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Repurposing Disulfiram as an Anti-Obesity Drug: Treating and Preventing Obesity in High-Fat-Fed Rats.

Background and objectivesA drug repurposing strategy is an approach for identifying new therapeutic uses for approved or investigational drugs. Thanks to the moderate cost of repurposing a drug compared to bringing new chemical entity to the market, drug repurposing is rapidly gaining ground. The aim of this work is to study the anti-obesity effect of disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor approved by the Food and Drug Administration (FDA) to treat chronic alcoholism since 1951.MethodsThirty male Albino rats were randomly assigned to six groups. G1, the control grou

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… Organization as one of the major challenges in public health in the twenty-first century, 2 there is still no clear-cut solution. 6 To date, the Food and Drug Administration (FDA) has approved only five drugs or drug combinations for long-term obesity treatment: orlistat, lorcaserin, liraglutide, bupropion-naltrexone … short-term use: benzphetamine, phentermine, phendimetrazine and diethylpropion. 7 Very recently, lorcaserin was withdrawn from the US market, as a safety clinical trial showed an increased occurrence of cancer. 8 Meanwhile, the European Medicines Agency has approved only three medicines, orlistat, bupropion-naltrexone …

General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (N … st, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, …

Peripheral kappa opioid receptors modulate cold hypersensitivity in a mouse model of chemotherapy-induced neuropathy.

Noxious cold sensation is commonly associated with peripheral neuropathies; however, there has been limited progress in understanding the mechanism. Here, we identify a novel role for peripherally expressed kappa opioid receptors [KORs] in noxious cold hypersensitivity in a mouse model of chemotherapy. In this model, we show that oxaliplatin-induced cold hypersensitivity is attenuated using norbinaltorphimine (NorBNI, KOR antagonist (10 mg/kg, i.p.) in both male and female mice. To further examine the role of KORs in cold hypersensitivity, we show that activation of KOR with U50,488 (KOR agoni

Antidepressant-like effects of dezocine in mice: involvement of 5-HT1A and κ opioid receptors.

Dezocine is an opioid with low efficacy at μ-opioid and κ-opioid receptors. It also inhibits the reuptake of norepinephrine and serotonin. Dezocine is an effective analgesic against various clinical painful conditions and is widely used in many Asian countries. Given the unique pharmacology of dezocine, the drug may also have antidepressant-like properties. However, no published preclinical study has explored this possibility. This study examined the potential antidepressant-like activity of dezocine in mice. Male ICR mice were used in the forced swimming test, the tail suspension test, the wa

Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain.

Expression of beta(2)-adrenoceptors (beta(2)-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of beta(2)-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of beta(2)-ARs with agonists such as clenbuterol, formoterol, metaproterenol and

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity.

Sialorphin is an exocrine and endocrine signaling mediator, which has been identified by a genomic approach. It is synthesized predominantly in the submandibular gland and prostate of adult rats in response to androgen steroids and is released locally and systemically in response to stress. We now demonstrate that the cell surface molecule to which sialorphin binds in vivo in the rat kidney is the membrane-anchored neutral endopeptidase (neprilysin; NEP, EC 3.4.24.11). NEP plays an important role in nervous and peripheral tissues, as it turns off several peptide-signaling events at the cell su

Parallel synthesis and biological activity of a new class of high affinity and selective delta-opioid ligand.

A considerable number of research papers describing the synthesis and testing of the delta opioid receptor (DOR) ligands, SNC-80 and TAN-67, and analogues of these two compounds, have been published in recent years. However, there have been few reports of the discovery of completely new structural classes of selective DOR ligand. By optimising a hit compound identified by high throughput screening, a new series of tetrahydroisoquinoline sulphonamide-based delta opioid ligands was discovered. The main challenge in this series was to simultaneously improve both affinity and physicochemical prope

Obesity Management in Adults: A Review.

IMPORTANCE: Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiova … tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide has the greatest effect, with mean weight loss of 21% at 72 weeks. Endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) can attain 10% to 13% weight loss at 6 months. Weig …

A tarantula peptide against pain via ASIC1a channels and opioid mechanisms.

Psalmotoxin 1, a peptide extracted from the South American tarantula Psalmopoeus cambridgei, has very potent analgesic properties against thermal, mechanical, chemical, inflammatory and neuropathic pain in rodents. It exerts its action by blocking acid-sensing ion channel 1a, and this blockade results in an activation of the endogenous enkephalin pathway. The analgesic properties of the peptide are suppressed by antagonists of the mu and delta-opioid receptors and are lost in Penk1-/- mice.

Current choices--good or bad--for the proactive management of postoperative ileus: A surgeon's view.

Postoperative ileus (POI) is frequently experienced by many patients undergoing abdominal operations and other surgical procedures. Postoper … se effects. A new class of agents, peripherally acting mu-opioid-receptor antagonists such as methylnaltrexone and alvimopan, may improve the pharmacologic management of POI and reshape the current paradigm of multimodal management of POI. Protocols that incorporate these agents may offer yet another avenue to mitigate the adverse effects of POI, and thus he …

Mu opioid modulation of oxytocin secretion in late pregnant and parturient rats. Involvement of noradrenergic neurotransmission.

We have investigated effects of micro- and kappa-opioid agonists and antagonists on plasma oxytocin levels and noradrenaline content in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of 20-day pregnant rats. beta-Endorphin, oxytocin, estrogen and progesterone profiles in late pregnant and parturient rats were also sought. Stage of estrous cycle was monitored by vaginal smear, and pro-estrous animals were left overnight with male. In the first set of experiments, pregnant rats were monitored and decapitated on days 20 and 21 and after the delivery of second pup. In the second se

Acute and chronic effects of opioids on delta and mu receptor activation of G proteins in NG108-15 and SK-N-SH cell membranes.

To compare activation of G proteins by opioid receptors, opioid agonist-stimulated guanosine 5'-O-(3-[35S]thiotriphosphate) ([35S]GTP gamma S) binding in the presence of excess GDP was assayed in membranes from NG108-15 (delta) and SK-N-SH (primarily mu) cells. Basal [35S]GTP gamma S binding consisted of a single class of low-affinity sites (KD 400-500 nM). Addition of agonists produced a high-affinity site 100-300-fold higher in affinity than the basal site. The receptor/transducer amplification factor (ratio of activated G protein Bmax to opioid receptor Bmax) was 10-fold higher for SK-N-SH

Intrathecal administration of dynorphin A and its fragments increase heart rate and arterial pressure in the urethane anesthetized rat: mediation by a nonopioid mechanism.

Intrathecal administration of 6.50 nmol of dynorphin A (dyn A) (1-13) and (1-17) to the ninth thoracic (T9) spinal segment provoked a transient (5-10 min) increased in heart rate (40-60 beats per minute (bpm] and arterial pressure (20-25 mmHg). Intravenous administration and administration to the second thoracic (T2) segment failed to mimic the effect of T9 administration, suggesting that the cardiovascular effects of T9 administration did not occur via diffusion to the periphery or to the brainstem. The cardioacceleratory and hypertensive responses to T9 dyn A (1-13) administration were preve

Contemporary treatment patterns of overweight and obesity: insights from the Mass General Brigham health care system.

ObjectiveThe objective of this study was to describe the prevalence of obesity, obesity-related conditions (ORCs), and antiobesity medication (AOM) eligibility and prescribing practice among eligible patients in a large health care system.MethodsIn this cross-sectional analysis of the multicenter Mass General Brigham health care system (Boston, Massachusetts) spanning 2018 to 2022, adults eligible for AOMs (BMI ≥ 30 kg/m2 or BMI 27-29.9 kg/m2 with ≥1 ORC) were identified. Among those AOM-eligible, the prevalence of prescriptions for AOMs approved for long-term weight management was evaluated.R

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… Overall, liraglutide 3.0 mg was the most frequently prescribed (45.8%), followed by semaglutide 2.4 mg (34.2%), naltrexone‐bupropion (10.7%), phentermine‐topiramate (6.3%), and orlistat (3.1%) (Table 4 ). … The proportion of naltrexone‐bupropion, phentermine‐topiramate, and orlistat prescriptions was generally similar across BMI categories. …

Навязчивое сексуальное поведение у депрессивных женщин

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… Studies have seen improvement with SSRIs, naltrexone, mood stabilizers (lithium, valproic acid), anti-androgens, and psychotherapy. The purpose of this case report is to sensitize clinicians of this condition as despite the increasing trend, CSB is still underreported and goes unrecognized. …

Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.

Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM)

Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats.

RATIONALE: The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future. OBJECTIVES: We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking b

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

BACKGROUND AND PURPOSE: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with

μ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice.

Acute challenges with psychostimulants such as amphetamine affect impulsive behavior in both animals and humans. With regard to amphetamine, it is important to unravel how this drug affects impulsivity since it is not only a widely abused recreational drug but also regularly prescribed to ameliorate maladaptive impulsivity. Therefore, we studied the effects of amphetamine in two rat models of impulsivity, the five-choice serial reaction time task and the delayed-reward task, providing measures of inhibitory control and impulsive choice, respectively. We focused on the role of opioid receptor a