Endogenous Opioid Peptides Research Articles

THE USE OF PHYSIOTHERAPY IN PATIENTS WITH HEARING IMPAIRMENT AND EAR NOISE

Damage to the inner ear can be a consequence of both acute and chronic diseases: infectious diseases, poisoning, stress, injuries, diseases of the cardiovascular system and many other conditions. The purpose of this work was to study the effectiveness of a new complex method of treating SNHL on the audiotone device. Electrostimulation has a positive effect on the peripheral structures of the auditory analyzer, on metabolic processes and the state of cerebral hemodynamics associated with the release of biologically active substances, endogenous opioid peptides into the bloodstream and cerebrospinal fluid. This method of treatment was used in 40 patients with chronic sensorineural hearing loss, who were under our supervision for 6 months. After the course of treatment, noise stopped in 24 patients, the intensity of noise decreased in 12 patients, the nature of noise changed, and 5 patients showed an improvement in hearing acuity by 10 Db and speech intelligibility. The obtained data indicates the effectiveness and expediency of using a complex method of treatment on the "audioton" device for CSNHL and recommends it as an independent method of treating ear noise.

Effects of lamb sex and ewe parity on suckling-related neonatal behaviors and weaning weight of small-tailed han lambs

Suckling behavior is essential for the growth, health, and welfare of the lamb. The factors that influence the suckling-related behavior varied across breeds, and they remain unclear in Small-tailed Han lamb. This study aims to investigate the effects of ewe parity, lamb sex, and birth order on the suckling-related behaviors of Small-tailed Han lamb. The neonatal behaviors of 36 lambs were observed during the first week after birth using focal-animal sampling methods, and the levels of cholecystokinin (CCK), endogenous opioid peptides and growth hormone (GH) were measured with ELISA methods before weaning. Results showed that male lambs began standing and suckling behaviors earlier than female lambs, and the duration of each suckling bout was longer in male lambs (P < 0.05). Lambs born to multiparous ewes more frequently suckled and attempted to stand earlier than lambs from primiparous ewes (P < 0.05). The weaning weights of male lambs and lambs from multiparous ewes were heavier, and the serum levels of CCK, opioid peptides, and GH were sometimes higher in these lambs before weaning (P < 0.05). Meanwhile, lamb birth order has no significant effect on the suckling-related behaviors of lambs (P > 0.05). In addition, the suckling-related behaviors of male lamb and lambs born to multiparous ewes were found to strongly correlate with each other. In conclusion, lamb sex and ewe parity could affect the suckling-related behaviors and weaning weights of Small-tailed Han lambs. Moreover, male lambs and lambs born to multiparous ewes seemed to have better suckling-related behaviors. Many of these behaviors were highly connected with one another. These phenomena may be related to the higher serum levels of CCK, opioid peptides, and GH. The effects of lamb sex on suckling-related behaviors were different from those of other breeds in previous research. The male lambs were observed to initiate sucking-related behaviors earlier in this study. Our findings will also help in extensively understanding the variability in the effects of these factors on suckling-related behavior across sheep breeds.

Opioid toxicity: histamine, hypersensitivity, and MRGPRX2.

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.

Ligand recognition and allosteric modulation of the human MRGPRX1 receptor.

The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.

Endogenous opioid systems alterations in pain and opioid use disorder.

Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids-primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies.

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system.

The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1β, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 μg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.

Effects Of Floatation Therapy On Endogenous Opioid Peptides After Resistance Exercise In Men

Effects Of Floatation Therapy On Endogenous Opioid Peptides After Resistance Exercise In Men

Abstract 106: In Utero Morphine Exposure Dysregulates The Endogenous Opioid System (EOS) And Increases Risk Factors For Cardiovascular Disease In The Adulthood Offspring

Chronic opioid exposure and opioid use disorder are associated with nearly a 2-fold increased risk of CVD and 16% increase in coronary artery disease. Opioid abuse during pregnancy increases 5 fold the incidence of neonatal opioid withdrawal syndrome (NOWS) and is associated with low birth weight; however, the effect of OUD among pregnant women on their offspring health is understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during the whole pregnancy are smaller and display high blood pressure. This study aimed to investigate the potential underlying mechanisms associated with increased blood pressure in MOR- exposed offspring. Sprague Dawley dams were treated with escalating doses of MOR (5-20 mg/kg/day, s.c) or saline (VEH) from gestational day 1 to 18, and pups were weaned on standard diet. Lipid profile was assessed as a risk factor for coronary artery disease using FPLC. MOR exposed offspring showed increased LDL (F-MOR vs. VEH ~2 fold; M-MOR vs. VEH ~1.5 fold mg/dL; n=6-8, p&lt;0.05). Leptin levels, normalized to body fat, were not different between groups (F-MOR 219.8±35 vs F-VEH 181.4±15.8 pg/g fat; M-MOR 207.2±26.7 vs M-VEH 200.3±23.3 pg/g fat, n=7-8). Although proteinuria was not different in MOR exposed rats vs. VEH (F-MOR 4.6±0.8 vs F-VEH 5.5±1mg/ml; M-MOR 29.1±1.4 vs M-VEH 37.5±2.95 mg/mL; n=7-8), creatinine clearance was reduced in MOR-exposed males but not females (M-MOR 0.51±0.1 vs M-VEH 0.87±0.3 mL/min, n=7-8). MOR-exposed offspring showed a greater reduction in the pressor response to mecamylamine (F-MOR -46.25±6 vs F-VEH -18.3±1.3, M-MOR -50.5±0.28 vs M-VEH -25±5.1 delta mmHg, p&lt;0.05). Proenkephalin, an endogenous opioid peptide that has been shown to inhibit the beta adrenergic receptor signaling, showed a ~3-fold reduction in heart and a ~7.5-fold reduction in the kidney cortex and outer medulla mRNA expression vs. VEH (-2ddCt, n=6-8, p&lt;0.05). Maternal MOR exposure increases the sympathetic tone, which could be associated with increased sympathetic outflow to the kidney and the heart. Reduced proenkephalin could be involved in potential crosstalk between adrenergic and opioid receptor signaling exacerbating the actions of catecholamines.

Opioidergic pathways and kisspeptin in the regulation of female reproduction in mammals.

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.

The role of enkephalinergic systems in substance use disorders.

Enkephalin, an endogenous opioid peptide, is highly expressed in the reward pathway and may modulate neurotransmission to regulate reward-related behaviors, such as drug-taking and drug-seeking behaviors. Drugs of abuse also directly increase enkephalin in this pathway, yet it is unknown whether or not changes in the enkephalinergic system after drug administration mediate any specific behaviors. The use of animal models of substance use disorders (SUDs) concurrently with pharmacological, genetic, and molecular tools has allowed researchers to directly investigate the role of enkephalin in promoting these behaviors. In this review, we explore neurochemical mechanisms by which enkephalin levels and enkephalin-mediated signaling are altered by drug administration and interrogate the contribution of enkephalin systems to SUDs. Studies manipulating the receptors that enkephalin targets (e.g., mu and delta opioid receptors mainly) implicate the endogenous opioid peptide in drug-induced neuroadaptations and reward-related behaviors; however, further studies will need to confirm the role of enkephalin directly. Overall, these findings suggest that the enkephalinergic system is involved in multiple aspects of SUDs, such as the primary reinforcing properties of drugs, conditioned reinforcing effects, and sensitization. The idea of dopaminergic-opioidergic interactions in these behaviors remains relatively novel and warrants further research. Continuing work to elucidate the role of enkephalin in mediating neurotransmission in reward circuitry driving behaviors related to SUDs remains crucial.

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression.

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-like-like 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

Mu-opioid receptor-dependent transformation of respiratory motor pattern in neonates in vitro.

Endogenous opioid peptides activating mu-opioid receptors (MORs) are part of an intricate neuromodulatory system that coordinates and optimizes respiratory motor output to maintain blood-gas homeostasis. MOR activation is typically associated with respiratory depression but also has excitatory effects on breathing and respiratory neurons. We hypothesized that low level MOR activation induces excitatory effects on the respiratory motor pattern. Thus, low concentrations of an MOR agonist drug (DAMGO, 10–200 nM) were bath-applied to neonatal rat brainstem-spinal cord preparations while recording inspiratory-related motor output on cervical spinal roots (C4-C5). Bath-applied DAMGO (50–200 nM) increased inspiratory motor burst amplitude by 40–60% during (and shortly following) drug application with decreased burst frequency and minute activity. Reciprocal changes in inspiratory burst amplitude and frequency were balanced such that 20 min after DAMGO (50–200 nM) application, minute activity was unaltered compared to pre-DAMGO levels. The DAMGO-induced inspiratory burst amplitude increase did not require crossed cervical spinal pathways, was expressed on thoracic ventral spinal roots (T4-T8) and remained unaltered by riluzole pretreatment (blocks persistent sodium currents associated with gasping). Split-bath experiments showed that the inspiratory burst amplitude increase was induced only when DAMGO was bath-applied to the brainstem and not the spinal cord. Thus, MOR activation in neonates induces a respiratory burst amplitude increase via brainstem-specific mechanisms. The burst amplitude increase counteracts the expected MOR-dependent frequency depression and may represent a new mechanism by which MOR activation influences respiratory motor output.

Descending control of nociception in insects?

Modulation of nociception allows animals to optimize chances of survival by adapting their behaviour in different contexts. In mammals, this is executed by neurons from the brain and is referred to as the descending control of nociception. Whether insects have such control, or the neural circuits allowing it, has rarely been explored. Based on behavioural, neuroscientific and molecular evidence, we argue that insects probably have descending controls for nociception. Behavioural work shows that insects can modulate nocifensive behaviour. Such modulation is at least in part controlled by the central nervous system since the information mediating such prioritization is processed by the brain. Central nervous system control of nociception is further supported by neuroanatomical and neurobiological evidence showing that the insect brain can facilitate or suppress nocifensive behaviour, and by molecular studies revealing pathways involved in the inhibition of nocifensive behaviour both peripherally and centrally. Insects lack the endogenous opioid peptides and their receptors that contribute to mammalian descending nociception controls, so we discuss likely alternative molecular mechanisms for the insect descending nociception controls. We discuss what the existence of descending control of nociception in insects may reveal about pain perception in insects and finally consider the ethical implications of these novel findings.

Delta Opioid Receptors and Enkephalinergic Signaling within Locus Coeruleus Promote Stress Resilience.

The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. LC is also innervated by several structures that synthesize and release the endogenous opioid peptide enkephalin onto LC upon stressor termination. While the role of CRF neurotransmission within LC in mediating anxiety-like behavior and the behavioral response to stress has been well characterized, the role of enkephalinergic signaling at LC-expressed δ-opioid receptors has been comparatively understudied. We have previously shown that acute stressor exposure increases LC activity and anxiety-like behavior for at least one week. Here, we extend these findings by showing that these effects may be mediated at least in part through stress-induced downregulation of DORs within LC. Furthermore, overexpression of DORs in LC blocks the effects of stress on both LC firing properties and anxiety-like behavior. In addition, intra-LC infusions of enkephalin blocked stress-induced freezing behavior and promoted conditioned place preference. These findings indicate that enkephalinergic neurotransmission at DORs within LC is an important component of the behavioral response to stress and may drive reward-related behavior as well.

Research progress of neuroendocrine mechanism of acupuncture for dyspnea

The paper reviewed the relevant studies on dyspnea treated with acupuncture over the past 20 years, as well as the underlying neuroendocrine mechanism from the perspective of central and peripheral vagus nerves, neurotransmitter, respiratory muscle function and anti-depression-anxiety function. It revealed that the central response area was regulated by acupuncture in treatment of dyspnea, which is similar to the area affected in acupuncture analgesia. Additionally, acupuncture generates its therapeutic effects on dyspnea through promoting the release of endogenous opioid peptides and the regulation of autonomic nerve, amygdale and hypothalamic-pituitary-adrenal axis.

Micelle-associated endomorphin-1 has ability to bind copper in the oxidation state either Cu(II) or Cu(I)

Reduction of Cu(II) to Cu(I) in an oxidizing extracellular environment is a potential risk factor for neurodegenerative diseases, because the re-oxidation of Cu(I) to Cu(II) can be coupled to generation of reactive oxygen species. However, little is known about how the brain is protected from the copper-induced oxidative stress. In the present study, interactions of the endogenous opioid peptide endomorphin-1 (EM1, Tyr-Pro-Trp-Phe-NH2) with ionic copper were investigated. EM1 cannot bind copper with ordinary metal coordination chemistry, since the chelate complex formation of EM1 with the metal ion is inhibited by the proline residue in the second position. In the presence of SDS micelles, however, a significant quenching of fluorescence of the tryptophan side chain of EM1 was observed on addition of copper ion, either Cu(II) or Cu(I). The spectral changes of the UV absorption of the tryptophan, which are diagnostic of cation–π interaction, were also brought about by addition of copper to EM1 only in the presence of micelles. The copper-induced spectral changes of both fluorescence and UV absorption disappeared upon the substitution of Tyr1 with alanine. The obtained results indicated that EM1 binds the copper ion through the π-electrons of aromatic side chains of Tyr1 and Trp3, which are in close contact each other in the micelle-associated form. The copper-catalyzed oxidation/reduction reaction process converting dopamine to neuromelanin, which involves potentially neurotoxic intermediates, is inhibited by EM1. Owing to the ability to bind both Cu(II) and Cu(I), EM1 may have the potential to suppress the copper-mediated oxidative stress in the brain. The present results suggest an antioxidative effect of EM1, distinct from its known analgesic effect.

Functional Characterization and Molecular Marker Development of the Proenkephalin as Biomarker of Food Addiction in Food Habit Domestication of Mandarin Fish (Siniperca chuatsi)

Proenkephalin (PENK), as the precursor of endogenous opioid enkephalin (ENK), is widely present in the nervous system and plays an important role in animal food addiction and rewarding behavior. In our study, we intend to study the functional characterization and molecular marker development of the penk gene related to food habit domestication of mandarin fish. We found that the penk gene of mandarin fish had three types of endogenous opioid peptide sequences. Compared with other tissues, penk mRNA was highly expressed in the whole brain. Intracerebroventricular (ICV) injection of lysine or methionine significantly increased the expression of penk mRNA. The expression of penk mRNA in the brain of mandarin fish that could be easily domesticated from eating live prey fish to artificial diets was significantly higher than those that could not. After feeding with high-carbohydrate artificial diets, the expression of penk mRNA showed no significant difference between mandarin fish with hypophagia and those that still ate normally. A total of four single nucleotide polymorphisms (SNP) loci related to easy domestication toward eating artificial diets were screened from the mandarin fish population. Additionally, the TT genotype at one of the loci was significantly correlated with the food habit domestication of mandarin fish.

Positive Allosteric Modulation of the Mu Opioid Receptor

Opioid therapeutics, such as morphine, that act at the mu‐opioid receptor (MOR) are the clinical standard for patients struggling to manage symptoms associated with pain. It is widely understood that although opioids are effective at treating pain, their use leads to the development of severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for a safer alternative to manage pain. One such alternative is to enhance the effects of the body’s endogenous opioid system by positive allosteric modulation (PAM) of MOR. A known PAM, BMS‐986122, enhances MOR agonist potency in cellular models and MOR agonist mediated antinociception in vivo. In addition, this PAM is active alone in a variety of mouse pain assays by promoting the activity of endogenous opioid peptides. Moreover, at an effective antinociceptive dose, BMS‐986122 alone produces less severe adverse effects than morphine as determined by measures of constipation, respiratory depression, and conditioned place preference. However, we do not yet know how the overall pharmacology of opioids is affected by PAMs or if all opioid drugs are equally sensitive to PAM modulation. Here we compare the ability of BMS‐986122 to enhance the action of three structurally diverse opioid drugs, morphine, methadone, and fentanyl, in an acute pain assay and in an assay examining respiratory depression using CD‐1 male and female mice. We show that BMS‐986122 increases the antinociceptive effects of the opioid therapeutics in the warm water tail withdrawal assay without promoting the ability of the drugs to lower blood oxygen levels or heart rate. Future work will assess the effects of BMS‐986122 in additional acute and chronic pain models and with a more diverse group of opioids. If additional experiments support the concept that BMS‐986122 enhances MOR‐mediated antinociception but not MOR‐mediated respiratory depression, this will validate the development of MOR‐PAMs as standalone pain medications and support the use of PAMs as opioid‐sparing drugs for the effective management of pain.

Investigation of Nociceptive Endogenous Opioid Dynamics in the Periaqueductal Gray

Opioid analgesics mimic endogenous opioid peptide function in nociceptive neural circuits by engaging mu opioid receptor (MOR) signaling, resulting in antinociception and pain relief. The ventrolateral periaqueductal gray (vlPAG) is a hub of nociceptive and endogenous opioid signaling in the brain. However, much remains unknown regarding opioid peptide release properties and the modulation of functionally distinct vlPAG MOR-expressing neurons during acute and chronic pain. Thus, the purpose of this study is to dissect the spatial and temporal activity dynamics of this opioid peptide and MOR signaling system in the vlPAG. In our initial approach to this objective, we employed a complementary set of novel adeno-associated viruses that drive expression of the genetically-encoded calcium indicator GCaMP6f selectively in MOR-positive cells, or expression of a novel fluorescent enkephalin sensor, DOR-Light. First, in freely behaving mice, our fiber photometry data demonstrated that vlPAG MOR-expressing neurons are responsive to noxious stimuli, displaying heightened nociceptive calcium transients corresponding with behavioral hyperalgesia following hindpaw injection of the inflammatory agent Complete Freund's Adjuvant (CFA). Second, viral retrograde labeling revealed several local and forebrain circuits expressing enkephalins, which innervate the vlPAG and may modulate nociception. Indeed, optogenetic activation of vlPAG enkephalinergic neurons produced antinociception in Penk-Cre mice during a ramped-temperature hotplate protocol. Finally, DOR-Light photometry recordings revealed CFA-related enhancement of enkephalin release in vlPAG during noxious hotplate exposure. We are continuing to explore our hypothesis that acute noxious and persistent inflammation conditions engage a similar nociceptive subset of vlPAG MOR neurons, which promote top-down release of enkephalins to regulate ongoing midbrain nociceptive signaling. Through precise optical excitation of different enkephalinergic circuits across the brain, we will determine neuropeptide release mechanics and subsequently control endogenous pain resolution, thereby providing foundational support for future targeted therapies that safely recruit the endogenous opioid system for chronic pain treatment. Grant support from 1F32DA055458-01 (awarded to Blake Kimmey).

Acupuncture from the perspective of evidence-based medicine - options of clinical use based on National Comprehensive Cancer Network (NCCN) guidelines.

Acupuncture is one of the oldest therapeutic methods. The traditional view of acupuncture is represented by influencing energy pathways through stimulation of specific points. The original meridian theory, which works with the assumption of normalization of the flowing energy Qi in the organism is, with increasing evidence, supplemented with information about the bio-logical impact of the use of acupuncture from the perspective of Western medicine. Specific stimulation of particular points on the body leads to the activation of hypothalamus and pituitary gland through neurotransmitters, resulting in a wide range of systemic effects. Stimulation of nerves in the muscle, which then trans-mits a signal to the spinal cord, midbrain, and hypothalamic-pituitary system, releases neurotransmitters, endogenous opioid peptides, or hormones. Stimulation of acupuncture points changes the levels of proinflammatory cytokines, including IL-1-beta, IL-6, IL-17, and TNF-alpha. Currently, according to the National Comprehensive Cancer Network (NCCN) guidelines, the following symptoms are indicated for acupuncture treatment: pain including neuropathic pain, arthralgia, and myalgia, especially in the aromatase inhibitors therapy, nausea, and vomiting, fatigue, vasomotor symptoms in women and vasomotor symptoms in men caused by androgen deprivation therapy. Acupuncture seems to be an effective and safe treatment method for many of the cancer symptoms or the side effects of cancer treatment, but, like any other treatment method, it has its indications and contraindications. This work aims to provide a comprehensive overview of the use of acupuncture in defined indications, according to current international guidelines. Thus, the therapeutic possibilities of symptomatic treatment of cancer and therapy of adverse events of oncological treatment can be extended.