Opioid Antagonist Research Articles

Engaging healthcare teams to increase access to medications for opioid use disorder.

To assess the effectiveness of evidence-based quality improvement (EBQI) as an implementation strategy to expand the use of medications for opioid use disorder (MOUD) within nonspecialty settings. We studied eight facilities in one Veteran Health Administration (VHA) region from October 2015 to September 2022 using administrative data. Initially a pilot, we sequentially engaged seven of eight facilities from April 2018 to September 2022 using EBQI, consisting of multilevel stakeholder engagement, technical support, practice facilitation, and data feedback. We established facility-level interdisciplinary quality improvement (QI) teams and a regional-level cross-facility collaborative. We used a nonrandomized stepped wedge design with repeated cross sections to accommodate the phased implementation. Using aggregate facility-level data from October 2015 to September 2022, we analyzed changes in patients receiving MOUD using hierarchical multiple logistic regression. Eligible patients had an opioid use disorder (OUD) diagnosis from an outpatient or inpatient visit in the previous year. Receiving MOUD was defined as having been prescribed an opioid agonist or antagonist treatment or a visit to an opioid substitution clinic. The probability of patients with OUD receiving MOUD improved significantly over time for all eight facilities (average marginal effect [AME]: 0.0057, 95% CI: 0.0044, 0.0070) due to ongoing VHA initiatives, with the probability of receiving MOUD increasing by 0.577 percentage points, on average, each quarter, totaling 16 percentage points during the evaluation period. The seven facilities engaging in EBQI experienced, on average, an additional 5.25 percentage point increase in the probability of receiving MOUD (AME: 0.0525, 95%CI: 0.0280, 0.0769). EBQI duration was not associated with changes. EBQI was effective for expanding access to MOUD in nonspecialty settings, resulting in increases in patients receiving MOUD exceeding those associated with temporal trends. Additional research is needed due to recent MOUD expansion legislation.

Antinociceptive in vivo activity and chemical profiling by UHPLC-MS/MS of stem bark and leaves extracts of Ficus maxima Mill. (Moraceae)

Ethnopharmacological relevanceFicus maxima is a medicinal plant extensively used in traditional medicine by Indigenous peoples across Central and South America. It is a member of the family Moraceae, subgenus Pharmacosycea, employed in treating various conditions, including intestinal parasites, gingivitis, internal inflammations, and snake bites. Despite its significant pharmacological potential, the species remains underrepresented in scientific literature. Aim of the studyThis study aimed to evaluate the in vivo antinociceptive properties of leaf (ELFM) and stem bark (EBFM) extracts from Ficus maxima. Additionally, the chemical composition of these extracts was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Materials and methodsPlant material was collected in Abaetetuba, Pará, Brazil, in October 2013 and subjected to static maceration to obtain crude ELFM and EBFM. Bio-guided fractionation was performed by sequential liquid-liquid partitioning with hexane (Hex), dichloromethane (DCM), and ethyl acetate (EtOAc), yielding the following fractions: ELFM-Hex and EBFM-Hex, ELFM-DCM and EBFM-DCM, and ELFM-EtOAc and EBFM-EtOAc. The biological activity of EBFM, ELFM, and their respective fractions were evaluated using the formalin-induced pain test and the hot plate test, followed by an assessment of their mechanisms of action. The UHPLC-MS/MS analysis was conducted using electrospray ionization (ESI) in both positive and negative modes. Metabolite annotation was facilitated by MS/MS libraries and molecular networks constructed on the GNPS platform. ResultsThe reactivity time to formalin in the neurogenic phase was reduced from 84.7 ± 7.6 s (100%) to 37.3 ± 4.7 s (44%), 33.1 ± 6.3 s (39%), 40.7 ± 7.4 s (48%), 57.2 ± 2.6 s (77%), 49.7 ± 4.1 s (58%), 46.8 ± 8.1 s (55%), and 52.4 ± 5.3 s (61%) after treatment with ASA, morphine, EBFM, ELFM, ELFM-Hex, ELFM-DCM, and ELFM-EtOAc at doses of 30 mg/kg, respectively. In the inflammatory phase, the reactivity time to formalin was reduced from 124.3 ± 25.9 s (100%) to 49.7 ± 4.7 s (40%), 9.8 ± 4.3 s (8%), 32.5 ± 8.5 s (26%), 59.8 ± 16.8 s (48%), and 54.4 ± 7.3 s (44%) after treatment with ASA, morphine, EBFM, ELFM, and ELFM-Hex at doses of 30 mg/kg, respectively. A reversal of the antinociceptive action of EBFM and ELFM was observed in the inflammatory phase after treatment with atropine, a muscarinic antagonist, and naloxone, an opioid antagonist, respectively. In the hot plate test, EBFM showed Antinociceptive Activity (AA) of 62.6 ± 9.2% after 90 min; however, there was a reversal of AA to 8.6 ± 2.8% when naloxone was used. The UHPLC-MS/MS metabolite analysis revealed the presence of loliolide (3), luteolin (13), lupeol (14), gallic acid (15), chlorogenic acid (16), pygenic acid A (17), and other metabolites from the alkaloids and fatty acids classes.

Role of l -arginine/nitric oxide/cyclic GMP/K ATP channel signaling pathway and opioid receptors in the antinociceptive effect of rutin in mice.

The l -arginine ( l -Arg)/nitric oxide/cyclic GMP/potassium channel (K ATP ) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l -Arg/nitric oxide/cyclic GMP/K ATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l -Arg/nitric oxide/cyclic GMP/K ATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l -Arg (a precursor of nitric oxide), S-nitroso- N -acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro- l -arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a K ATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20 min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/K ATP channel pathway.

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Take-home naloxone administered in emergency settings: feasibility of intervention implementation in a cluster randomized trial

BackgroundOpioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT).MethodsWe undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events.ResultsAt two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported.ConclusionStaff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned.Trial RegistrationISRCTN13232859 (Registered 16/02/2018).

Ultra-Long-Term Delivery of Hydrophilic Drugs Using Injectable In Situ Cross-Linked Depots.

Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as in situ forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create in situ cross-linked depots (ISCD). The ISCD's solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. In vivo studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platform's biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions.

Pharmacological Treatments for Gambling Disorder: A Current Review of Literature

This narrative review aims to examine pharmacological treatment modalities for gambling disorder (GD) by analyzing recent literature and identifying significant trends in the field. A thorough examination of relevant literature, focusing primarily on recent studies and reviews, in order to identify significant pharmacological treatment approaches and current trends. Results: The review identifies several pharmacological approaches for GD, including opioid antagonists, serotonergic agents, dopaminergic modulators, glutamatergic agents, and mood stabilizers. Recent studies suggest that opioid antagonists such as naltrexone and nalmefene show promise in reducing gambling urges and behaviors. Additionally, serotonergic agents like selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy in alleviating the impulsivity and compulsivity associated with GD. Dopaminergic and glutamatergic agents, while showing some potential, require further investigation for their role in GD treatment. Mood stabilizers, particularly lithium, appear to be beneficial, especially in individuals with co-occurring bipolar affective disorder. Pharmacological interventions play a crucial role in the management of GD, with opioid antagonists and SSRIs emerging as promising options. However, further research is needed to elucidate the optimal pharmacotherapeutic approach and develop more targeted treatments for GD. Integration of pharmacotherapy with psychotherapeutic interventions may enhance treatment outcomes for individuals with GD.

The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150mg/kg, SC) for 36h and continuous intravenous infusion of vehicle (20μL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) for the full 36h. NLX elicited pronounced withdrawal signs in rats treated for 48h with morphine (150mg/kg, SC), plus continuous infusion of vehicle (20μL/h, IV) that began at the 36h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12h infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) that began at the 36h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.

Gabapentinoids Increase the Potency of Fentanyl and Heroin and Decrease the Potency of Naloxone to Antagonize Fentanyl and Heroin in Rats Discriminating Fentanyl.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. SIGNIFICANCE STATEMENT: The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

Baicalein isolated from Oroxylum indicum acts as a potent µ- and κ-opioid receptor antagonist agent via the reversal of agonist-mediated cAMP inhibition

The opioid receptors play a pivotal role in the treatment of several neuropsychiatric and neurological disorders. Oroxylum indicum (L.) Kurtz is a very important medicinal plant with several therapeutic applications. It is a main constituent of the Ayurvedic formulation ‘Dashmool’ used for multifaceted disorders by the Indians. However, the constituents of this plant in neurological conditions have not been well studied. Here, we performed activity-guided isolation of compounds for opioid receptor modulator activity. In the study, we found that the isolated compound baicalein (3) has shown the most potent and competitive antagonistic activity at 20 mg/kg dose in vivo experiments. The acute dose of 3 (20 mg/kg) and pan opioid receptor antagonist naloxone (20 mg/kg) block the morphine-induced antinociception and the paw withdrawal latency decreases up to 8.3 s and 9.6 s, respectively. The in silico studies also support our in vitro data that compound 3 binds with MOR and KOR.

Pharmacological interventions for pruritus in adult palliative care patients.

Pharmacological interventions for pruritus in adult palliative care patients.

Synthetic opioids have disrupted conventional wisdom for treating opioid overdose

More than 90 % of opioid overdose deaths in North America are now caused by synthetic opioids, and while they are not as prevalent in the European illicit drug market, there are indications that they may become so in the near future. Multiple publications have argued that neither higher doses of naloxone nor more potent opioid receptor antagonists are needed to reverse a synthetic opioid overdose. However, the unique physicochemical properties of synthetic opioids result in a very rapid onset of respiratory depression compared to opium-based molecules, reducing the margin of opportunity to reverse an overdose. While intravenous administration rapidly delivers the high naloxone concentrations needed to reverse a synthetic opioid overdose, this option is often unavailable to first responders. A translational mechanistic model of opioid overdose developed by the FDA’s Division of Applied Regulatory Science provides an unbiased approach to evaluate the effectiveness of overdose reversal strategies. Reports using this model demonstrated the naloxone tools (2mg intramuscular and 4mg intranasal) used by many first responders can result in an unacceptable loss of life following a synthetic opioid (fentanyl, carfentanil) overdose. Moreover, sequential (2.5minutes between doses) administration of up to four doses of intranasal naloxone was no more effective at reducing the incidence of cardiac arrest (a surrogate endpoint for lethality) than a single dose, suggesting that attempts at titration may not provide the rapid absorption required to reverse a synthetic opioid overdose. This model was also used to compare the effectiveness of intranasal naloxone to intranasal nalmefene, a recently FDA-approved opioid receptor antagonist with a more rapid absorption and a higher affinity at mu-opioid receptors compared to intranasal naloxone. Intranasal nalmefene resulted in large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone. Furthermore, simultaneous administration of four doses of intranasal naloxone was needed to reduce the incidence of cardiac arrest to levels approaching those produced by a single dose of intranasal nalmefene. These data are consistent with evidence that synthetics have indeed disrupted conventional wisdom in the treatment of opioid overdose.

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 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.

Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial cocultures through actions independent of opioid receptors.

Besides having high potency and efficacy at the µ-opioid (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuron (MSN) activity via opioid receptors or α1-adrenoceptors in dopamine type 1 or type 2 receptor (D1 or D2)-expressing MSNs. In neuronal and mixed-glial cocultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of cocultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by coexposure to the opioid receptor antagonist naloxone (10 µM) but fully negated by coadministering the pan-α1-adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α1A-adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α1-adrenoceptor action, α1-adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry and Adra1a mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a nonopioid receptor-dependent pathway, which may be modulated via complex actions in α1-adrenoceptor-expressing striatal neurons and/or glia.NEW & NOTEWORTHY Acute fentanyl exposure attenuated the activity of striatal medium spiny neurons (MSNs) in vitro and in dopamine D2, but not D1, receptor-expressing MSNs in ex vivo slices. By contrast, sustained fentanyl exposure suppressed the spontaneous activity of MSNs cocultured with glia through a nonopioid receptor-dependent mechanism modulated, in part, by α1-adrenoceptors. Fentanyl exposure can affect striatal function via a nonopioid receptor mechanism of action that appears mediated by α1-adrenoreceptor-expressing striatal neurons and/or astroglia.

Off-Label Use of Lamotrigine and Naltrexone in the Treatment of Ketamine Use Disorder: A Case Report.

Ketamine is a dissociative anesthetic increasingly utilized in United States medical settings for the treatment of mental health conditions. Additionally, it is increasingly used in nonmedical settings for its dissociative properties. While nonmedical ketamine use and ketamine use disorder (KUD) have been observed internationally, KUD, and approaches to its treatment, have not been previously described in the US. We present the case of a 32-year-old man with KUD who experienced severe cravings despite receipt of residential and intensive outpatient substance use disorder treatment. He resumed use after an initial period of abstinence and was subsequently started on lamotrigine and naltrexone for treatment of depressive symptoms and cravings. This combination altered his experience while on ketamine, resulting in nausea and decreased hallucinogenic effects. In addition, it substantially decreased his cravings, aiding him in achieving longer-term abstinence in combination with receipt of dialectical behavioral therapy, familial support, and involvement in 12-step programming. KUD is a poorly described condition that may become more prevalent as US ketamine use increases. Combining treatment of depressive symptoms and cravings, in this case with lamotrigine and naltrexone, may be a promising pharmacotherapeutic strategy. Lamotrigine, an antiepileptic with glutamate modulating effects, has been utilized to decrease cravings in a variety of substance use disorders. Naltrexone is an opioid antagonist approved for alcohol use disorder and opioid use disorder and is used off-label for stimulant use disorder. This combination offers a possible pharmacotherapeutic option for KUD with more research needed to further evaluate.

Abstract We092: Naltrindole Attenuates Superoxide Release in Polymorphonuclear Leukocytes by a Novel Mechanism devoid of Delta opioid receptor antagonism Related to Reduced Intracellular Calcium Levels

Introduction: Naltrindole (NTI), known as a delta opioid receptor antagonist, inhibited phorbol 12-myristate 13-acetate (PMA) induced superoxide (SO) release in polymorphonuclear leukocytes (PMNs). PMNs do not express opioid receptors. We propose NTI reduces PMN SO by reducing intracellular calcium (Ca 2+ ). To test this hypothesis, we did experiments using KB-R7943 (KB) as a positive control, known to reduce intracellular Ca 2+ via inhibition of the reverse mode Na + /Ca 2+ exchanger. Naloxone (NX), a broad-spectrum opioid receptor antagonist, was used as a negative control. We predict that NTI will diminish PMA-induced PMN SO release similar to KB, while NX will have no effect, and that there will be no difference in cell viability compared to vehicle controls. Methods: Male Sprague Dawley (SD) rat PMNs (5x10 6 ) were incubated for 15 min at 37 o C in the presence or absence (dH 2 O vehicle control) of NTI (10 - 200 µM), KB (5-20 µM), and NX (100-200 µM). PMN SO release was measured by the change in absorbance at 550 nm over 420 sec via ferricytochrome c reduction after PMA stimulation (100 nM). The cell viability was determined microscopically by 0.2% trypan blue exclusion at the end of PMN SO release assay. Data were analyzed using ANOVA Fisher’s PLSD post-hoc test. Results: NTI significantly decreased PMN SO release at 200 μM (n=10, 0.196±0.06, p<0.05) compared to vehicle control (n=22, 0.731±0.07) or NX 100/200 μM (n=3, 0.593±0.06), and NTI at 100 μM (n=7, 0.461±0.08, p<0.05) versus vehicle control. Likewise, KB significantly decreased PMN SO release at 20 μM (n=7, 0.507±0.07), 10 μM (n=7, 0.552±0.07), and 5 μM (n=5, 0.615±0.11) compared to vehicle control (n=10, 0.908±0.07). Cell viability was statistically similar (80-90±5%) among all study groups. Conclusion: NTI (10-200 μM) and KB (5-20 µM) exhibited concentration-dependent effects in reducing PMN SO release without compromising cell viability. The results suggest that the novel effect of NTI maybe mediated through a reduction in intracellular Ca 2+ and independent of delta opioid receptor antagonism. These results are consistent with the effects of NTI, KB and NX in myocardial ischemia/reperfusion injuries. Future studies will assess the effects of NTI on ROS attenuation in human umbilical vein endothelial cells.

Exploring the analgesic potential of isorhamnetin: insights from formalin-induced pain and diabetic neuropathy models.

Isorhamnetin, a naturally occurring flavonoid compound, holds paramount importance as a primary constituent within several medicinal plants, exhibiting profound pharmacological significance. The aim of this study is to investigate the pain-relieving attributes of isorhamnetin in murine models through both formalin-induced pain and diabetic neuropathy scenarios. To achieve our objective, isorhamnetin was orally administered to mice at varying dosage levels (10 to 100 mg/kg). Pain-related behaviors were assessed using the formalin test during its secondary phase. Additionally, the potential pain-alleviating effect of isorhamnetin was evaluated in a diabetic neuropathy model induced by streptozotocin. Additionally, we carried out advanced interventions using naloxone, which is a well-known antagonist of opioid receptors, yohimbine, which blocks α2-adrenergic receptors, and methysergide, which inhibits serotonergic receptors, during the formalin test. The oral intake of isorhamnetin showed a decrease in behaviors associated with pain that was proportional to the dose observed during the second phase of the formalin test when induced by formalin. In the diabetic neuropathy model, isorhamnetin administration effectively reversed the reduced pain threshold observed. Notably, naloxone, the opioid receptor antagonist, effectively counteracted the pain-relieving effect produced by isorhamnetin in the formalin test, whereas yohimbine and methysergide did not yield similar outcomes. Isorhamnetin also led to a reduction in elevated spinal cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) levels triggered by formalin, with this effect reversed by pre-treatment with naloxone. The compound also suppressed heightened spinal phosphorylated CREB (p-CREB) levels caused by diabetic neuropathy. This research determined that isorhamnetin has notable abilities to relieve pain in models of formalin-induced pain and diabetic neuropathy. The pain-relieving mechanism of isorhamnetin in the formalin-induced pain model seems to be connected to the activation of spinal opioid receptors and the adjustment of CREB protein amounts. This insight improves our knowledge of how isorhamnetin could be used therapeutically to treat pain conditions stemming from formalin-induced pain and diabetic neuropathy.

A novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers.

The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.

Discriminative stimulus properties of two training doses of gabapentin in rats: Substitution by pregabalin, diazepam, and pentobarbital.

Gabapentin is used for the treatment of many conditions, including seizures, pain, and anxiety. Increasing reports of nonprescribed use suggest that gabapentin may elicit positive subjective effects. The present study was conducted to examine the subjective effects of gabapentin using rats trained to discriminate either a 30.0 mg/kg or 300.0 mg/kg dose of gabapentin versus vehicle on a two-choice drug discrimination task. Both doses of gabapentin were established as discriminative stimuli, and the 300.0 mg/kg dose was more readily established compared to the 30.0 mg/kg dose. Full substitution (> 80% gabapentin-lever responding) occurred by the training drug and by the gabapentinoid compound pregabalin. Partial substitution (> 20% gabapentin-lever responding) was shown by the opioid compounds morphine and fentanyl, and dose combinations of the opioid receptor antagonist naltrexone with the gabapentin training doses reduced the percentage of gabapentin-lever responding to below 80%. Partial substitution for both training doses of gabapentin occurred with the cannabinoid Δ⁹-tetrahydrocannabinol. The barbiturate compound pentobarbital and the benzodiazepine compound diazepam were only tested for substitution for the 300.0 mg/kg dose of gabapentin and these compounds produced full substitution. These findings demonstrate that gabapentin establishes a robust discriminative cue and exhibits stimulus effects closely similar to pregabalin, pentobarbital, and diazepam. Since pregabalin, pentobarbital, and diazepam carry a risk of problematic use and are classified as controlled substances, further evaluations of gabapentin's risks in this regard are warranted. (PsycInfo Database Record (c) 2024 APA, all rights reserved).