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Annual Review of Neuroscience Jul 2018Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and... (Review)
Review
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
Topics: Analgesics, Opioid; Animals; Humans; Pain; Pain Perception; Receptors, G-Protein-Coupled
PubMed: 29852083
DOI: 10.1146/annurev-neuro-080317-061522 -
Cell Jan 2023Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid...
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
Topics: Humans; Analgesics, Opioid; Opioid Peptides; Receptors, Opioid, mu; Receptors, Opioid
PubMed: 36638794
DOI: 10.1016/j.cell.2022.12.026 -
Seminars in Immunopathology May 2018The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and... (Review)
Review
The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein (CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation. The activation of MrgprX1 degranulates mast cells to communicate with sensory nerve and cutaneous cells for developing neurogenic inflammation. Mrgprs and transient receptor potential vanilloid 4 (TRPV4) are crucial for the generation of skin diseases like rosacea, while SP, CGRP, somatostatin, β-endorphin, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) can modulate the immune system during psoriasis development. The increased level of SP, in atopic dermatitis, induces the release of interferon (IFN)-γ, interleukin (IL)-4, tumor necrosis factor (TNF)-α, and IL-10 from the peripheral blood mononuclear leukocytes. We are finally starting to understand the intricate connections between the skin neurons and resident skin cells and how their interaction can be key to controlling inflammation and from there the pathogenesis of diseases like atopic dermatitis, psoriasis, and rosacea.
Topics: Animals; Humans; Neurogenic Inflammation; Neuropeptides; Skin; Skin Diseases
PubMed: 29713744
DOI: 10.1007/s00281-018-0675-z -
International Journal of Molecular... Dec 2020β-Endorphins are peptides that exert a wide variety of effects throughout the body. Produced through the cleavage pro-opiomelanocortin (POMC), β-endorphins are the... (Review)
Review
β-Endorphins are peptides that exert a wide variety of effects throughout the body. Produced through the cleavage pro-opiomelanocortin (POMC), β-endorphins are the primarily agonist of mu opioid receptors, which can be found throughout the body, brain, and cells of the immune system that regulate a diverse set of systems. As an agonist of the body's opioid receptors, β-endorphins are most noted for their potent analgesic effects, but they also have their involvement in reward-centric and homeostasis-restoring behaviors, among other effects. These effects have implicated the peptide in psychiatric and neurodegenerative disorders, making it a research target of interest. This review briefly summarizes the basics of endorphin function, goes over the behaviors and regulatory pathways it governs, and examines the variability of β-endorphin levels observed between normal and disease/disorder affected individuals.
Topics: Animals; Behavior; Behavior, Animal; Brain; Energy Metabolism; Humans; Inflammation; Stress, Physiological; beta-Endorphin
PubMed: 33396962
DOI: 10.3390/ijms22010338 -
The Journal of Headache and Pain Sep 2018There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain... (Review)
Review
BACKGROUND
There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain conditions, including. However, what exact role exercise plays in migraine prevention is unclear. Here, we review the associations between physical exercise and migraine from an epidemiological, therapeutical and pathophysiological perspective.
METHODS
The review was based on a primary literature search on the PubMed using the search terms "migraine and exercise".
RESULTS
Low levels of physical exercise and high frequency of migraine has been reported in several large population-based studies. In experimental studies exercise has been reported as a trigger factor for migraine as well as migraine prophylaxis. Possible mechanisms for how exercise may trigger migraine attacks, include acute release of neuropeptides such as calcitonin gene-related peptide or alternation of hypocretin or lactate metabolism. Mechanisms for migraine prevention by exercise may include increased beta-endorphin, endocannabinoid and brain-derived neurotrophic factor levers in plasma after exercise.
CONCLUSION
In conclusion, it seems that although exercise can trigger migraine attacks, regular exercise may have prophylactic effect on migraine frequency. This is most likely due to an altered migraine triggering threshold in persons who exercise regularly. However, the frequency and intensity of exercise that is required is still an open question, which should be addressed in future studies to delineate an evidence-based exercise program to prevent migraine in sufferers.
Topics: Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Endocannabinoids; Exercise; Exercise Therapy; Humans; Migraine Disorders; Orexins
PubMed: 30203180
DOI: 10.1186/s10194-018-0902-y -
Neuropharmacology Jun 2020Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and... (Review)
Review
Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions. This article is part of the special issue on Neuropeptides.
Topics: Affect; Amygdala; Animals; Chronic Pain; Corticotropin-Releasing Hormone; Emotions; Humans; Neuropeptides; Neurophysins; Oxytocin; Protein Precursors; Vasopressins
PubMed: 32188569
DOI: 10.1016/j.neuropharm.2020.108052 -
Neuropharmacology Aug 2020The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid... (Review)
Review
The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid receptors throughout the body. These receptors respond to endogenous opioid peptides that are expressed as polypeptide hormones that are processed by proteolytic cleavage. Endogenous opioids are expressed throughout the peripheral and central nervous system and regulate many different neuronal circuits and functions. One of the key functions of endogenous opioid peptides is to modulate our responses to pain. This review will focus on the descending pain modulatory circuit which consists of the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM). RVM projections modulate incoming nociceptive afferents at the level of the spinal cord. Stimulation within either the PAG or RVM results in analgesia and this circuit has been studied in detail in terms of the actions of exogenous opioids, such as morphine and fentanyl. Further emphasis on understanding the complex regulation of endogenous opioids will help to make rational decisions with regard to the use of opioids for pain. We also include a discussion of the actions of endogenous opioids in the amygdala, an upstream brain structure that has reciprocal connections to the PAG that contribute to the brain's response to pain.
Topics: Amygdala; Animals; Humans; Opioid Peptides; Pain; Pain Management; Pain Perception; Periaqueductal Gray; Receptors, Opioid
PubMed: 32422213
DOI: 10.1016/j.neuropharm.2020.108131 -
Cell Metabolism Feb 2021Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and...
Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPR) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPR and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.
Topics: Animals; Cell Line, Tumor; Energy Metabolism; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria; Neurons; Physical Conditioning, Animal; Pro-Opiomelanocortin
PubMed: 33535098
DOI: 10.1016/j.cmet.2021.01.003 -
The Cochrane Database of Systematic... Jul 2019Polycystic ovarian syndrome (PCOS) is characterised by the clinical signs of oligo-amenorrhoea, infertility and hirsutism. Conventional treatment of PCOS includes a...
BACKGROUND
Polycystic ovarian syndrome (PCOS) is characterised by the clinical signs of oligo-amenorrhoea, infertility and hirsutism. Conventional treatment of PCOS includes a range of oral pharmacological agents, lifestyle changes and surgical modalities. Beta-endorphin is present in the follicular fluid of both normal and polycystic ovaries. It was demonstrated that the beta-endorphin levels in ovarian follicular fluid of otherwise healthy women who were undergoing ovulation were much higher than the levels measured in plasma. Given that acupuncture impacts on beta-endorphin production, which may affect gonadotropin-releasing hormone (GnRH) secretion, it is postulated that acupuncture may have a role in ovulation induction via increased beta-endorphin production effecting GnRH secretion. This is an update of our previous review published in 2016.
OBJECTIVES
To assess the effectiveness and safety of acupuncture treatment for oligo/anovulatory women with polycystic ovarian syndrome (PCOS) for both fertility and symptom control.
SEARCH METHODS
We identified relevant studies from databases including the Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CNKI, CBM and VIP. We also searched trial registries and reference lists from relevant papers. CENTRAL, MEDLINE, Embase, PsycINFO, CNKI and VIP searches are current to May 2018. CBM database search is to November 2015.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that studied the efficacy of acupuncture treatment for oligo/anovulatory women with PCOS. We excluded quasi- or pseudo-RCTs.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the studies, extracted data and assessed risk of bias. We calculated risk ratios (RR), mean difference (MD), standardised mean difference (SMD) and 95% confidence intervals (CIs). Primary outcomes were live birth rate, multiple pregnancy rate and ovulation rate, and secondary outcomes were clinical pregnancy rate, restored regular menstruation period, miscarriage rate and adverse events. We assessed the quality of the evidence using GRADE methods.
MAIN RESULTS
We included eight RCTs with 1546 women. Five RCTs were included in our previous review and three new RCTs were added in this update of the review. They compared true acupuncture versus sham acupuncture (three RCTs), true acupuncture versus relaxation (one RCT), true acupuncture versus clomiphene (one RCT), low-frequency electroacupuncture versus physical exercise or no intervention (one RCT) and true acupuncture versus Diane-35 (two RCTs). Studies that compared true acupuncture versus Diane-35 did not measure fertility outcomes as they were focused on symptom control.Seven of the studies were at high risk of bias in at least one domain.For true acupuncture versus sham acupuncture, we could not exclude clinically relevant differences in live birth (RR 0.97, 95% CI 0.76 to 1.24; 1 RCT, 926 women; low-quality evidence); multiple pregnancy rate (RR 0.89, 95% CI 0.33 to 2.45; 1 RCT, 926 women; low-quality evidence); ovulation rate (SMD 0.02, 95% CI -0.15 to 0.19, I = 0%; 2 RCTs, 1010 women; low-quality evidence); clinical pregnancy rate (RR 1.03, 95% CI 0.82 to 1.29; I = 0%; 3 RCTs, 1117 women; low-quality evidence) and miscarriage rate (RR 1.10, 95% CI 0.77 to 1.56; 1 RCT, 926 women; low-quality evidence).Number of intermenstrual days may have improved in participants receiving true acupuncture compared to sham acupuncture (MD -312.09 days, 95% CI -344.59 to -279.59; 1 RCT, 141 women; low-quality evidence).True acupuncture probably worsens adverse events compared to sham acupuncture (RR 1.16, 95% CI 1.02 to 1.31; I = 0%; 3 RCTs, 1230 women; moderate-quality evidence).No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes.We were uncertain whether acupuncture improved ovulation rate (measured by ultrasound three months post treatment) compared to relaxation (MD 0.35, 95% CI 0.14 to 0.56; 1 RCT, 28 women; very low-quality evidence) or Diane-35 (RR 1.45, 95% CI 0.87 to 2.42; 1 RCT, 58 women; very low-quality evidence).Overall evidence ranged from very low quality to moderate quality. The main limitations were failure to report important clinical outcomes and very serious imprecision.
AUTHORS' CONCLUSIONS
For true acupuncture versus sham acupuncture we cannot exclude clinically relevant differences in live birth rate, multiple pregnancy rate, ovulation rate, clinical pregnancy rate or miscarriage. Number of intermenstrual days may improve in participants receiving true acupuncture compared to sham acupuncture. True acupuncture probably worsens adverse events compared to sham acupuncture.No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes as the women in these trials did not seek fertility.We are uncertain whether acupuncture improves ovulation rate (measured by ultrasound three months post treatment) compared to relaxation or Diane-35. The other comparisons did not report on this outcome.Adverse events were recorded in the acupuncture group for the comparisons physical exercise or no intervention, clomiphene and Diane-35. These included dizziness, nausea and subcutaneous haematoma. Evidence was very low quality with very wide CIs and very low event rates.There are only a limited number of RCTs in this area, limiting our ability to determine effectiveness of acupuncture for PCOS.
Topics: Abortion, Spontaneous; Acupuncture Therapy; Cyproterone Acetate; Drug Combinations; Ethinyl Estradiol; Female; Humans; Infertility, Female; Menstruation; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic
PubMed: 31264709
DOI: 10.1002/14651858.CD007689.pub4 -
JBRA Assisted Reproduction Jan 2019Primary dysmenorrhea is a painful uterine contraction caused by endometrial laceration. Drug therapies and complementary medicine have been used to treat dysmenorrhea....
OBJECTIVES
Primary dysmenorrhea is a painful uterine contraction caused by endometrial laceration. Drug therapies and complementary medicine have been used to treat dysmenorrhea. The aim of this study was to investigate and offer an updated perspective on the treatments for dysmenorrhea.
METHODS
The present study was conducted in accordance with the PRISMA checklist for systematic reviews and meta-analyses. The required information was collected based on searches for the following keywords: treatment, primary dysmenorrhea, medicinal plants, chemical drugs, and herbs. Searches were performed on databases Pubmed, Web of Sciences, Scopus, Iran medex, and SID by March 2018 to find literature in the English and Persian languages on this subject without a time limit.
RESULTS
This review included 17 papers, 10 of which on complementary medicine, three on drug therapies, and four on acupuncture and acupressure. The largest and smallest samples had 303 and 24 patients, respectively. Length of treatment ranged from one to six months and the measures most commonly used in the studies were the visual analogue scale and clinical efficacy. Reported complications included gastrointestinal events, nausea, vomiting, diarrhea, abdominal pain, and liver and kidney disorders.
CONCLUSION
Medicinal plants, drugs, and acupressure seem to suppress pain by reducing the level of prostaglandins, mediating nitric oxide, increasing beta-endorphin levels, blocking the calcium channel, and enhancing circulatory flow through the uterine pathway. Further trials are required to confirm the benefits of the procedures described and ensure the absence of complications.
Topics: Acupressure; Acupuncture Therapy; Complementary Therapies; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Dysmenorrhea; Female; Gynecology; Humans; Treatment Outcome
PubMed: 30521155
DOI: 10.5935/1518-0557.20180083