Opioid Activity Research Articles

Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.

Introduction: There is a major societal need for analgesics with less tolerance, dependence, and abuse liability. Preclinical rodent studies suggest that bifunctional ligands with both mu (MOPr) and delta (DOPr) opioid peptide receptor activity may produce analgesia with reduced tolerance and other side effects. This study explores the structure-activity relationships (SAR) of our previously reported MOPr/DOPr lead, benzylideneoxymorphone (BOM) with C7-methylene-substituted analogs. Methods: Analogs were synthesized and tested in vitro for opioid receptor binding and efficacy. One compound, nitro-BOM (NBOM, 12) was evaluated for antinociceptive effects in the warm water tail withdrawal assay in C57BL/6 mice. Acute and chronic antinociception was determined, as was toxicologic effects on chronic administration. Molecular modeling experiments were performed using the Site Identification by Ligand Competitive Saturation (SILCS) method. Results: NBOM was found to be a potent MOPr agonist/DOPr partial agonist that produces high-efficacy antinociception. Antinociceptive tolerance was observed, as was weight loss; this toxicity was only observed with NBOM and not with BOM. Modeling supports the hypothesis that the increased MOPr efficacy of NBOM is due to the substituted benzylidene ring occupying a nonpolar region within the MOPr agonist state. Discussion: Though antinociceptive tolerance and non-specific toxicity was observed on repeated administration, NBOM provides an important new tool for understanding MOPr/DOPr pharmacology.

Anti-neuropathic Pain Mechanistic Study on A. conyzoides Essential Oil, Precocene II, Caryophyllene, or Longifolene as Single Agents and in Combination with Pregabalin.

Neuropathic pain has become a contributor to the global burden of illness. However, the currently available drugs exhibit inadequate pain relief and significant side effects. Our previous study demonstrated that the essential oil of Ageratum conyzoides exerts potent antineuropathic pain activity through opioid receptor activation. Precocene II, longifolene, and caryophyllene are the largest component of the A. conyzoides essential oil. The objective of the study was to determine the anti-neuropathic pain activity of precocene II, longifolene, and caryophyllene as single agents and in combination with pregabalin. Possible mechanisms of action involving the opioid receptor, ATP-sensitive potassium channel, and gammaaminobutyric acid (GABA) were further investigated. The experimental animals (male mice Swiss Webster) were divided randomly into seven groups, namely, Normal control (naïve mice), Negative control (CMC 1%), Sham (CMC 1%), Positive control (Pregabalin 0,195 mg/ 20 g BW of mice), Test I (Precocene II 21.09 mg/Kg BW), Test II (Longifolene 9.94 mg/Kg BW), and Test III (Caryophyllene 3.64 mg/Kg BW). Each group contained 3 animals. The test groups that demonstrated anti-neuropathic pain activity were further tested in combination with pregabalin, followed by mechanistic studies. The negative, positive, and test I-III groups were induced with chronic constriction injury. The results of the study demonstrated that caryophyllene and longifolene, but not precocene II, exerted anti-neuropathic pain activity. The caryophyllene was shown to involve in the activation of opioid receptors and ATP-sensitive potassium channels. It was also reported to increase GABA concentration in the spinal cord. We further found that longifolene exerted its action via opioid receptor activation. The combination of A. conyzoides essential oil, longifolene, or caryophyllene with pregabalin demonstrated additive anti-neuropathic pain activity. Taken together, the results of the present study suggested that the A. conyzoides essential oil and caryophyllene have the potential to be developed as novel drugs to treat neuropathic pain.

Comparative Pharmacology and Toxicology of Tramadol & Tapentadol

Pain is a common symptom in various health conditions and can significantly impact a person's quality of life if not managed properly. Although non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen are widely used for mild to moderate pain, they may not suffice for moderate to severe pain requiring combination therapy. In such cases, synthetic drugs like Tramadol and Tapentadol offer effective pain relief with improved safety profiles. This article aims to compare the pharmacokinetics, pharmacodynamics, and safety profiles of Tapentadol and Tramadol.
 Tapentadol, a direct-acting synthetic opioid, demonstrates a reliable mode of action as it starts working upon reaching the bloodstream. In contrast, Tramadol requires metabolic conversion into active metabolites, resulting in a delayed onset of action. Furthermore, Tramadol's effectiveness is dependent on the presence of the CYP2D6 enzyme, with approximately 6% of Caucasians being deficient in this enzyme. Dosage adjustments may be required for individuals with impaired liver or kidney function.
 Both Tapentadol and Tramadol primarily affect mu-opioid receptors (MOR), providing potent pain relief. However, Tramadol also inhibits the reuptake of noradrenaline and serotonin, while Tapentadol lacks an effect on serotonin. Tapentadol exhibits a higher affinity for MOR receptors, making it a more potent central acting painkiller compared to Tramadol. Nevertheless, Tapentadol's increased opioid activity increases the likelihood of mild and transient opioid-like side effects, such as drowsiness, constipation, and respiratory depression.
 In terms of toxicology, both Tapentadol and Tramadol offer a safer alternative to morphine with reduced side effects. Tapentadol's greater opioid activity translates into a higher potential for opioid-related side effects, whereas Tramadol's serotonergic activity is associated with a higher incidence of vomiting and nausea. The absence of significant effects on CYP450 enzymes distinguishes Tapentadol from Tramadol, reducing the likelihood of drug interactions.
 Overall, Tapentadol demonstrates several advantages over Tramadol, including faster onset of action, greater pain relief, and fewer side effects related to serotonergic activity. However, it is essential to consider that Tapentadol, although more effective, carries a higher probability of side effects associated with its increased opioid activity. Clinicians should carefully evaluate individual patient characteristics and requirements when selecting between these two medications for pain management.

Kappa opioid receptor activation increases thermogenic energy expenditure which drives increased feeding

Opioid receptors, including the kappa opioid receptor (KOR), exert control over thermoregulation and feeding behavior. Notably, activation of KOR stimulates food intake, leading to postulation that KOR signaling plays a central role in managing energy intake. KOR has also been proposed as a target for treating obesity. Herein, we report studies examining how roles for KOR signaling in regulating thermogenesis, feeding, and energy balance may be interrelated using pharmacological interventions, genetic tools, quantitative thermal imaging, and metabolic profiling. Our findings demonstrate that activation of KOR in the central nervous system causes increased energy expenditure via brown adipose tissue activation. Importantly, pharmacologic, or genetic inhibition of brown adipose tissue thermogenesis prevented the elevated food intake triggered by KOR activation. Furthermore, our data reveal that KOR-mediated thermogenesis elevation is reversibly disrupted by chronic high-fat diet, implicating KOR signaling as a potential mediator in high-fat diet-induced weight gain.

Food-inspired peptides from spinach Rubisco endowed with antioxidant, antinociceptive and anti-inflammatory properties.

Rubiscolin-6 (amino acid sequence: YPLDLF) is a selective δ-opioid receptor peptide isolated from spinach Rubisco. Its synthetic analogue, peptide YPMDIV is the most potent described so far for its increased opioid activity, thus in this work it was considered as lead compound for the design of twelve new analogues e.g. LMAS1-12. Firstly all the novel compounds have been tested for their antinociceptive and anti-inflammatory capacity in vitro and in vivo in order to evaluate their ability to maintain or loss the original activity. Among them peptides LMAS5-8 gave the best results, thus their antioxidant properties have been investigated along with their enzymatic inhibitory ability. Peptide LMAS6 shows a strong antioxidant (154.25mg TE/g CUPRAC) and inhibitor activity on tyrosinase (84.49mg KAE/g), indicating a potential role in food industry as anti-browning agent, while peptides LMAS5 and LMAS7 possess a modest cholinesterase inhibitory activity suggesting a conceivable use for nutraceuticals production.

Ligand and G-protein selectivity in the κ-opioid receptor

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—Gi1, GoA, Gz and Gg—using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

The Role of Opioid Receptors in Cancer.

Opioids are one of the most potent drugs for treating moderate to severe pain. Despite irrefutable clinical application in chronic pain management, the long-term use of opioids has been increasingly questioned due to undesired side effects that demand attention. Opioids such as morphine mediate clinically relevant effects primarily through the µ-opioid receptor that go beyond their classical role as analgesics, causing potentially fatal side effects such as tolerance, dependence, and addiction. Furthermore, there is growing evidence that opioids affect immune system function, cancer progression, metastasis, and recurrence. Though a biological plausibility, the clinical evidence for the action of opioids on cancer is mixed, revealing a more complex picture as researchers struggle to establish a vital link between opioid receptor agonists, cancer progression, and suppression, or both. Thus, in light of the uncertainty of opioid effects on cancer, in this review, a focused overview of the role of opioid receptors in modulating cancer progression, their underlying signaling mechanisms, and the biological activity of opioid receptor agonists and antagonists is provided.

A COMPARISON OF DEXMEDETOMIDINE AND BUPRENORPHINE AS AN ADJUVANT WITH 0.5% BUPIVACAINE IN PERIPHERAL NERVE STIMULATOR (PNS) GUIDED SUPRACLAVICULAR BRACHIAL PLEXUS BLOCK - A PROSPECTIVE DOUBLE BLINDED RANDOMIZED CLINICAL STUDY

Background And Aims: We compared the block quality and characteristics between dexmedetomidine versus buprenorphine as an adjuvant to bupivacaine in Peripheral nerve stimulator guided supraclavicular brachial plexus block. The quality of block by dexemetomidine was found to be better than buprenorphine and thus has opioid sparing action. Duration of sensory and motor block along with duration of analgesia were the primary outcomes studied. Methods:Total 80 patients of either sex, 40 patients in each group presenting for upper limb surgeries Each participant fullling our inclusion criteria then included. Results: In our study group D represents the group that received dexemotomidine while group B represents the group that received buprenorphine Mean duration of sensory block in group D was (704.05± 123.16) min and in group B it was (543.25 ± 60.14) min while mean duration of motor block in Group D (& (662.05± 121.83) was longer than Group B (397.50±56.51) and Duration of analgesia in Group D (782.88 ±115.44) was also longer than Group B (636.25±53.62).The results were statistically signicant. Conclusion: Dexmedetomidine I dose of 1ug/kg prolongs the duration of sensory and motor blockade and duration of analgesia as compared with buprenorphine when used as an adjuvant to 0.5%bupivacaine in supraclavicular brachial plexus block, with no major adverse side effects

Scaling down synaptic strength results in changes to the pattern of fictive breathing in a model of the brainstem respiratory network: medullary and pontine sources

Opioids remain a primary vehicle for pain management prescribed by clinicians. However, opioid-induced respiratory depression (OIRD) can cause apneas and be fatal at elevated doses. Two sites of action for these opioids have been suggested in the brainstem, one in the pons and the other in the preBötzinger Complex of the medulla. Additionally, there is electrophysiological evidence suggesting that an inward-rectifying K + current is opened upon μ-opioid receptor (μOR) activation causing neuronal hyperpolarizations. Activation of μORs may cause depletion of glutamate release from excitatory neurons. Our previous simulation efforts have demonstrated the plausibility of presynaptic actions of opioids among inspiratory neurons of the medulla and pons in depressing inspiratory drive or eliciting apnea within specific and singular synaptic connections. Here, we tested the effects of diminishing the strength of excitatory synaptic currents among several different classes of respiratory neurons in a large-scale model of the brainstem respiratory network and whether it would replicate OIRD. We simulated the simultaneous actions of μOR on multiple presynaptic sites among the medullary inspiratory network. We began by scaling down the synaptic conductances of target populations of medullary inspiratory neurons. The core of the model is made up of neurons that produce the fundamental inspiratory rhythm (“I-Driver” neurons), as well as neurons that normally have an inspiratory decrementing (“I-Dec”) or inspiratory augmenting (“I-Aug”) firing pattern and various expiratory phase firing patterns (“E-Dec,” “E-Aug,” “E-Tonic”). I-Driver neurons are analogous to medullary preBötzinger Complex neurons that putatively express μORs. In our model, these neurons project back onto other I-Driver neurons to promote recurrent excitation but also project onto I-Aug and I-Dec populations. Decreasing the synaptic strength from I-Driver neurons to these populations collectively slows fictive breathing until extended apnea occurs. To further understand how this apnea develops we systematically scaled down the synaptic strengths of I-Driver to each of the other specific populations and found that the excitatory connection from I-Driver to I-Dec populations is most influential in producing apnea. However, we also found that excitatory drive from tonic, non-respiratory modulated (NRM) neurons in the pons to the medulla could influence this pattern by grading down synaptic strength. In addition to any direct hyperpolarizing effects of opioids on μOR-expressing neurons, these data support the plausibility that OIRD could arise from changes due to glutamate release. This work was supported by the National Institutes of Health grant 1R01HL155721-01, 1R01HL163008, and T32HL134621. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pain Self-Efficacy (PSEQ) score of

BACKGROUND CONTEXTPain self-efficacy, or the belief that one can carry out activities despite pain, has been shown to be associated with back and neck pain severity. However, the literature correlating psychosocial factors to opioid use, barriers to proper opioid use, and Patient-Reported Outcome Measurement Information System (PROMIS) scores is sparse. PURPOSEThe primary aim of this study was to determine whether pain self-efficacy is associated with daily opioid use in patients presenting for spine surgery. The secondary aim was to determine whether there exists a threshold self-efficacy score that is predictive of daily preoperative opioid use and subsequently to correlate this threshold score with opioid beliefs, disability, resilience, patient activation, and PROMIS scores. PATIENT SAMPLEFive hundred seventy-eight elective spine surgery patients (286 females; mean age of 55 years) from a single institution were included in this study. STUDY DESIGN/SETTINGRetrospective review of prospectively collected data. OUTCOME MEASURESPROMIS scores, daily opioid use, opioid beliefs, disability, patient activation, resilience. METHODSElective spine surgery patients at a single institution completed questionnaires preoperatively. Pain self-efficacy was measured by the Pain Self-Efficacy Questionnaire (PSEQ). Threshold linear regression with Bayesian information criteria was utilized to identify the optimal threshold associated with daily opioid use. Multivariable analysis controlled for age, sex, education, income, and Oswestry Disability Index (ODI) and PROMIS-29, version 2 scores. RESULTSOf 578 patients, 100 (17.3%) reported daily opioid use. Threshold regression identified a PSEQ cutoff score of <22 as predictive of daily opioid use. On multivariable logistic regression, patients with a PSEQ score <22 had two times greater odds of being daily opioid users than those with a score ≥22. Further, PSEQ <22 was associated with lower patient activation; increased leg and back pain; higher ODI; higher PROMIS pain, fatigue, depression, and sleep scores; and lower PROMIS physical function and social satisfaction scores (p<.05 for all). CONCLUSIONSIn patients presenting for elective spine surgery, a PSEQ score of <22 is associated with twice the odds of reporting daily opioid use. Further, this threshold is associated with greater pain, disability, fatigue, and depression. A PSEQ score <22 can identify patients at high risk for daily opioid use and can guide targeted rehabilitation to optimize postoperative quality of life.

Kappa opioid activation changes protein profiles in different regions of the brain relevant to depression

Depression is a widespread disorder with a significant burden on individuals and society. There are various available treatments for patients with depression. However, not all patients respond adequately to their treatment. Recently, the opioid system has regained interest in depression studies. Research in animals and humans suggest that blocking the kappa opioid receptor (KOR) may potentially alleviate the symptoms of depression. The mechanism behind this effect is not fully understood. Stress and alterations in hypothalamic-pituitary-adrenal axis (HPA-axis) activity are thought to play a crucial role in depression. This study aimed to characterize stress hormones and stress-related protein expression following activation of KOR using a selective agonist. The longitudinal effect was investigated 24 h after KOR activation using the selective agonist U50,488 in Sprague Dawley rats. Stress-related hormones and protein expression patterns were explored using multiplex bead-based assays and western blotting. We found that KOR activation caused an increase in both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in serum. Regarding protein assays in different brain regions, phosphorylated glucocorticoid receptors also increased significantly in thalamus (THL), hypothalamus (HTH), and striatum (STR). C-Fos increased time-dependently in THL following KOR activation, extracellular signal-regulated kinases 1/2 (ERK1/2) increased significantly in STR and amygdala (AMG), while phosphorylated ERK1/2 decreased during the first 2 h and then increased again in AMG and prefrontal cortex (PFC). This study shows that KOR activation alters the HPA axis and ERK signaling which may cause to develop mood disorders.

Discovery and Binding Mechanism of Pyrazoloisoquinoline-Based Novel β-Arrestin Inverse Agonists of the Kappa-Opioid Receptor.

Chronic exposure to stress or unwanted stimuli has been known to activate kappa opioid receptor/dynorphin (KOR/DYN) systems, which could induce depressive states and develop into some psychiatric disorders. Here, we report the first discovery of pyrazoloisoquinoline-based novel KOR β-arrestin inverse agonists through synthesis, structure-activity relationships, optimization, and the biological evaluations of μ/κ/δ opioid receptor activities with cAMP and β-arrestin recruitment assays. The optimized compound 7q shows potent and selective β-arrestin inverse agonism at KOR with an EC50 value of 9.33 nM in contrast to lower activities at DOR and no activity at MOR. Moreover, we use molecular dynamics simulations to predict the binding mode of the inverse agonist and propose a mechanism for the inverse agonism. We find that the transmembrane helix 6 position of the activated state is different for the OR subtypes, leading to significantly different interactions between the receptor and β-arrestin.

The efficacy of nalmefene on anesthetic recovery of patients: a study protocol for a multicenter randomized controlled trial

IntroductionSo far, the recovery quality after general anesthesia is still unsatisfied. Nalmefene is a drug to treat opioid overdose and reverse opioid actions. We aim to investigate the efficacy of nalmefene on optimizing the recovery quality of patients after general anesthesia.MethodsIt is a prospective, placebo-controlled, two-arm parallel groups, multicentre, double-blind, randomized (PPPMDR) clinical trial. The participants (n = 520) will be randomly assigned into two groups. Each patient will receive either: a single dose of nalmefene 0.25 µg/kg in the intervention group, or the same volume of 0.9% NaCl solution in the control group at the end of the surgery. The primary outcome will be the time interval between the end of anaesthesia and recovery endpoints achieved (Aldrete recovery score ≥ 9) in post-anesthesia care unit (PACU). The other variables are the time interval from the end of operation to extubation; Richmond Agitation Sedation Scale (RASS) score at extubation; the time at Montreal Cognitive Assessment Scale (MoCA) orientation score ≥ 5; visual analog scale (VAS) score and adverse effects including postoperative nausea and vomiting (PONV), and pruritus in PACU and 24 h postoperatively.AnalysisThis trial aims to study whether small dose of nalmefene can shorten the time from the end of surgery to Aldrete score ≥ 9 and improve opioid-induced side effects.This trial focuses on providing the reliable clinical evidence for satisfactory quality of recovery.Ethics and disseminationThis clinical trial has been approved and supported by the ethics committee of the Renji Hospital, Shanghai Jiaotong University, School of Medicine (KY2020-150); Shanghai Tongren Hospital (2021–030-01);The First Affiliated Hospital of Guangxi Medical University (2021–032); and The First Affiliated Hospital of Zhengzhou University(2021-KY-0495–003). Analysis of the study results will be submitted to a peer-reviewed journal for publication.Trial registrationClinicalTrials.gov, NCT04713358, Registered on September 23, 2021.

Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma.

Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin. All four selected cell lines display an increased cell proliferation and upregulation of MOR-1 when exposed to morphine. Furthermore, morphine promotes cell migration, while naloxone inhibits it. The effects on cell signaling pathways were analyzed using WB, demonstrating morphine activation of AKT and S6, key proteins in the PI3K/AKT/mTOR axis. A significant synergistic cytotoxic effect between cisplatin and naloxone in all cell lines is observed. In vivo studies of nude mice harboring HSC3 tumor treated with naloxone demonstrate a decrease in tumor volume. The synergistic cytotoxic effect between cisplatin and naloxone is observed in the in vivo studies as well. Our findings suggest that opioids may increase HNSCC cell proliferation via the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, MOR blockage may chemo-sensitize HNSCC to cisplatin.

Experimental and computational study of membrane permeabilization and translocation of the dynorphin A neuropeptide.

Dynorphins are endogenous neuropeptides that function as ligands for the κ-opioid receptor. In addition to opioid activity, dynorphins can induce several pathological effects such as neurological dysfunctions and cell death. Previous studies have suggested that Dynorphin A (DynA) mediates some pathogenic actions through formation of transient pores in lipid domains or translocation across the plasma membrane. Here, we use planar bilayer electrophysiology to show that DynA induces pore formation in negatively charged membranes. We find a large variability in pore conformations showing equilibrium conductance fluctuations, what disregards electroporation as the dominant mechanism of pore formation. Ion selectivity measurements showing cationic selectivity indicate that positive protein charges of DynA are stabilized by phosphatidyl serine negative charges in the formation of combined structures. We complement this study with computational simulations that assess the stability of diverse peptide arrangements in the hydrophobic core of the bilayer. We show that DynA is capable of assembling in charged membranes to form water-filled pores that conduct ions. Furthermore, we find that DynA generates membrane permeabilization events compatible with a translocation of the protein across the planar bilayer when using a neutral lipid. In these conditions, DynA is still capable of forming water-filled pores similar to those in a charged membrane, but translocation seems to be favored.

Structures of the entire human opioid receptor family

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-Gi 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.

Mu Opioid Receptor Activation Mediates (S)-ketamine Reinforcement in Rats: Implications for Abuse Liability

Background(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown. MethodsWe investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability. ResultsWe found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine–induced activation of the nucleus accumbens, a key brain reward region. A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and activity and decreased heroin reinforcement without producing changes in NMDA receptor or kappa opioid receptor density. ConclusionsThese results suggest that (S)-ketamine’s abuse liability in humans is mediated in part by brain MORs.

Morphological reorganization of periodontic tissues under experimental opioid influence for twelve weeks

Peculiarities of pathomorphological changes of periodontal components of rats under the long-term opioid influence during twelve weeks in the experiment have been studied.Objective – to determine the features of structural changes in the tissues of the periodontal complex of rats under conditions of long-term experimental action of opioids for twelve weeks.Methods. Adult male rats were administered the opioid analgesic nalbuphine for 12 weeks, in gradually increasing doses every 2 weeks. The initial dose was 0.212 mg / kg, 11-12 weeks - 0.3 mg / kg. Components of the dental organ of the upper and lower jaws of rats were used as material for histological examination. Sampling was performed at the end of week 12 of the experiment.Results. On histological preparations in the epithelium of the gums thinning, ulcers, desquamation, as well as the presence of areas of necrosis and inflammatory infiltrates were determined. Microscopic examinations of the epithelium of the free part of the gums in the gingival sulcus revealed foci of necrosis, accumulation of purulent bodies, damage to the epithelium of attachment and defragmentation of circular periodontal fibers, which led to the formation of periodontal pockets. Destruction of collagen fibers, purulent bodies, fibrinoid edema and fibrinoid necrosis were noted in the own plate. In the constituent components of the periodontium, the destruction of fibers with detachment from the connective tissue membrane of the dental cell, as well as signs of mucoid edema were determined. In the connective tissue of the periodontium observed thrombosis and stasis due to the coordination of blood cells, excessive proliferation of microvessels, diapedetic hemorrhage, which led to the progression of hypoxia.Conclusions. The experimental action of the opioid for 12 weeks revealed alternative changes, which were due to the deepening of dystrophy, necrosis of the soft tissues of the periodontium and severe hemomicrocirculation. Diffuse progression of the inflammatory-dystrophic process was due to insufficient activity of reparative processes, which indicated the irreversible nature of changes in the periodontium, which developed against the background of chronic opioid exposure.

Analgesic effects of main indole alkaloid of kratom, mitragynine in acute pain animal model

Mitragynine exerts its analgesic effect mainly via opioid receptors activation. Additionally, the effect may be mediated via mitragynine’s anti-inflammatory property and non-opioid receptor pain pathways, namely through the TRPV1 receptor. No studies identify hitherto, hence, the current study aimed to investigate the mitragynine’s analgesic effect via the anti-inflammatory property, non-opioid receptor (TRPV1) and the effective dose (ED) to alleviate pain. Male and female Sprague Dawley rats were pre-treated intraperitoneally with either mitragynine (1, 5, 10, 13, 15 or 30 mg/kg), vehicle, or indomethacin (1 mg/kg) 30 min before inducing inflammatory pain using acetic acid. The writhes and pain-related withdrawal behaviour occurrence were counted within a 1-h duration. Percentage of writhes inhibition, pain-related withdrawal behaviour aggregate, ED50 and ED95 were determined. The body temperature was recorded and TRPV1 expression in the rats' brains was measured. Mitragynine (except 1 mg/kg) significantly reduced the number of writhes compared with the vehicle administered group. Mitragynine (30 mg/kg) demonstrated 99.5% inhibition of writhing behaviour and low withdrawal behaviour score compared with vehicle and indomethacin and successfully blocked the hypothermia induced by acetic acid. The overall ED50 and ED95 values of mitragynine were 3.62 and 20.84 mg/kg, respectively. The percentage of writhing inhibition and withdrawal behaviour were similar in both genders. Mitragynine (15 and 30 mg/kg) significantly reduced the TRPV1 expression in the brain of the rats. Mitragynine alleviated pain-like behaviour and showed analgesic effects via anti-inflammatory and non-opioid receptor pathways. The findings also suggest that mitragynine might regulate some physiological functions of the rat.

Novel Approaches in Molecular Imaging and Neuroimaging of Fibromyalgia

Fibromyalgia (FM) represents a condition that is still controversial in its entity, pathophysiology, diagnosis and management. The aim of this review is to focus on imaging aspects of FM, especially on novel approaches in molecular imaging, with a special focus on neuroimaging. Novel functional and molecular imaging findings may represent, eventually, future biomarkers both in research settings and in terms of clinical practice. Several imaging techniques have already been tested in clinical trials in the FM field, including functional MRI, positron emission tomography (PET) imaging with 18F-FDG in FM, PET imaging of the dopaminergic system, PET imaging of the GABAergic system, PET imaging with neuroinflammation and neuroimmune parameters, PET imaging of the opioid system and H215O-PET activation studies. Therefore, the potential role in the FM field of fMRI and different PET tracers has been discussed in different settings, serving as a comprehensive guide of novel imaging options both in research and in the clinical field.