at T2 and at T3 in Treatment Group A than in Treatment Group B. Related to changes over the sampling time, ccortisol concentrations in horses were significantly higher at T1 than at T0 in Treatment Group A, and at T1, T2 and T3 than at T0, in Treatment Group B. ACTH concentrations were significantly higher at T1, T2 and T3 than at T0, only in Treatment Group B. β-endorphin concentrations at T3 were significantly higher than at T0, only in Treatment Group B. Results showed differences in the TRHs' stress levels between rider groups, with significantly lower cortisol concentrations in Treatment Group A than in Treatment Group B. Thus, although sessions' workload stress was equivalent, the minor response of HPA axis could be related to different effects of horse-human interaction. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the regulation of pain hypersensitivity induced by the spinal synaptic transmission mechanisms underlying interleukin (IL)‐10 and glucagon‐like peptide 1 receptor (GLP‐1R) agonist exenatide‐induced pain anti‐hypersensitivity in neuropathic rats through spinal nerve ligations. Methods: Neuropathic pain model was established by spinal nerve ligation of L5/L6 and verified by electrophysiological recording and immunofluorescence staining. Microglial expression of β‐endorphin through autocrine IL‐10‐ and exenatide‐induced inhibition of glutamatergic transmission were performed by behavioral tests coupled with whole‐cell recording of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) through application of endogenous and exogenous IL‐10 and β‐endorphin. Results: Intrathecal injections of IL‐10, exenatide, and the μ‐opioid receptor (MOR) agonists β‐endorphin and DAMGO inhibited thermal hyperalgesia and mechanical allodynia in neuropathic rats. Whole‐cell recordings of bath application of exenatide, IL‐10, and β‐endorphin showed similarly suppressed enhanced frequency and amplitude of the mEPSCs in the spinal dorsal horn neurons of laminae II, but did not reduce the frequency and amplitude of mIPSCs in neuropathic rats. The inhibitory effects of IL‐10 and exenatide on pain hypersensitive behaviors and spinal synaptic plasticity were totally blocked by pretreatment of IL‐10 antibody, β‐endorphin antiserum, and MOR antagonist CTAP. In addition, the microglial metabolic inhibitor minocycline blocked the inhibitory effects of IL‐10 and exenatide but not β‐endorphin on spinal synaptic plasticity. Conclusion: This suggests that spinal microglial expression of β‐endorphin mediates IL‐10‐ and exenatide‐induced inhibition of glutamatergic transmission and pain hypersensitivity via presynaptic and postsynaptic MORs in spinal dorsal horn. [ABSTRACT FROM AUTHOR]

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

Endorphins are endogenous peptides that play a role in the regulation of pain, behavior, neuroendocrine and autonomic functions. In our study, we aimed to investigate the role of β endorphins in these effects of midazolam and dexmedetomidine. In this experimental study, 36 rats were divided into 6 groups. Group 1: (control) (n=6): An average of 100-150μl CSF samples were obtained after general anesthesia was achieved. An intracardiac 3-4ml blood sample was then taken. Group 2: (sham) (n=6): intraperitoneal 1 mL saline was administered. For all other groups after general anesthesia; Group 3: (midazolam-1) (n=6): intraperitoneal 4mg/kg midazolam was administered. Group 4: (midazolam-2) (n=6): 12mg/kg midazolam was administered intraperitoneally. Group 5: (Dexmedetomidine-1) (n=6): Dexmedetomidine 50µg/kg was administered intraperitoneally. Group 6: (Dexmedetomidine-2) (n=6): Dexmedetomidine 150 µg/kg was administered intraperitoneally. CSF and plasma samples were taken with the same method. All samples were stored at -80 °C. No statistically significant difference was found between the levels of rat CSF β-endorphin. However, when the plasma ß-endorphin levels of rats were evaluated, there was a statistically significant difference between the groups. No difference was found between the levels of plasma ß-endorphin in the patients who received midazolam, while plasma ß-endorphin levels of 50 µg/kg with dexmedetomidine were found to be lower than the control group. However, the values of the 150 µg/kg dexmedetomidine group did not support this result. Different findings from both this study and in vitro and human studies; the number of subjects, the use of different drug doses, the differences in measurement times, the absence of control groups may be due to methodological differences, and more research is needed. [ABSTRACT FROM AUTHOR]

Occurrence of coronary artery disease in combination with anxiety-depressive disorders is common in clinical practice. In such patients, affective disorders significantly may cause progression of atherosclerotic processes, thus complicating the course of cardiac pathology and prognosis. Distinct markers of immune inflammation, first of all, cytokines are of particular importance for the pro-atherogenic effects in atherosclerotic foci. Endogenous opiate peptides are considered the main regulators of these processes at the neuroimmune level. Their role for stabilization of cytokine levels in evolving inflammation in atherosclerotic plaque, and during adaptation of heart muscle to stressful effects was previously shown. Despite reliable data on the role of immune inflammatory markers in atherogenesis, the validity of the regulatory role of opiate peptides in this process, questions still exist about the effects of affective disorders upon neuropeptide-cytokine status of the immune system in the patients with chronic ischemic heart disease (IHD). Another issue concerns the ranges of these changes in painful and painless forms of myocardial ischemia.Therefore, the purpose of our study was to assess the impact of severity of anxiety-depressive disorders upon the neuropeptide-cytokine status of immune system in patients with various clinical variants of chronic IHD, as well as comparisons of these changes expressed in painlul and painless myocardial ischemia.Appropriate groups were formed, then being divided into subgroups, according to the percentage of painful and painless episodes of angina pectoris: Group 1 (n = 36) included patients with chronic coronary artery disease occurring and moderate-grade anxiety/depression; Group 2 (n = 34) consisted of patients with chronic coronary artery disease and mild anxiety-depressive disorders; Group 3 (n = 20) included patients with chronic coronary artery disease without anxiety and depressive disorders; Group 4 (n = 22) represented controls (healthy persons). As based on presence of painful and painless episodes of stenocardia, the following subgroups were specified: in the 1 st group of patients, painful form of IHD was detected in 44% of cases (n = 17); painless form of IHD was detected in 56% of patients (n = 19); in the 2 nd group of patients, painful form of IHD is in 52% of the examined persons (n = 18), painless form of IHD was revealed in 48% of cases (n = 16); in the 3 rd group, the painful form of IHD was confirmed in 37% of patients (n = 8), painless form of IHD was observed in 63% of patients (n = 12). In all these groups, the following parameters were evaluated: the state of psychophysiological status determined by psychological testing, the levels of vegetative regulation (β-endorphin), the function of cardiovascular system (SMECG), and the levels of peripheral blood TNFα, IL-1β, IL-6 and IL-4, IL-10 were also measured.As based on the data of clinical and laboratory examination, we have suggested that, in the patients with chronic IHD, anxiety and depressive disorders exert a direct pathological effect on the neuropeptide-cytokine status of immune system expressed as suppression of β-endorphin, increased level of pro-inflammatory cytokines and a decrease in anti-inflammatory factors. Meanwhile, these changes are especially pronounced in the patients with painless myocardial ischemia.

Abstract Objectives Prurigo is a treatment‐resistant inflammatory disease of unknown etiology. Persistent and severe itch is a major and important clinical symptom, but pathological mechanisms and/or actual mediators for itch in prurigo remain to be defined. Methods We investigated blood levels of β‐endorphin, dynorphin A, and autotaxin in adult patients with prurigo (n = 18), including prurigo nodularis, prurigo chronica multiformis, and other forms. Patients with hemodialysis, hepatic dysfunction, and pregnancy were excluded. Immunofluorescence staining for β‐endorphin and autotaxin in lesional skin was also performed. In addition, β‐endorphin and autotaxin synthesis of cultured epidermal keratinocytes in response to several cytokine stimulation was assessed in vitro. Results Blood levels of β‐endorphin were higher in patients with prurigo than in control subjects (n = 20), while dynorphin A levels were comparable in the two groups. Blood autotaxin levels also were increased in patients with prurigo compared to control subjects. On the one hand, epidermal expression of β‐endorphin was increased in skin lesions of prurigo chronica multiformis, but not in prurigo nodularis. On the other hand, enhanced expression of autotaxin was observed in the epidermis in both prurigo nodularis and prurigo chronica multiformis. In vitro studies showed that β‐endorphin‐expressing epidermal keratinocytes increased following stimulation with TNF‐α, interleukin‐31, and/or IFN‐γ. Autotaxin was also detected in the cytoplasm of cultured epidermal keratinocytes. The fraction of autotaxin‐expressing cells increased when stimulated with TNF‐α and/or interleukin‐31. Conclusions Imbalance of opioid receptor signals and/or the autotaxin‐lysophosphatidic acid axis may contribute, at least in part, to the pathogenesis and intractable pruritus in some of the patients with prurigo.