Low-frequency electroacupuncture exerts antinociceptive effects through activation of POMC neural circuit induced endorphinergic input to the periaqueductal gray from the arcuate nucleus.

It has been widely recognized that electroacupuncture (EA) inducing the release of ß-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 ß-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 ß-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 ß-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 ß-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 ß-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 ß-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.

The opioid peptide ß-endorphin interferes with the pituitary-testis axis in the Mozambique tilapia Oreochromis mossambicus.

Although the involvement of ß-endorphin (ß-ERP) in vertebrate reproduction has been suggested, its role in testicular activity is not clear in fish. We describe the influence of ß-ERP on spermatogenesis in a cichlid fish in the present paper. In comparison to the control group, the administration of ß-ERP (3 µg) caused a significant increase in the number of spermatogonia-A and spermatids. Following treatment with ß-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 ß-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 ß-ERP. In contrast, the intensity of AR immunoreactivity and the percentage of LH immunolabeling were substantially increased in fish treated with 3 µg ß-ERP compared to those in the control group. These findings reveal for the first time that a low dose of ß-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 ß-ERP exerts modulatory effects at the testicular and hypophysial levels through alterations in AR expression and LH secretory activity, respectively, in teleosts.

Arsenic exposure and pruritus: Evidence from observational, interventional, and mendelian randomization studies.

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 ß-endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of ß-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 (ß = -0.98, p = 0.04). CONCLUSION: Arsenic exposure is associated with pruritus, and ß-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.

Acute Low Dose Naltrexone Increases ß-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice.

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 ß-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 ß-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 ß-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.

Systemic and Peripheral Mechanisms of Cortical Stimulation-Induced Analgesia and Refractoriness in a Rat Model of Neuropathic Pain.

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-1ß in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased ß-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 ß-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 ß-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.

Comparative Determination of Natural Antibodies for the Assessment of the Cardiovascular System and the Level of Human Difficulty.

A comparative analysis of natural antibodies to ß-endorphin, angiotensin, dopamine, serotonin, parameters of the cardiovascular system and anxiety levels was carried out for 241 athletes of various qualifications and sports. The obtained indicators of the cardiovascular system were compared with reference values. A significant increase in the level of natural antibodies to angiotensin was established for all groups of athletes. In the case of dopamine, serotonin, these differences are associated with the qualification of the athlete, for ß-endorphin, differences in the level of the indicator depending on the sport were found. A group of individuals with high levels of situational and personal anxiety was found among highly qualified athletes. An increase in blood pressure in athletes of cyclic sports and martial arts is adaptive, and in athletes of speed-strength sports it leads to a change in the walls of the myocardium. As a result of the study, the possibility of a comprehensive determination of natural antibodies and functional indicators as diagnostic markers for assessing the state of the human cardiovascular system has been shown.

The Clash of Two Epidemics: the Relationship Between Opioids and Glucose Metabolism.

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 ß-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 ß-endorphin levels. 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.

[Effect of iodine-bromine baths on stress-systems indicators in children with autism spectrum disorders]. / Vliyanie iodobromnykh vann na pokazateli stress-sistem u detei s rasstroistvami autisticheskogo spektra.

The continuous increase in the prevalence of autism spectrum disorders (ASD) in the population, the debatable nature of many aspects of etiology, pathogenesis, and treatment of these disorders justify the urgent need for the development of effective medical rehabilitation methods affecting the pathogenetic mechanisms.Exposure of children with ASD to external stimuli in excessive force often leads to the stress-systems response not corresponding to the compensation abilities of the body. OBJECTIVE: To evaluate the effect of iodine-bromine baths on stress-system indicators in children with ASD. MATERIAL AND METHODS: The study involved 74 children with ASD (F84) aged 3 to 14 years (mean age 6.23±0.37 years) included in the main group (MG). The control group (CG) consisted of 25 healthy children.The examination included detailed history taking, examination by specialists, assessment of disease severity using CARS scale, evaluation of ß-endorphin, adrenocorticotropic hormone (ACTH), and cortisol levels in blood serum by ELISA. Thirty-four (45.9%) children had a moderate autism level (total score 30-37), and 40 (54.1%) children had severe autism (total score 37-60). In the MG, there were 27 (36.5%) children with mild symptoms of hyperactivity (subgroup A) and 47 (63.5%) children with severe aggression, tantrums, and increased hyperactivity (subgroup B). All MG patients were assigned into two subgroups by randomization: Subgroup 1: 30 children with ASD received health resort treatment (HRT) without iodine-bromine baths (IB); Subgroup 2: 44 children with ASD received similar HRT and IB. RESULTS: Statistically significant increase of ß-endorphin, ACTH and cortisol levels (p<0.01, p<0.05, p<0.01, respectively) in children with ASD (compared to those in CG children) was identified. In children without hyperactivity, a moderate increase of these parameters was noted; significantly higher values were observed in children with severe hyperactivity, impulsiveness, and aggression (p<0.05, p<0.001, respectively). After treatment, there was a statistically significant increase in ß-endorphin level in subgroup 1 children who received HRT without IB, while in children of subgroups A and B (p<0.05, p<0.05, p<0.01, respectively), there was a decrease in ACTH level (p<0.05, p<0.01, p<0.001 respectively) and a trend towards a cortisol level decrease. Inclusion of IB in HRT course associated with a significant decrease of ß-endorphin level in children of subgroups A and B (p<0.001), a decrease of ACTH level (p<0.001) and cortisol (p<0.001, p<0.01, p<0.001, respectively), which resulted in vicious circle breaking and normalization of relations between stress-limiting and stress-releasing parts of pathogenesis. CONCLUSION: Most children with autism spectrum disorders showed significant increases in ß-endorphin, adrenocorticotropic hormone, and cortisol levels, indicating dysfunction between the stress-limiting and stress-releasing systems, as well as between the central and peripheral parts of the stress-releasing chain. The tonic effect of resort treatment was noted, limiting its use in children with autism spectrum disorders, increased hyperactivity, and aggression. The inclusion of iodine-bromine baths in resort treatment has a calming non-medicinal effect and can be recommended for use in children with symptoms of severe hyperactivity.

Proteolytic Cleavage of Bioactive Peptides and Protease-Activated Receptors in Acute and Post-Colitis.

The protease activity in inflammatory bowel disease (IBD) and irritable bowel syndrome has been studied extensively using synthetic fluorogenic substrates targeting specific sets of proteases. We explored activities in colonic tissue from a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model by investigating the cleavage of bioactive peptides. Pure trypsin- and elastase-like proteases on the one hand and colonic tissue from rats with TNBS-induced colitis in the acute or post-inflammatory phase on the other, were incubated with relevant peptides to identify their cleavage pattern by mass spectrometry. An increased cleavage of several peptides was observed in the colon from acute colitis rats. The tethered ligand (TL) sequences of peptides mimicking the N-terminus of protease-activated receptors (PAR) 1 and 4 were significantly unmasked by acute colitis samples and these cleavages were positively correlated with thrombin activity. Increased cleavage of ß-endorphin and disarming of the TL-sequence of the PAR3-based peptide were observed in acute colitis and linked to chymotrypsin-like activity. Increased processing of the enkephalins points to the involvement of proteases with specificities different from trypsin- or chymotrypsin-like enzymes. In conclusion, our results suggest thrombin, chymotrypsin-like proteases and a set of proteases with different specificities as potential therapeutic targets in IBD.

Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants.

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and ß-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of ß-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants.

The GLP-1 receptor herbal agonist morroniside attenuates neuropathic pain via spinal microglial expression of IL-10 and ß-endorphin.

OBJECTIVES: To assess the protective effect of the glucagon-like peptide-1 receptor (GLP-1R) agonist morroniside against neuropathic pain and its downstream mechanisms of activating microglial GLP-1R/interleukin-10 (IL-10)/ß-endorphin antinociceptive pathway. METHODS: Spinal nerve ligation-induced neuropathic pain rats were intrathecally injected with morroniside, with mechanical paw withdrawal threshold being assessed. The expression of spinal and cultured microglia IL-10 and ß-endorphin were detected with qRT-PCR. KEY FINDINGS: Morroniside alleviated mechanical allodynia in neuropathic rats, which was blocked by inhibiting or depleting microglia. In addition, neutralizing spinal IL-10 or ß-endorphin with specialized antibodies or blocking the µ-opioid receptor was able to fully reverse the morroniside-induced mechanical antiallodynia. Morroniside treatment stimulated the gene expression of IL-10 and ß-endorphin in the spinal lumbar enlargements of neuropathic rats as well as in primary cultured microglia. Furthermore, pretreatment with the IL-10 antibody blocked morroniside-stimulated ß-endorphin expression in the spinal cords of neuropathic rats and cultured primary microglia, whereas the ß-endorphin antibody failed to affect morroniside-stimulated gene expression of IL-10. CONCLUSIONS: These results reveal that morroniside produces therapeutic effects in neuropathy through spinal microglial expression of IL-10 and subsequent ß-endorphin after activation of GLP-1R.

Lemairamin, isolated from the Zanthoxylum plants, alleviates pain hypersensitivity via spinal α7 nicotinic acetylcholine receptors.

Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and ß-endorphin, while lemairamin treatment induced IL-10 and ß-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-ß-endorphin antiserum or µ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/ß-endorphin pathway following α7nAChR activation.

Ameliorative effect of green odor against UVB-induced immunosuppression of contact hypersensitivity.

Ultraviolet (UV) irradiation to the eye induces photoimmunosuppression. In here, we examined the effect of green odor against immunosuppression of contact hypersensitivity in the eye induced by ultraviolet B (UVB) irradiation. Systemic immunosuppression was induced in ICR mice sensitized with 0.5% oxazolone through the skin by a single exposure to UVB. Consecutive green odor treatment significantly counteracted UVB irradiation-induced immunosuppression of the contact hypersensitivity (CHS) response. The green odor treatment increased dopamine and ß-endorphin levels in the brain and the plasma, respectively, and decreased the plasma corticosterone concentration in the oxazolone-sensitized mice after UVB irradiation to the eye, in contrast with that in acetone-treated mice (treatment negative control). Green odor prevented UVB irradiation-induced photoimmunosuppression of the CHS response by regulating the dopamine/ß-endorphin/corticosterone pathway.

A novel theory on the predictive value of variation in the ß-endorphin system on the risk and severity of PTSD.

Despite growing interest in genetic and psychosocial indicators of heightened susceptibility to posttraumatic stress disorder (PTSD), a predictive model, which explains why some individuals develop PTSD in response to life-threatening traumatic events, while others, when faced with the same or similar experiences, do not, has thus far remained out of reach. In this paper, we review the literature on gene-environment interactions in ß-endorphin system functioning with regard to PTSD and suggest that variation, both genetic and with regard to environmental stimuli, in systems which, like the ß-endorphin system, distort human perception of life-threatening traumatic experiences may account for some of the variance in resilience to the disorder. Given the role of ß-endorphin in both social connections and physical exercise, this becomes especially relevant with regard to military selection, training, and leadership processes.

Activation of GPR40 produces mechanical antiallodynia via the spinal glial interleukin-10/ß-endorphin pathway.

BACKGROUND: The G protein-coupled receptor 40 (GPR40), broadly expressed in various tissues such as the spinal cord, exerts multiple physiological functions including pain regulation. This study aimed to elucidate the mechanisms underlying GPR40 activation-induced antinociception in neuropathic pain, particularly related to the spinal glial expression of IL-10 and subsequent ß-endorphin. METHODS: Spinal nerve ligation-induced neuropathic pain model was used in this study. ß-Endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Double immunofluorescence staining of ß-endorphin with glial and neuronal cellular biomarkers was also detected in the spinal cord and cultured primary microglia, astrocytes, and neurons. RESULTS: GPR40 was expressed on microglia, astrocytes, and neurons in the spinal cords and upregulated by spinal nerve ligation. Intrathecal injection of the GPR40 agonist GW9508 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in neuropathic rats, with Emax values of 80% and 100% MPE and ED50 values of 6.7 and 5.4 µg, respectively. Its mechanical antiallodynia was blocked by the selective GPR40 antagonist GW1100 but not GPR120 antagonist AH7614. Intrathecal GW9508 significantly enhanced IL-10 and ß-endorphin immunostaining in spinal microglia and astrocytes but not in neurons. GW9508 also markedly stimulated gene and protein expression of IL-10 and ß-endorphin in cultured primary spinal microglia and astrocytes but not in neurons, originated from 1-day-old neonatal rats. The IL-10 antibody inhibited GW9508-stimulated gene expression of the ß-endorphin precursor proopiomelanocortin (POMC) but not IL-10, whereas the ß-endorphin antibody did not affect GW9508-stimulated IL-10 or POMC gene expression. GW9508 increased phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and its stimulatory effects on IL-10 and POMC expression were blocked by each MAPK isoform inhibitor. Spinal GW9508-induced mechanical antiallodynia was completely blocked by intrathecal minocycline, IL-10 neutralizing antibody, ß-endorphin antiserum, and µ-opioid receptor-preferred antagonist naloxone. CONCLUSIONS: Our results illustrate that GPR40 activation produces antinociception via the spinal glial IL-10/ß-endorphin antinociceptive pathway.

Transgenic increase in the ß-endorphin concentration in cerebrospinal fluid alleviates morphine-primed relapse behavior through the µ opioid receptor in rats.

BACKGROUND: Opioid-primed relapse is a global burden. Although current strategies have improved, optimal therapy is urgently needed. METHODS: A recombinant adenovirus (Ad-NEP) expressing ß-endorphin (ß-EP) was designed and injected intracerebroventricularly (icv) into the right lateral ventricle in rats. Spatial and temporal ß-EP expression in the lateral ventricle wall, subventricular zone and adjacent choroid plexus and the ß-EP concentration in the cerebrospinal fluid (CSF) were observed during a 21-day period. A morphine priming-induced conditioned place preference (CPP) rat model was established. The ß-EP-ir neuron counts, CSF ß-EP concentration, and CPP score, which were used to evaluate morphine-primed reinstatement following extinction, were recorded 7 days after the icv injection. Additionally, the rats were pretreated with the irreversible µ opioid receptor antagonist ß-funaltrexamine (ß-FNA) and the selective κ opioid receptor antagonist nor-binaltorphimine (nor-BNI) to identify the receptor-dependent mechanism. RESULTS: Both peak ß-EP expression in target neurons and the peak CSF ß-EP concentration occurred 7 to 8 days after Ad-NEP icv injection. The sustainable increase in the CSF ß-EP concentration was correlated with a decrease in the CPP score 7 days after the Ad-NEP icv injection. Furthermore, reinstatement was almost reversed by ß-FNA pretreatment 24 hours before the behavioral test, but nor-BNI had little effect. CONCLUSION: The increasing cerebrospinal fluid ß-endorphin concentrations showed that the therapeutic effect on opioid relapse occurred predominantly through a µ opioid receptor-dependent mechanism. The Ad-NEP adenovirus can be considered an alternative therapy for opioid relapse.

Low-intensity walking as mild medication for pressure control in prehypertensive and hypertensive subjects: how far shall we wander?

Successful prevention and treatment of hypertension depend on the appropriate combination of antihypertensive drug therapy and nondrug lifestyle modification. While most hypertension guidelines recommend moderate- to high-intensity exercise, we decided to explore a mild yet effective type of exercise to add to hypertension management, especially in populations with complications or frailty. After comparing the short-term cardiovascular effects of low-speed walking versus high-speed walking for 3 kilometers (km) (3 km/h versus 6 km/h) in young, healthy volunteers, we delivered low-speed walking (low-intensity walking, 2.5 metabolic equivalents of task, METs) as exercise therapy in 42 prehypertensive and 43 hypertensive subjects. We found that one session of 3 km low-intensity walking exerted a transient pressure-lowering effect as well as a mild negative chronotropic effect on heart rate in both the prehypertensive and hypertensive subjects; these short-term benefits on blood pressure and heart rate were accompanied by a brief increase in urine ß-endorphin output. Then we prescribed regular low-intensity walking with a target exercise dose (exercise volume) of 500-1000 METs·min/week (50-60 min/day and 5-7 times/week) in hypertensive subjects in addition to their daily activities. Regular low-intensity walking also showed mild but significant blood pressure-lowering and heart rate-reducing effects in 7 hypertensive subjects within two months. It is hypothesized that regular low-intensity exercise of the necessary dose could be taken as a pragmatic and supplementary medication for hypertension management.

Oral dehydroepiandrosterone restores ß-endorphin response to OGTT in early and late postmenopause.

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.

Blood dopamine level enhanced by caffeine in men after treadmill running.

The aim of this study was to investigate the plasma dopamine and serum serotonin levels in humans with and without caffeine (CAFF) ingestion during treadmill running exercise. Thirty male volunteers participated in the randomized experiment involving two groups: CON (n = 15, 200 mL of tap water) versus CAFF (n = 15, 3 mg/kg CAFF and 200 mL tap water). After treadmill running, the dopamine level was significantly increased in the CAFF group (P < 0.01) and was significantly higher than in the CON group (P < 0.01). Serotonin was significantly increased in both groups after treadmill running (P < 0.05). However, serotonin levels showed no significant statistical difference between the groups. Prolactin and cortisol were significantly increased in both groups after treadmill running (P < 0.01). However, there was no significant statistical difference between groups. ß-endorphin level was significantly increased in the CAFF group at after treadmill running (P < 0.01) and was significantly higher than in CON after treadmill running (P < 0.01). In conclusion, 3 mg/kg CAFF ingestion before treadmill running stimulated dopamine release without inhibiting serotonin, which may reduce central fatigue.

Physiology and Pharmacology of Positive Reinforcement.

An original concept of a two-stage mechanism of positive reinforcement is proposed. The first stage, "virtual" reinforcement, is formed in parallel with the action result acceptor when the result is still not achieved. At this stage, the importance of the planned result and the probability of its achievement are assessed. The greater are these indices, the stronger is "virtual" reinforcement. Hypothetically, the "virtual" reinforcement is mediated by dopamine release from nerve terminals in the mesencephalon. The "real" reinforcement (the second stage) occurs after achievement of the result. Probably, an important role in the mechanisms of the "real" reinforcement is given to endogenous opioids, cannabinoids, and GABA. Based on the advanced hypothesis on interaction between the central and peripheral subdivisions of the corresponding neurochemical systems, the review focuses on possibility of pharmacological intervention into the mechanisms of positive reinforcement by modifying activity of the peripheral opioid and dopamine receptors with the ligands that cannot cross blood-brain barrier.