Effects Of Opioid Agonists Research Articles

Effects of chronic naltrexone treatment on relapse-related behavior and neural responses to fentanyl in awake nonhuman primates.

Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD.

Underlying mechanisms for psychotropic effects of delta opioid receptor agonists

Underlying mechanisms for psychotropic effects of delta opioid receptor agonists

Integrated exercise program in opioid agonist therapy clinics and effect on psychological distress: study protocol for a randomized controlled trial (BAReAktiv)

BackgroundSubstance use disorder is associated with unhealthy lifestyle choices, resulting in adverse social and health consequences. People with opioid use disorder receiving opioid agonist therapy, in particular, have high morbidity and reduced quality of life. Physical activity is recommended as an adjunctive treatment for people with substance use disorder, but there is minimal evidence from randomized controlled trials on the effects of this among people with substance use disorder receiving opioid agonist therapy.MethodsBAReAktiv is a multicentre randomized controlled trial. The study aims to recruit 324 patients receiving opioid agonist therapy (parallel groups randomized 1:1 to integrated exercise intervention or control, superiority trial). A 16-week group-based integrated exercise intervention with workouts twice a week. The exercise program consists of endurance and resistance training. The target group will be patients 18 years and older receiving opioid agonist therapy in outpatient clinics in several centers in Western Norway. The primary outcome of the study is the effect on psychological distress measured by Hopkins’ symptom checklist with ten items. Secondary outcome measures include physical functioning assessed with a 4-min step test, activity level, fatigue symptoms, quality of life, and changes in inflammation markers. This study will provide improved knowledge on the effects of an integrated exercise program in opioid agonist therapy.DiscussionSystematically integrating exercise programs for people receiving opioid agonist therapy could lead to a shift towards a stronger focus on health behaviors in outpatient care. Integrating exercise could benefit patient recovery and reduce disease burden. Further scale-up will be considered if the provided exercise program is safe and effective.Trial registrationClinicalTrials.gov. NCT05242848. Registered on February 16, 2022.

Daily methocinnamox treatment dose-dependently attenuates fentanyl self-administration in rhesus monkeys

Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that might be an effective treatment for opioid use disorder (i.e., preventing relapse and overdose). In nonhuman primates, MCAM selectively blocks the positive reinforcing effects of mu opioid receptor agonists, including heroin, fentanyl, and its ultra-potent analogs (e.g., carfentanil) with a single administration of MCAM being effective for up to two weeks. Because treatment of opioid use disorder would involve repeated administration of a medication, MCAM was studied in rhesus monkeys (3 males and 2 females) responding under a fixed-ratio self-administration procedure for a range of doses of fentanyl (0.000032–0.1 mg/kg/infusion). The fentanyl self-administration dose-effect curve was determined before and during treatment with progressively increasing daily doses of MCAM (0.001–0.1 mg/kg) given subcutaneously 1 h before the session. MCAM dose-dependently shifted the fentanyl dose-effect curve rightward and then, at larger doses, downward. The largest treatment dose of MCAM (0.1 mg/kg/day) shifted the curve more than 120-fold rightward with monkeys receiving doses much larger than the likely lethal dose of fentanyl with no adverse effect or observable change in behavior. This study demonstrates that MCAM reliably and dose-dependently decreases fentanyl self-administration and prevents opioid overdose, with no evidence of adverse effects over a broad dose range, further supporting the potential therapeutic utility of this novel antagonist.

The Effects of Chronic Naltrexone on Reinstatement of Opioid-Induced Drug-Seeking Behavior and Antinociception.

Opioid addiction is a chronic relapsing disorder in which drug-seeking behavior during abstinence can be provoked by exposure to a µ-opioid receptor (MOR) agonist or opioid-associated cues. Opioid self-administration behavior in laboratory subjects can be reinstated by priming with MOR agonists or agonist-related stimuli, providing a procedure suitable for relapse-related studies. The opioid antagonist naltrexone has been forwarded as a medication that can forestall relapse and, in an extended-release formulation, has demonstrated some treatment success. However, chronic naltrexone treatment has not been extensively investigated in nonhuman subjects and aspects of its pharmacology remain uncertain. For example, the relative effectiveness of naltrexone in reducing the priming strength of opioid agonists differing in efficacy is not well understood. Here, using intravenous self-administration and warm-water tail withdrawal procedures, we investigated changes in the direct reinforcing effects of oxycodone and in the priming strength and antinociceptive effects of opioid agonists in squirrel monkeys (n = 4) during chronic treatment with naltrexone (0.2 mg/kg/d). Results show that naltrexone produced: 1) a 10-fold rightward shift in the dose-response function for the reinforcing effects of oxycodone, and 2) in reinstatement and antinociception experiments, comparable rightward shifts in the dose-response functions for higher-efficacy MOR agonists (methadone, heroin, and oxycodone) but rightward and downward shifts in the dose-response functions for lower-efficacy MOR agonists (buprenorphine, nalbuphine, and butorphanol). These results suggest that, although chronic naltrexone should be effective in forestalling relapse following exposure to lower- and higher-efficacy agonists, the inability of lower-efficacy agonists to surmount naltrexone antagonism may complicate the prescription of opioids for pain. SIGNIFICANCE STATEMENT: Although naltrexone is commonly used in the treatment of opioid use disorder, its ability to reduce the priming strength of opioid agonists has not been extensively investigated. This study shows that chronic naltrexone treatment induces rightward shifts in the reinstatement and antinociceptive properties of higher efficacy opioid agonists, but rightward and downward shifts for lower efficacy opioid agonists, suggesting lower efficacy agonists may not be able to surmount naltrexone-induced antagonism of these two effects, and perhaps naltrexone offers greater protection against lower efficacy agonists.

Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review.

Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approvalby the FDA, tianeptine has been distributed online and at small retail locations. The term "gas station drugs" refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as "Zaza" and "Tianna Red." It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans—A Systematic Review and Treatment Guideline

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

Quantitative proteomic analysis reveals the effects of mu opioid agonists on HT22 cells.

Introduction: At present, the mu opioid receptor is the most important neuroaesthetics receptor in anesthesiology research, and the damage that it does to the nervous system is unknown. Methods: We investigated the effects of loperamide, an agonist of the mu opioid receptor, on protein expression in HT22 cells using stable isotope labeling of amino acids in cell culture (SILAC), immobilized metal affinity chromatography (IMAC) enrichment, and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 7,823 proteins were identified. Results and Discussion: Bioinformatic analysis revealed that mu opioid receptor agonism can induce distinct changes in the proteome of HT22 cells. These findings improve our understanding of narcotic drugs.

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund’s adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1β, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress.

Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla.

Functional magnetic resonance imaging (fMRI) has been used to study the influence of opioids on neural circuitry implicated in opioid use disorder, such as the cortico-striatal-thalamo-cortical (CSTC) circuit. Given the increase in fentanyl-related deaths, this study was conducted to characterize the effects of fentanyl on patterns of brain activation in awake nonhuman primates. Four squirrel monkeys were acclimated to awake scanning procedures conducted at 9.4 Tesla. Subsequently, test sessions were conducted in which a dose of fentanyl that reliably maintains intravenous (IV) self-administration behavior in monkeys, 1μg/kg, was administered and the effects on patterns of brain activity were assessed using: (1) a pharmacological regressor to elucidate fentanyl-induced patterns of neural activity, and (2) seed-based approaches targeting bilateral anterior cingulate, thalamus, or nucleus accumbens (NAc) to determine alterations in CSTC functional connectivity. Results showed a functional inhibition of BOLD signal in brain regions that mediate behavioral effects of opioid agonists, such as cingulate cortex, striatum and midbrain. Functional connectivity between each of the seed regions and areas involved in motoric, sensory and cognition-related behavior generally decreased. In contrast, NAc functional connectivity with other striatal regions increased. These results indicate that fentanyl produces changes within CSTC circuitry that may reflect key features of opioid use disorder (e.g. persistent drug-taking/seeking) and thereby contribute to long-term disruptions in behavior and addiction. They also indicate that fMRI in alert nonhuman primates can detect drug-induced changes in neural circuits and, in turn, may be useful for investigating the effectiveness of medications to reverse drug-induced dysregulation.

A239 COMBINED CANNABINOID RECEPTOR 1 AND MU-OPIOID RECEPTOR AGONISTS SYNERGISTICALLY INHIBIT VISCERAL PAIN IN VIVO WITHOUT ADVERSE SIDE EFFECTS OR TOLERANCE

Abstract Background Previously we have shown that both cannabinoid 1 receptor (CB1R) and mu-opioid receptor (MOR) agonists inhibit mechanosensitivity of colonic nociceptive nerves. However, it is unknown whether agonists of cannabinoid and opioid receptors have a synergistic interaction, such that very low doses of these agonists can be employed to reduce visceral pain and side effects. Aims To determine the effects of combined cannabinoid and opioid receptor agonists on visceral pain and its side effects. Methods Telemetric transmitters were surgically implanted into the abdominal cavity of C57/BL6 mice, with electrodes sutured to the external oblique muscle to measure the visceromotor response (VMR) to colorectal distention using a 4F arterial embolectomy catheter (volume range 20–80 µL). Mice were injected intraperitoneally with vehicle, arachidonyl-2’-chloroethylamide (ACEA), a selective CB1R agonist (0.3, 1, 3 mg/kg), HU-308, a selective CB2R agonist (0.3, 1, 3mg/kg), morphine, a MOR agonist (0.3, 3 mg/kg), or a combination, 30-minutes prior to distention. To assess side effects, pulse oximetry, heart rate, fecal pelleting, and locomotion (via an open-field maze) were measured. Data was analyzed with one or two-way ANOVA with post-hoc Bonferroni multiple comparisons test. Results ACEA dose-dependently reduced VMR (P<0.01 vs. vehicle, N=5); at the 80 µL distention, reductions of 35% (P<0.01) and 62% (P<0.01) were observed for 1 mg/kg and 3 mg/kg respectively. In contrast, HU-308 did not reduce VMR at any dose (P=0.17, N=8). Morphine (0.3 mg/kg) did not reduce VMR (P>0.99), while a higher dose (3 mg/kg) attenuated VMR (P<0.01 vs. vehicle, N=5); reductions of 32% (P<0.01) and 61% (P<0.01) at 60 and 80 µL distentions respectively. Interestingly, a combination of sub-analgesic doses of ACEA (0.3 mg/kg) and morphine (0.3 mg/kg) significantly reduced VMR (P<0.01 vs vehicle, N=5); compared to vehicle, VMR was reduced by 21% at 40 µL (P<0.05), 27% at 60 µL (P<0.01) and 60% at 80 µL (P<0.01). Chronic administration (2x/day for 6 days) of this combination did not alter the magnitude of its inhibitory effect (P=0.67, N=5), suggesting tolerance did not develop. While analgesic doses of morphine (3mg/kg) decreased oxygen saturation (P<0.01), heart rate (P<0.01) and fecal pelleting (i.e., GI motility; P<0.05), the sub-analgesic combination of ACEA and morphine had no effect (P>0.99 for all, N=5). Locomotion was unchanged by the agonists alone or combined (P=0.17). Conclusions A combination of sub-analgesic doses of CB1R and MOR agonists significantly inhibits visceral pain in vivo, without development of sides effects or tolerance with chronic use. Thus, combining low doses of CB1R and MOR agonists may be an effective visceral pain management strategy. Funding Agencies NSERC

Opioid receptor signaling suppresses leukemia through both catalytic and non-catalytic functions of TET2.

Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells invitro and mouse and human AML models invivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.

Naltrexone Implant for Opioid Use Disorder.

The continued rise in the availability of illicit opioids and opioid-related deaths in the United States has left physicians, researchers, and lawmakers desperate for solutions to this ongoing epidemic. The research into therapeutic options for the treatment of opioid use disorder (OUD) began with the introduction of methadone in the 1960s. The approval of oral naltrexone initially showed much promise, as the drug was observed to be highly potent in antagonizing the effects of opioids while producing no opioid agonist effects of its own and having a favorable side effect profile. Patients that routinely take their naltrexone reported fewer days of heroin use and had more negative drug tests than those without treatment. Poor outcomes in OUD patients treated with naltrexone have been directly tied to short treatment time. Studies have shown that naltrexone given orally vs. as an implant at the 6-month interval showed a higher non-compliance rate among those who used oral medications at the 6-month mark and a slower return to use rate. There were concerns that naltrexone could possibly worsen negative symptoms seen in opiate use disorder related to blockade of endogenous opioids that are important for pleasurable stimuli. Studies have shown that naltrexone demonstrated no increase in levels of anxiety, depression and anhedonia in participants and another study found that those treated with naltrexone had a significant reduction in mental health-related hospitalizations. The latter study also concluded that there was no increased risk for mental health-related incidents in patients taking naltrexone via a long-acting implant. Although not yet FDA approved in the United States, naltrexone implant has shown promising results in Europe and Australia and may provide a novel treatment option for opioid addiction.

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis.

Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.

Characterization of the Discriminative Stimulus Effects of Binary Mixtures of Mu Opioid Receptor Agonists in Rats Discriminating Fentanyl.

Drug overdose deaths involving synthetic opioids, primarily fentanyl, have risen dramatically over the past decade and are currently the driving force of the opioid epidemic in the United States. Fentanyl analogs with greater potency than fentanyl (e.g., carfentanil) pose serious risk to public health. Although fentanyl analogs are primarily encountered by humans as constituents of a mixture of drugs, research has primarily evaluated the effects of these drugs alone. The present study characterized interactions between mu opioid receptor agonists in seven male Sprague-Dawley rats trained to discriminate 10 μg/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for each drug alone and in binary mixtures (fentanyl:heroin, fentanyl:carfentanil, and heroin:carfentanil) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the ED50 for each drug when given alone. Dose addition analyses were used to determine the nature of the drug-drug interaction for each mixture. Additive interactions were observed for all binary mixtures at each fixed dose ratio, except the 1:3 fentanyl:carfentanil mixture, which exhibited supra-additive effects at the 80% effect level. These results suggest a lack of a significant interaction between the discriminative stimulus effects of these mu opioid receptor agonists at the doses tested in this study. Future studies expanding these findings to the respiratory depressant effects of these drugs are of significant importance to rule out possible interactions directly relevant to opioid overdose that occur at doses much larger than those tested in this study. SIGNIFICANCE STATEMENT: In the United States, drug overdose deaths involving synthetic opioids, primarily fentanyls including superpotent fentanyl analogs (e.g., carfentanil), have increased 12-fold over the past decade. Although previous studies have evaluated the effects of carfentanil alone, fentanyl analogs are encountered by humans as a mixture with other drugs; this study determined the effects of mixtures of carfentanil and other opioids (fentanyl and heroin) to characterize interactions between these drugs that might contribute to their apparent increased lethality in humans.

Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists.

Partial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small-molecule NOP receptor ligands may be more suitable as therapeutic agents. This study investigated the cardiovascular and renal responses produced by the novel nonpeptide NOP agonists AT-403, AT-090, AT-127, and AT-039. Changes in mean arterial pressure (MAP), heart rate (HR), renal excretory function and occurrence of sedation and hyperphagia were determined before and after i.v. bolus injection or infusion of the NOP agonists in conscious Sprague-Dawley rats. Additional studies involving (i) measurement of renal sympathetic nerve activity (RSNA) and (ii) renal denervation were conducted to investigate the role of the renal nerves in the cardiorenal responses to AT-039. Bolus i.v. injection of AT-403, AT-090, AT-127 and AT-039 produced significant decreases in MAP and HR and a sodium-sparing diuresis. AT-403, AT-090, and AT-127, but not AT-039, induced sedation and hyperphagia at all doses tested. Infusion i.v. of AT-039 produced hypotension and aquaresis without adverse central nervous system effects or change in HR, responses that were also observed in renal denervated rats. Nonpeptide NOP agonists decrease blood pressure and produce aquaresis in conscious rodents. Due to lack of sedation and hyperphagia, AT-039 represents a novel NOP agonist that may be useful for treatment of hypertension and/or volume overload/hyponatraemic states.

Glutamate Buffering Capacity and Blood-Brain Barrier Protection of Opioid Receptor Agonists Biphalin and Nociceptin.

Opioids play crucial roles in the regulation of many important brain functions including pain, memory, and neurogenesis. Activation of opioid receptors is reported to have neuroprotective effects after ischemic reperfusion injury. The objective of this study was to understand the role of biphalin and nociceptin, opioid receptor agonists, on blood-brain barrier (BBB) integrity during ischemic stroke. In this study, we aimed to measure the effect of biphalin and nociceptin on astrocytic glutamate uptake and on expression of excitatory amino acid transporter to study the indirect role of astrocytes on opioid receptor-mediated BBB protection during in vitro stroke conditions. We used mouse brain endothelial cells (bEnd.3) and primary astrocytes as an in vitro BBB model. Restrictive BBB properties were evaluated by measuring [14C] sucrose paracellular permeability and the redistribution of the tight junction proteins. The protective effect of biphalin and nociceptin on BBB integrity was assessed after exposing cells to oxygen glucose deprivation (OGD) and glutamate. It was observed that combined stress (2 mM glutamate and 2 hours of OGD) significantly reduced glutamate uptake by astrocytes; however, biphalin and nociceptin treatment increased glutamate uptake in primary astrocytes. This suggests a role of increased astrocytic buffering capacity in opioid-meditated protection of the BBB during ischemic stroke. It was also found that the combined stress significantly increased [14C] sucrose paracellular permeability in an in vitro BBB model. Biphalin and nociceptin treatment attenuated the effect of the combined stress, which was reversed by the opioid receptor antagonists, suggesting the role of opioid receptors in biphalin and nociception's BBB modulatory activity. SIGNIFICANT STATEMENT: There is an unmet need for discovering new efficacious therapeutic agents to offset the deleterious effects of ischemic stroke. Given the confirmed roles of opioid receptors in the regulation of central nervous system functions, opioid receptor agonists have been studied as potential neuroprotective options in ischemic conditions. This study adds to the knowledge about the cerebrovascular protective effects of opioid receptor agonists and provides insight about the mechanism of action of these agents.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids

The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (−)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (−)-CP 55,940. To establish (±)-U-50488 as a discriminative stimulus, rats (n = 12) were trained to discriminate intraperitoneal (i.p.) administration of 5.6 mg/kg of (±)-trans-U-50488 from saline under a fixed-ratio 20 (FR-20) schedule of food reinforcement. Then, antinociception was assessed using two procedures: warm water tail withdrawal and von Frey paw withdrawal. Diuretic effects were assessed in separate rats (n = 6/group). Doses of (±)-U-50488 and (−)-U-50488 that served as discriminative stimuli produced significant increases in urine output, but at lower doses than those that produced antinociception. In contrast, (+)-U-50488 alone had no discriminative stimulus or diuretic effects at the doses tested, but did produce antinociception in the von Frey assay. When three cannabinoids and morphine were tested in the (±)-U-50488 discrimination procedure to determine the similarity of these drugs' discriminative stimulus effects to those for (±)-U-50488, the rank order similarity was (−)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ morphine. (−)-CP 55,940 alone (0.056 mg/kg) partially substituted for the discriminative stimulus effects of (±)-U-50488 and produced significant diuretic and antinociceptive effects. (−)-CP 55,940 in combination with (±)-U-50488 also produced a two-fold leftward shift in the discriminative stimulus curve for (±)-U-50488, and near-additive antinociception with (±)-U-50488 and (+)-U-50488. Further, the diuretic effect of (−)-CP 55,940 was enhanced by a dose of (+)-U50488, which itself did not alter urine output. These data together indicate that a combination of cannabinoid and kappa opioid agonists can enhance diuresis, but may have limited potential for serving as opioid-sparing pharmacotherapeutics for treatment of pain.