The stimulation of myocardium repair is restricted due to the limited understanding of heart regeneration. Interestingly, endogenous opioid peptides such as dynorphins and enkephalins are suggested to support this process. However, the mechanism-whether through the stimulation of the regenerative capacity of cardiac stem cells or through effects on other cell types in the heart-is still not completely understood. Thus, a model of the spontaneous cardiomyogenic differentiation of mouse embryonic stem (mES) cells via the formation of embryoid bodies was used to describe changes in the expression and localization of opioid receptors within cells during the differentiation process and the potential of the selected opioid peptides, dynorphin A and B, and methionin-enkephalins and leucin-enkephalins, to modulate cardiomyogenic differentiation in vitro. The expressions of both κ- and δ-opioid receptors significantly increased during mES cell differentiation. Moreover, their primary colocalization with the nucleus was followed by their growing presence on the cytoplasmic membrane with increasing mES cell differentiation status. Interestingly, dynorphin B enhanced the downregulation gene expression of Oct4 characteristic of the pluripotent phenotype. Further, dynorphin B also increased cardiomyocyte-specific Nkx2.5 gene expression. However, neither dynorphin A nor methionin-enkephalins and leucin-enkephalins exhibited any significant effects on the course of mES cell differentiation. In conclusion, despite the increased expression of opioid receptors and some enhancement of mES cell differentiation by dynorphin B, the overall data do not support the notion that opioid peptides have a significant potential to promote the spontaneous cardiomyogenesis of mES cells in vitro.

• Keywords
• dynorphins, enkephalins, heart regeneration, mouse embryonic stem cells, opioid receptors,
• MeSH
• Cell Differentiation physiology   MeSH
• Myocytes, Cardiac cytology   physiology   MeSH
• Myocardium cytology   MeSH
• Mouse Embryonic Stem Cells cytology   metabolism   MeSH
• Mice MeSH
• Opioid Peptides metabolism   MeSH
• Receptors, Opioid metabolism   MeSH
• Regeneration physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Opioid Peptides MeSH
• Receptors, Opioid MeSH

Neuronal voltage-gated calcium channels play a pivotal role in the conversion of electrical signals into calcium entry into nerve endings that is required for the release of neurotransmitters. They are under the control of a number of cellular signaling pathways that serve to fine tune synaptic activities, including G-protein coupled receptors (GPCRs) and the opioid system. Besides modulating channel activity via activation of second messengers, GPCRs also physically associate with calcium channels to regulate their function and expression at the plasma membrane. In this mini review, we discuss the mechanisms by which calcium channels are regulated by classical opioid and nociceptin receptors. We highlight the importance of this regulation in the control of neuronal functions and their implication in the development of disease conditions. Finally, we present recent literature concerning the use of novel μ-opioid receptor/nociceptin receptor modulators and discuss their use as potential drug candidates for the treatment of pain.

• Keywords
• G-protein coupled receptors, Mu opioid receptor, Nociception opioid receptor, Voltage-gated calcium channels,
• MeSH
• Calcium Channel Agonists pharmacology   MeSH
• Calcium Channel Blockers pharmacology   MeSH
• Humans MeSH
• Neurons drug effects   physiology   MeSH
• Analgesics, Opioid pharmacology   MeSH
• Receptors, Opioid agonists   physiology   MeSH
• Calcium Signaling drug effects   physiology   MeSH
• Calcium Channels physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Calcium Channel Agonists MeSH
• Calcium Channel Blockers MeSH
• Analgesics, Opioid MeSH
• Receptors, Opioid MeSH
• Calcium Channels MeSH

PURPOSE: As deaths from the illicit drug poisoning crisis continue to rise in Canada, increasing the number of healthcare professionals qualified to effectively prescribe opioids could be beneficial. The willingness of family medicine residents to undertake structured training in prescribing opioids for Opioid Agonist Treatment (OAT) and pain management have not been well described. MATERIALS AND METHODS: Family medicine residents (n = 20) in British Columbia, Canada, were asked about their experience with and willingness to enrol in OAT training. Informed by the Consolidated Framework for Implementation Research, data were analysed thematically using NVivo software. RESULTS: Four themes were identified: (1) challenges to training implementation, (2) feelings and attitudes on prescribing practices, (3) helpful learning spaces and places of substance use training, and (4) recommendations for implementing training. Preparedness, exposure, and supportive learning environments for substance use education increased willingness to pursue OAT accreditation, while ineffective learning experiences, mixed feelings about opioid prescribing, and lack of protected time were the most common reasons for unwillingness. CONCLUSIONS: Protected time and a range of clinical experiences appear to facilitate residents' willingness to complete OAT and opioid training. Implementation strategies to enhance the uptake of OAT accreditation in family medicine residency must be prioritised.

• Keywords
• Training, family medicine, opioid agonist treatment, opioids, pain management,
• MeSH
• Practice Patterns, Physicians' MeSH
• Humans MeSH
• Analgesics, Opioid * therapeutic use   MeSH
• Substance-Related Disorders * drug therapy   MeSH
• Family Practice MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Canada MeSH
• Names of Substances
• Analgesics, Opioid * MeSH

The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations.

• Keywords
• addiction, chronic pain, immune cells, opioid drugs, opioid receptors, stem cells,
• MeSH
• Biomarkers MeSH
• Chronic Pain drug therapy   etiology   metabolism   MeSH
• Immune System drug effects   immunology   metabolism   MeSH
• Stem Cells drug effects   metabolism   MeSH
• Humans MeSH
• Analgesics, Opioid pharmacology   MeSH
• Receptors, Opioid genetics   metabolism   MeSH
• Gene Expression Regulation * MeSH
• Inflammation complications   etiology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• Analgesics, Opioid MeSH
• Receptors, Opioid MeSH

Integrated behavioral paradigms such as nociceptive processing coupled to anti-nociceptive responsiveness include systemically-mediated states of alertness, vigilance, motivation, and avoidance. Within a historical and cultural context, opium and its biologically active compounds, codeine and morphine, have been widely used as frontline anti-nociceptive agents. In eukaryotic cells, opiate alkaloids and opioid peptides were evolutionarily fashioned as regulatory factors in neuroimmune, vascular immune, and systemic immune communication and auto-immunoregulation. The significance of opioidergic regulation of immune function was validated by the identification of novel μ and δ opioid receptors on circulating leukocytes. The novel μ3 opioid receptor subtype has been characterized as an opioid peptide-insensitive and opiate alkaloid-selective G protein-coupled receptor (GPCR) that is functionally linked to the activation of constitutive nitric oxide synthase (cNOS). Opioid peptides stimulate granulocyte and immunocyte activation and chemotaxis via activation of a novel leukocyte δ2 receptor subtype. However, opiate alkaloid μ3 receptor agonists inhibit these same cellular activities. Opiate coupling to cNOS and subsequent production and release of mitochondrial nitric oxide (NO) suggests an evolutionary linkage to similar physiological events in prokaryotic cells. A subpopulation of immunocytes from Mytilus edulis and Leucophaea maderae and human granulocytes respond to low opioid concentrations, mediated by the adherence-promoting role of (D-Ala2-D-Met5)-enkephalinamide (DAMA), which is blocked by naloxone in a dose-dependent manner. Neutral endopeptidase 24.11 (NEP), or enkephalinase (CD10), is present on both human and invertebrate immunocytes. Alkaloids, including morphine, are found in both prokaryotic and eukaryotic cells and may have evolved much later in evolution through horizontal gene transfer. It is possible that opioid-mediated regulatory activities were conserved and elaborated during evolution as the central nervous system (CNS) became immunologically isolated by the blood-brain barrier. Thus, opioid receptor coupling became significant for cognitive and behavioural processes. Although opioid peptides and alkaloids work synergistically to suppress nociception, they mediate different actions in immune surveillance. Increased understanding of the evolutionary development of opioid receptors, nociceptive and anti-nociceptive pathways, and immunomodulation may help in the understanding of the development of tolerance to the clinical use of opiates for pain management. The significance of endogenous morphine's importance to evolution can be ascertained by the number of physiological tissues and systems that can be affected by this chemical messenger mechanism, which transcends pain. An integrated review is presented of opioid and opiate receptors, immunomodulation, and pain associated with inflammation, from an evolutionary perspective.

• Keywords
• Behavior, Immunomodulation, Inflammation, Mitochondria, Nitric Oxide, Opiate, Opioid, Opioid receptors, Pain,
• MeSH
• Biological Evolution MeSH
• Pain metabolism   MeSH
• Behavior MeSH
• Immunity MeSH
• Immunomodulation MeSH
• Humans MeSH
• Morphine metabolism   MeSH
• Opioid Peptides metabolism   MeSH
• Nitric Oxide metabolism   MeSH
• Receptors, Opioid genetics   metabolism   MeSH
• Inflammation metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Morphine MeSH
• Opioid Peptides MeSH
• Nitric Oxide MeSH
• Receptors, Opioid MeSH

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is difficult and controversial. Therefore, the search for novel, safe and efficient analgesics is an important but still elusive goal for contemporary medicine. In the recent years, the antinociceptive potential of endocannabinoids and opioids has been emphasized. However, concerns for the safety of their use limit their clinical applications. the possibility of modulating the activity of endocannabinoids by regulation of their synthesis and/or degradation offers an innovative approach to the treatment of pain. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neurotransmitter solutions can be used in the pharmacological studies of nociception in the orofacial area. The aim of this review is to present the effects of pharmacological activity of opioids and endocannabinoids affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.

• MeSH
• Cannabinoid Receptor Agonists therapeutic use   MeSH
• Endocannabinoids metabolism   therapeutic use   MeSH
• Humans MeSH
• Facial Pain drug therapy   metabolism   physiopathology   MeSH
• Analgesics, Opioid therapeutic use   MeSH
• Opioid Peptides metabolism   MeSH
• Pain Threshold drug effects   MeSH
• Receptors, Cannabinoid drug effects   metabolism   MeSH
• Receptors, Opioid agonists   metabolism   MeSH
• Reflex drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cannabinoid Receptor Agonists MeSH
• Endocannabinoids MeSH
• Analgesics, Opioid MeSH
• Opioid Peptides MeSH
• Receptors, Cannabinoid MeSH
• Receptors, Opioid MeSH

Opioid agonist therapy (OAT) has been available in a standard regime in the Czech Republic since 2000. Buprenorphine is the leading medication, while methadone is available only in a few specialised centres. There is an important leakage of buprenorphine onto the illicit market, and the majority of Czech opioid users are characterised by the misuse (and injecting) of diverted buprenorphine medications. Most prescribed buprenorphine for OAT is not covered by current national health insurance schemes, and patients have to pay considerable prices to afford their treatment. This affordability barrier together with limited accessibility is likely the leading factor of limited coverage of OAT and of recent stagnation in the number of patients in the official treatment programmes in the Czech Republic. It also encourages doctor shopping and the re-selling of parts of their medication at a higher price, which represents the main factor that drives the Czech illicit market for buprenorphine, but at the same time co-finances the medication of clients in official OAT programmes. Improving access to OAT by making it financially affordable is essential to further increase OAT coverage and is one of the factors that can reduce the illicit market with OAT medications.

• Keywords
• Access, Availability, Barriers, Buprenorphine, Cost, Crime, Diversion, Heroin, Illicit market, Mortality, Opioid substitution treatment, Opioids,
• MeSH
• Buprenorphine * MeSH
• Adult MeSH
• Health Services Accessibility statistics & numerical data   MeSH
• Middle Aged MeSH
• Humans MeSH
• Methadone therapeutic use   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Narcotics therapeutic use   MeSH
• Opiate Substitution Treatment statistics & numerical data   MeSH
• Analgesics, Opioid * MeSH
• Opioid-Related Disorders epidemiology   rehabilitation   MeSH
• Substance-Related Disorders epidemiology   MeSH
• Illicit Drugs MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Buprenorphine * MeSH
• Methadone MeSH
• Narcotics MeSH
• Analgesics, Opioid * MeSH
• Illicit Drugs MeSH

BACKGROUND: Knowledge of co-occurring mental disorders (termed 'dual diagnosis') among patients receiving opioid agonist treatment (OAT) is scarce. This study aimed (1) to estimate the prevalence and structure of dual diagnoses in two national cohorts of OAT patients and (2) to compare mental disorders between OAT patients and the general populations stratified on sex and standardized by age. METHODS: A registry-linkage study of OAT patients from Czechia (N = 4,280) and Norway (N = 11,389) during 2010-2019 was conducted. Data on mental disorders (F00-F99; ICD-10) recorded in nationwide health registers were linked to the individuals registered in OAT. Dual diagnoses were defined as any mental disorder excluding substance use disorders (SUDs, F10-F19; ICD-10). Sex-specific age-standardized morbidity ratios (SMR) were calculated for 2019 to compare OAT patients and the general populations. RESULTS: The prevalence of dual diagnosis was 57.3% for Czechia and 78.3% for Norway. In Czechia, anxiety (31.1%) and personality disorders (25.7%) were the most prevalent, whereas anxiety (33.8%) and depression (20.8%) were the most prevalent in Norway. Large country-specific variations were observed, e.g., in ADHD (0.5% in Czechia, 15.8% in Norway), implying differences in screening and diagnostic practices. The SMR estimates for any mental disorders were 3.1 (females) and 5.1 (males) in Czechia and 5.6 (females) and 8.2 (males) in Norway. OAT females had a significantly higher prevalence of co-occurring mental disorders, whereas SMRs were higher in OAT males. In addition to opioid use disorder (OUD), other substance use disorders (SUDs) were frequently recorded in both countries. CONCLUSIONS: Results indicate an excess of mental health problems in OAT patients compared to the general population of the same sex and age in both countries, requiring appropriate clinical attention. Country-specific differences may stem from variations in diagnostics and care, reporting to registers, OAT provision, or substance use patterns.

• Keywords
• Dual diagnosis, Opioid agonist treatment, Opioid use disorder, Psychiatric comorbidity, Registry-based study,
• MeSH
• Diagnosis, Dual (Psychiatry) MeSH
• Adult MeSH
• Mental Disorders * epidemiology   drug therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Opiate Substitution Treatment * statistics & numerical data   MeSH
• Analgesics, Opioid therapeutic use   MeSH
• Personality Disorders epidemiology   MeSH
• Opioid-Related Disorders * epidemiology   drug therapy   MeSH
• Prevalence MeSH
• Registries * MeSH
• Aged MeSH
• Sex Factors MeSH
• Anxiety Disorders epidemiology   drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Norway epidemiology   MeSH
• Names of Substances
• Analgesics, Opioid MeSH

The role of opioid kappa1 and kappa2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid kappa receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 - 48% in untreated rats. Administration of the opioid kappa1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42%. Administration of the opioid kappa receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41%. The non-selective opioid kappa receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid kappa receptor, the peripherally acting opioid kappa2 receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid ?2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid kappa2 receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid ? receptor antagonist TIPP[psi] and the selective opioid µ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid kappa2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid kappa1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid kappa receptor antagonists is not dependent on the occupancy of opioid kappa receptor.

• MeSH
• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer administration & dosage   toxicity   MeSH
• Myocardial Infarction metabolism   pathology   prevention & control   MeSH
• Administration, Intravenous MeSH
• Myocytes, Cardiac drug effects   metabolism   pathology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Narcotic Antagonists administration & dosage   MeSH
• Analgesics, Opioid administration & dosage   toxicity   MeSH
• Piperazines administration & dosage   MeSH
• Rats, Wistar MeSH
• Pyrrolidines administration & dosage   toxicity   MeSH
• Receptors, Opioid, kappa agonists   metabolism   MeSH
• Myocardial Reperfusion Injury metabolism   pathology   prevention & control   MeSH
• Signal Transduction MeSH
• Arrhythmias, Cardiac chemically induced   physiopathology   MeSH
• Heart Rate drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer MeSH
• GR 89696 MeSH Browser
• ICI 199441 MeSH Browser
• kappa(1) opioid receptor MeSH Browser
• kappa(2) opioid receptor MeSH Browser
• Narcotic Antagonists MeSH
• Analgesics, Opioid MeSH
• Piperazines MeSH
• Pyrrolidines MeSH
• Receptors, Opioid, kappa MeSH

One of the central issues in present experimental pain research is to establish the identity, location, and mechanism of action of various opioids (opioid peptides and alkaloids) and multiple opioid receptors in the modulation of nociceptive processes. At the cerebral level, studies employing several experimental approaches point to an essential role of beta-endorphin in analgesia, induced by electrical stimulation of the periaqueductal grey of the midbrain. Tolerance and cross-tolerance studies suggest that mu-opioid receptors mediate this effect. The significance of delta- and, in particular, chi-opioid receptors in cerebral pain modulation is less well documented. At the spinal level, nociception is relayed in the dorsal horn, where opioid peptides as well as all types of opioid receptors are abundant. mu-opioid receptor-mediated antinociceptive processes appear to be most important in this region, but delta-opioid receptors may also be involved. In addition, a role of chi-opioid receptors can be demonstrated under certain conditions. Recent experiments indicate that opioids may also modulate nociception in the periphery, in particular in inflamed tissue. The identification of opioid receptors and their endogenous ligands, the opioid peptides, marked the beginning of a new era in pain research. The differentiation of several types of opioid receptors and the subsequent characterization of a series of opioid peptides illustrate the striking complexity of opioid systems. The implications of this multiplicity for neurobiology in general and for the understanding of pain mechanisms in particular are presently not fully understood. In this presentation some aspects of opioidergic pain control at various levels of the neuraxis will be discussed.

• MeSH
• Analgesics MeSH
• Pain drug therapy   physiopathology   MeSH
• Central Nervous System drug effects   physiology   MeSH
• Endorphins physiology   therapeutic use   MeSH
• Humans MeSH
• Receptors, Opioid physiology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Analgesics MeSH
• Endorphins MeSH
• Receptors, Opioid MeSH