Opioid System Research Articles

Cannabinoids and General Anesthetics: Revisiting Molecular Mechanisms of Their Pharmacological Interactions.

Cannabis has been used for recreation and medical purposes for more than a millennium across the world; however, its use's consequences remain poorly understood. Although a growing number of surgical patients are regular cannabis consumers, little is known regarding the pharmacological interactions between cannabis and general anesthetics; consequently, there is not a solid consensus among anesthesiologists on the perioperative management of these patients. The existing evidence about the molecular mechanisms underlying pharmacological interactions between cannabinoids and anesthetic agents, both in animal models and in humans, shows divergent results. While some animal studies have demonstrated that phytocannabinoids (tetrahydrocannabinol [THC], cannabidiol [CBD], and cannabinol [CBN]) potentiate the anesthetic effects of inhalation and intravenous anesthetics, while others have found effects comparable with what has been described in humans so far. Clinical studies and case reports have consistently shown increased requirements of GABAergic anesthetic drugs (isoflurane, sevoflurane, propofol, midazolam) to achieve adequate levels of clinical anesthesia. Several potential molecular mechanisms have been proposed to explain the effects of these interactions. However, it is interesting to mention that in humans, it has been observed that the ingestion of THC enhances the hypnotic effect of ketamine. Animal studies have reported that cannabinoids enhance the analgesic effect of opioids due to a synergistic interaction of the endogenous cannabinoid system (ECS) with the endogenous opioid system (EOS) at the spinal cord level and in the central nervous system. However, human data reveals that cannabis users show higher scores of postoperative pain intensity as well as increased requirements of opioid medication for analgesia. This review aims to improve understanding of the molecular mechanisms and pharmacological interactions between cannabis and anesthetic drugs and the clinical outcomes that occur when these substances are used together.

Opioid receptor and dopaminergic gene expression increase in the brains of dominant medaka Oryzias latipes males after repeated fights.

The central opioid system and dopaminergic activity in mammals play key roles in mediating social reward, impulsivity, cognition, decision making, and motivation for learning and social interactions. Repeated positive fighting experiences enhance the gene expression levels of μ-type opioid receptor (Mor), tyrosine hydroxylase (Th), an enzyme involved in dopamine synthesis, and dopamine receptor type 2 (D2r) in the reward-related brain regions of aggressive mice. However, it remains unclear whether the opioid system and dopaminergic activity are associated with repeated winning in fish. In this study, we investigated changes in the expression levels of Mor, Th1, and D2r in different regions of the brain of adult medaka Oryzias latipes males after intermittent and continuous fight for 3 days. When a pair of males was provided a fighting opportunity for 20 min per day, we noted that within the 3-day observation period, aggressive winning males showed significantly higher expression levels of Mor in telencephalon and diencephalon, Th1 in diencephalon, and D2r in telencephalon than subordinate losing males. However, no such differences in gene expression level were observed between winning and losing males in the 3-day continuous fight. Further, no differences were detected in the total number of aggressive actions among the winners from each fighting test. However, the total number of "chase" actions, with a stronger aggressiveness index, was higher for the repeated winning male in the three-time intermittent fight than for the winner in the 3-day continuous fight. These findings suggest that repeated intermittent winning experiences with strong aggressiveness could be perceived as a reward by O. latipes males.

Endogenous opioid receptor system mediates costly altruism in the human brain

Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [11C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain.

Mu and Delta Opioid Receptors Modulate Inhibition within the Prefrontal Cortex Through Dissociable Cellular and Molecular Mechanisms.

The endogenous opioid system regulates behaviors that rely on prefrontal cortex (PFC) function. Previous studies have described Mu and Delta opioid receptor expression within cortical GABAergic interneurons, but a detailed understanding of how opioids regulate different interneuron subtypes and cortical microcircuits has not been reported. We use whole-cell patch-clamp electrophysiology, genetically engineered mice, and optogenetics to assess MOR and DOR regulation of PFC inhibitory transmission, demonstrating that MOR and DOR inhibition of interneurons display qualitative and quantitative variation across GABAergic circuits within mouse prelimbic PFC.

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

A Small-molecule Antagonist Radiotracer for Positron Emission Tomography Imaging of the Mu Opioid Receptor.

The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. In the present study, we sought to design and characterize a library of 24 non-agonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood-brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of 1A and 3A at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [ 11 C] 1A was prepared via metallophotoredox of the aryl-bromide functional group to [ 11 C]methyl iodide. The nascent radiotracer demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [ 11 C] 1A binding, though the interactions were not as pronounced as naloxone's ability to displace [ 11 C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.

Study on peripheral antinociception induced by hydrogen peroxide (H2O2): characterization and mechanisms.

The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.

Impacts of endogenous opioid blockade and sex on working memory among ad-libitum and abstinent smokers and non-smokers

BackgroundResearch examining the effects of opioid receptor antagonists on working memory is limited by small sample sizes that are often comprised of only male participants. Moreover, they have yielded mixed findings, and no studies have examined such effects in the context of chronic nicotine use and temporary nicotine withdrawal. MethodsMale and female participants completed two lab visits at which they were administered either 50 mg naltrexone or an identical placebo (one at each lab using double-blind, counterbalanced administration). After a medication absorption period, performance on a mental arithmetic (working memory) task was assessed by number of correct responses, errors, and number of attempts. Participants were either non-smokers or regular smokers who were randomly assigned to use nicotine ad-libitum or to abstain from nicotine for 24 h prior to both lab visits. ResultsThe results indicate a significant main effect of opioid blockade on number of correct answers and accuracy rate during the mental arithmetic task, with poorer performance after opioid blockade compared to placebo. In addition, compared to male participants, female participants made fewer answer attempts, had fewer correct answers, and a lower accuracy rate. We did not find evidence of any differences based on smoking group (non-smoker, smoking abstinence, or ad-libitum smoking), nor were there any significant interaction effects. ConclusionsThe findings suggest a modulating role of the endogenous opioid system in working memory function. Further investigation is needed to help identify the underlying mechanisms explaining the effects of the endogenous opioid system on working memory.

Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial.

The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity. This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

The macroscale routing mechanism of structural brain connectivity related to body mass index.

Understanding the brain's mechanisms in individuals with obesity is important for managing body weight. Prior neuroimaging studies extensively investigated alterations in brain structure and function related to body mass index (BMI). However, how the network communication among the large-scale brain networks differs across BMI is underinvestigated. This study used diffusion magnetic resonance imaging of 290 young adults to identify links between BMI and brain network mechanisms. Navigation efficiency, a measure of network routing, was calculated from the structural connectivity computed using diffusion tractography. The sensory and frontoparietal networks indicated positive associations between navigation efficiency and BMI. The neurotransmitter association analysis identified that serotonergic and dopaminergic receptors, as well as opioid and norepinephrine systems, were related to BMI-related alterations in navigation efficiency. The transcriptomic analysis found that genes associated with network routing across BMI overlapped with genes enriched in excitatory and inhibitory neurons, specifically, gene enrichments related to synaptic transmission and neuron projection. Our findings suggest a valuable insight into understanding BMI-related alterations in brain network routing mechanisms and the potential underlying cellular biology, which might be used as a foundation for BMI-based weight management.

Integrative intrinsic brain activity and molecular analyses of the interaction between first-episode depression and age

BackgroundNumerous studies have underscored the presence of abnormal intrinsic neural activity (INA) in individuals with depression. However, recognizing that the age stage may influence the pathophysiology of depression, our study sought to delve into the interplay of depression and age on INA and molecular architecture. MethodsOne hundred and thirty-eight first-episode depression patients and 120 healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging. The participants were stratified into four groups based on age. Utilizing amplitude of low-frequency fluctuation (ALFF) analyses, we employed an ANCOVA to compare INA patterns in four groups. Additionally, we conducted correlation analyses between ALFF and neurotransmitter maps to elucidate molecular underpinnings of INA abnormalities. ResultsIn comparison to adolescents with early-onset depression and adult HC, adult-onset depression exhibited increased ALFF in the right paracentral lobule. Conversely, early-onset depression, when contrasted with adolescent HC, displayed reduced ALFF in the right paracentral lobule. The interactive brain regions affected by ALFF alterations were associated with serotonergic, GABAergic, and opioid neurotransmitter systems. LimitationsThe present study was limited to its cross-sectional design. ConclusionsThis study illuminates an antagonistic effect of depression and age on brain activity in paracentral lobule and provides molecular underpinnings of the corresponding INA abnormalities related to key neurotransmitter systems. These insights may prove valuable in the development of neuromarkers for clinical intervention and treatment of depression.

Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness.

Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.

Opiorphin: an endogenous human peptide with intriguing application in diverse range of pathologies.

Mammalian zinc ectopeptidases have significant functions in deactivating neurological and hormonal peptide signals on the cell surface. The identification of Opiorphin, a physiological inhibitor of zinc ectopeptidases that inactivate enkephalin, has revealed its strong analgesic effects in both chemical and mechanical pain models. Opiorphin achieves this by increasing the transmission of endogenous opioids, which are dependent on the body's own opioid system. The function of opiorphin is closely linked to the rat sialorphin peptide, which inhibits pain perception by enhancing the activity of naturally occurring enkephalinergic pathways that depend on μ- and δ-opioid receptors. Opiorphin is highly intriguing in terms of its physiological implications within the endogenous opioidergic pathways, particularly in its ability to regulate mood-related states and pain perception. Opiorphin can induce antidepressant-like effects by influencing the levels of naturally occurring enkephalin, which are released in response to specific physical and/or psychological stimuli. This effect is achieved through the modulation of delta-opioid receptor-dependent pathways. Furthermore, research has demonstrated that opiorphin's impact on the cardiovascular system is facilitated by the renin-angiotensin system (RAS), sympathetic ganglia, and adrenal medulla, rather than the opioid system. Hence, opiorphin shows great potential as a solitary candidate for the treatment of several illnesses such as neurodegeneration, pain, and mood disorders.

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration.

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naïve, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

Longitudinal associations between beta-endorphin, nonsuicidal self-injury and comorbid psychopathology

Homeostasis models posit that nonsuicidal self-injury (NSSI) serves, in part, to upregulate the endogenous opioid system in order to compensate for an opioid deficiency. A few studies have demonstrated lower basal levels of beta-endorphin (BE), an endogenous opioid, in individuals with NSSI. However, longitudinal studies are missing. Hence, the present study aimed to investigate the longitudinal associations between NSSI, comorbid psychopathology (i.e., borderline personality disorder and depressive symptoms), pain sensitivity and basal BE levels in adolescents with NSSI. N = 53 adolescents with NSSI disorder undergoing specialized treatment participated in baseline and one-year follow-up assessments. BE was measured in plasma; pain sensitivity was assessed with a heat pain stimulation paradigm. Associations between BE and change in NSSI, borderline personality disorder and depressive symptoms as well as pain sensitivity were examined using negative binomial and linear regression analyses. We found that an increase in basal BE was significantly associated with a decrease in depressive symptoms. No associations between BE and NSSI, borderline personality disorder symptoms or pain sensitivity were observed. Our findings may confirm a role of plasma BE in the etiology of depressive symptoms but challenge current models of endogenous opioid homeostasis in NSSI.

Artemisinin and deoxyartemisinin isolated from Artemisia annua L. promote distinct antinociceptive and anti-inflammatory effects in an animal model

Artemisia annua L., known for antimalarial activity, has demonstrated evidence of anti-inflammatory potential. Previously our research group reported the anti-inflammatory and antinociceptive effect of a sesquiterpene lactone-enriched fraction (Lac-FR) obtained from plant, containing artemisinin and deoxyartemisinin. Both the isolated compounds and Lac-FR evaluated on experimental animal models, in the formalin test showed that deoxyartemisinin reduced both neurogenic pain (56.55 %) and inflammatory pain (45.43 %). These findings were superior to the effect of artemisinin (reduction of 28.66 % and 33.35 %, respectively). In the tail flick test, the antinociceptive effect reported as a percentage of the maximum possible effect (%MPE), deoxyartemisinin showed a lower antinociceptive effect (41.57 %) compared to morphine (75.94 %) in 0.5 h. After 1.5 h, the MPE of deoxyartemisinin (87.99 %) exceeded the effect of morphine (47.55 %), without reversal with naloxone. The MPE of artemisinin (23.3 %) observed after 2 h was lower than deoxiartemisinin, without reversal with the opioid antagonist. Lac-FR and artemisinin demonstrated reductions in ear edema of 43.37 % and 48.19 %, respectively, higher than the effect of deoxyartemisinin (33.64 %). Artemisinin reduced tumor necrosis factor alpha (TNF-α) (76.96 %) more selectively when compared to interleukin-1beta (IL-1β) (48.23 %) and interleukin-6 (IL-6) (44.49 %). Lac-FR showed greater selectivity in IL-6 reduction (56.49 %) in relationship to TNF-α (46.71 %) and IL-1β (45.12 %), whereas deoxyartemisinin selectively reduced TNF-α (37.37 %). The results of our study indicate that the lactones isolated did not have relationship with the opioid system. Deoxyartemisinin showed a higher antinociceptive potential than artemisinin. Whereas, artemisinin showed a higher reduction of inflammation and mediators, with a better anti-inflammatory activity outcome.

Effects of Online Naloxone Training for Laypersons: An Extended-Baseline Assessment

Background: While laypersons can play a crucial role in administering naloxone in opioid overdoses, they must be recruited and trained to effectively manage overdose events as good Samaritans. This study aimed to examine the effectiveness of a technology-based intervention that recruited and trained laypersons to administer naloxone. Methods: Opioid Rapid Response System (ORRS) was an online recruitment and training intervention which capitalized on social cognitive theory and a digital media engagement model to mobilize laypersons to administer intranasal naloxone. ORRS was developed based on a randomized waitlisted controlled trial (N = 220). This secondary analysis is a within-group, extended-baseline assessment of the waitlisted group (n = 106), considering that they served as their own control prior to receiving the training. ORRS was conducted in five counties of Indiana with adults who did not self-identify as a certified first responder. Five indices were generated from 23 variables: knowledge of overdose signs, knowledge of overdose management, self-efficacy in responding, concerns about responding, and intent to respond. Paired t-test compared changes between 3 timepoints. Results: Three indices had significantly greater increases associated with training compared to extended baseline: recognizing opioid overdose signs (difference = 0.08; 95%CI = 0.02, 0.15; t = 2.48; p = 0.01); knowledge of overdose management (difference = 0.27; 95%CI = 0.18, 0.35; t = 5.99; p < 0.01); and self-efficacy in overdose management (difference = 0.68; 95%CI = 0.45, 0.91; t = 5.78; p < 0.01). Concerns related to overdose management significantly decreased as expected (difference = −1.53; 95%CI = −1.86, −1.21; t = −9.27; p < 0.01). Conclusions: ORRS provided strong support for self-efficacy, concerns, and knowledge related to overdose management, and the digital modality accelerates largescale dissemination.

Opioid access barriers for cancer pain relief in Vietnam: A qualitative study.

154 Background: Although the World Health Organization designates opioids as an essential medication and recommends them as the cornerstone for managing moderate to severe cancer pain, their accessibility is severely restricted, particularly in low and middle-income countries. Despite Vietnam's early endeavors in the advancement of palliative care, including a revised opioid prescription policy in 2008, opioid use for cancer pain remains suboptimal, with oral morphine available only in a few major hospitals. To inform comprehensive strategies for improving opioid access, this study aims to explore the views of healthcare providers, regulators, cancer patients, and caregivers in Vietnam on the barriers to safely accessing opioids for cancer pain management. Methods: We conducted a qualitative, descriptive study and recruited five healthcare providers, six cancer patients and caregivers, and six regulators (i.e., policymakers in the Ministry of Health, heads or deputy heads of pharmacy, oncology, or palliative care departments) across Vietnam via purposeful sampling technique. Data were collected using semi-structured interviews, and the audio recordings were transcribed verbatim and subjected to inductive content analysis using a Framework Method. Results: Five categories of barriers were identified: 1) Patient-related barriers (fear of addiction and other side effects, morphine's association with impending death, negative administration experiences, religious beliefs); 2) Professional-related barriers (knowledge and experience deficit, fear of addiction and other side effects, concerns about opioid diversion and associated liabilities, lack of guidance, education, and training); 3) Medicine-related barriers (limited oral morphine availability, limited domestic pharmaceutical manufacturers and suppliers, supply interruptions, poor variety of opioid types and formulations, difficulties accessing parenteral opioids); 4) Services delivery barriers (scarce palliative and home care services); 5) Regulatory barriers (lack of information on opioid distribution channels, difficulties obtaining confirmation letters for patients' opioid usage needs, overly strict regulation enforcement). Conclusions: Barriers to opioid access for cancer pain control in Vietnam are multifactorial and mutually reinforcing, necessitating interdisciplinary solutions to overcome them. This approach should involve enhancing education about the appropriate use and management of opioids, along with current opioid policies for patients, communities, healthcare providers, and regulators; enacting and implementing policies mandating oral morphine availability at local health facilities; expanding palliative care services; utilizing telemedicine; and establishing an electronic opioid prescription monitoring system.

Role of opioid receptors in phagocytosis regulation and production of Th1/Th2 cytokines under acute cold stress in non-immune mice

Endogenous opioid system plays an important role in the regulation of body functions under stress, providing stress-protective, analgesic and immunoregulatory effects. The aim of this work was to assess the effect of acute cold stress on the in vivo production of adaptive immunity cytokines IL-2, IL-4, IFNγ, phagocytosis, and production of reactive oxygen species in non-immunized mice with induced blockage of opioid receptors. The object of the study were male white mice subjected to acute cold stress at -20 °C for 10 or 60 minutes. To block opioid receptors, naloxone hydrochloride was used, which was administered subcutaneously at a dose of 0.2 mg/kg 20 min before inducing the stress. After the cold exposure, spleen and peritoneal lavage were obtained from the animals. The cytokine concentrations were determined using ELISA technique. The absorption activity of CD11+ cells of the peritoneal cavity was assessed using FITC-stained St.cohnii with a flow cytometer; the production of reactive oxygen species was assessed using the reaction of luminol-dependent chemiluminescence. It was found that the both cold stress regimens caused naloxone-independent inhibition of spontaneous IFNγ production. In stimulated cultures, an inhibitory effect on IFNγ secretion was registered in animals subjected to stress for only 60 min, being also independent on the opioid receptor blockade. IL-2 production decreased in stimulated cultures against the background of 60 min stress naloxone independently. Both variants of cold stress had no effect on IL-4 production. Stress for 60 min inhibited absorption activity of CD11+ cells from the peritoneal lavage and activated production of oxygen radicals, being, however, canceled by naloxone administration. Hence, acute cold stress led to naloxone-independent inhibition of Th1 cytokine production by splenocytes, naloxone-dependent inhibition of phagocytosis and activation of the microbicidal potential of peritoneal cavity cells.

Isolation, purification, and characterization of lectins from medicinal plant Combretum glutinosum seeds endowed with analgesic and antiulcer properties

In the pursuit of safer and more effective treatments, there is a growing interest in plant-derived compounds, particularly lectins, because of their diverse pharmacological properties. This study focused on isolating, purifying, and characterizing lectin from Combretum glutinosum seeds (CGSLs) to assess its potential as an analgesic and antiulcer agent. CGSL extraction involved defatting and buffer extraction, followed by purification using ammonium sulfate fractionation and fetuin-agarose affinity column chromatography. The isolectins (iso-CGSLs), each consisting of 60 kDa and 57 kDa heterodimeric subunits, displayed glycoprotein properties with a 40 % neutral sugar content. They exhibited peak activity at 55 °C and remained stable for up to the fifth day at room temperature. The activity exhibited a pH dependence, peaking between 7.5 and 10.5, and all seemingly operated independently of metal ions. CGSL, at optimal doses ranging from 6 to 12 mg/kg, had significant analgesic effects on acetic acid-induced writhing and hot plate tests in mice. Evaluation using 0.7 % acetic acid resulted in notable pain reduction across all doses (P < 0.05). The analgesic effect of lectin was partially reversed by naloxone (a morphine antagonist), indicating partial involvement of the opioid receptor system. Furthermore, CGSL exhibited antiulcer effects in ethanol-induced gastric ulcer models in rats, highlighting its therapeutic potential as a natural alternative for analgesic and antiulcer treatments.