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Nature Jun 2024Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which...
Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs. Among the opioid receptors, µ-opioid receptors have a key role, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.
Topics: Animals; Female; Male; Mice; Analgesics, Opioid; Central Amygdaloid Nucleus; Dopamine; Dopaminergic Neurons; Fentanyl; Mice, Inbred C57BL; Nucleus Accumbens; Opioid-Related Disorders; Optogenetics; Receptors, Opioid, mu; Reinforcement, Psychology; Substance Withdrawal Syndrome; Ventral Tegmental Area
PubMed: 38778097
DOI: 10.1038/s41586-024-07440-x -
A synthetic peptide exerts nontolerance-forming antihyperalgesic and antidepressant effects in mice.Neurotherapeutics : the Journal of the... May 2024Chronic pain is a prevalent and persistent ailment that affects individuals worldwide. Conventional medications employed in the treatment of chronic pain typically...
Chronic pain is a prevalent and persistent ailment that affects individuals worldwide. Conventional medications employed in the treatment of chronic pain typically demonstrate limited analgesic effectiveness and frequently give rise to debilitating side effects, such as tolerance and addiction, thereby diminishing patient compliance with medication. Consequently, there is an urgent need for the development of efficacious novel analgesics and innovative methodologies to address chronic pain. Recently, a growing body of evidence has suggested that multireceptor ligands targeting opioid receptors (ORs) are favorable for improving analgesic efficacy, decreasing the risk of adverse effects, and occasionally yielding additional advantages. In this study, the intrathecal injection of a recently developed peptide (VYWEMEDKN) at nanomolar concentrations decreased pain sensitivity in naïve mice and effectively reduced pain-related behaviors in nociceptive pain model mice with minimal opioid-related side effects. Importantly, the compound exerted significant rapid-acting antidepressant effects in both the forced swim test and tail suspension test. It is possible that the rapid antihyperalgesic and antidepressant effects of the peptide are mediated through the OR pathway. Overall, this peptide could both effectively provide pain relief and alleviate depression with fewer side effects, suggesting that it is a potential agent for chronic pain and depression comorbidities from the perspective of pharmaceutical development.
PubMed: 38777742
DOI: 10.1016/j.neurot.2024.e00377 -
BioRxiv : the Preprint Server For... Apr 2024Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to...
Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.
PubMed: 38766079
DOI: 10.1101/2024.04.02.585967 -
Heliyon May 2024The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (-), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3,...
The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (-), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (-), 3,5-dipropyl-1, 3, 5-thiadiazine-2-thione () and (2-(5-alkyl/aryl-6-thioxo-1, 3, 5-thiadiazine-3-yl) alkyl acetate/benzoate) (-) was accomplished one pot reaction. The structures of the synthesized compounds were characterized through NMR and Mass spectrometry. The anti-nociceptive activity of compounds was performed on BALB/C mice by hot plate method, where compounds , (50 g/kg), and (50, 100 g/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time of 15, 30, and 60 min, while compounds and (100 g/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time interval of 15 and 30 min. Compounds , , and showed moderate activity. Among the tested hits, compounds (17.3 ± 2.2), (16.2 ± 2.1), and (16.1 ± 2.1) showed significant anti-nociceptive potential. Molecular docking studies on the most active anti-nociceptive hits indicated that the activity might be attributed to the ability of the compounds to target μ-opioid receptor (μOR) effectively. Furthermore, compounds and showed anti-bacterial activity against and with MIC of 40.97 and 54.77 g/mL, respectively. In addition, the predicted ADMET profile of , , and indicates that these molecules follow the drug-likeness criteria, and their activity can be enhanced through structural optimization.
PubMed: 38765157
DOI: 10.1016/j.heliyon.2024.e30435 -
Brain Research Sep 2024Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment...
Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment options have only limited efficacy. Past research has shown that iron-dependent programmed cell death, also known as ferroptosis, plays a critical role in the pathogenesis of SCI. The sigma-1 receptor (Sig-1R) is widely distributed in the central nervous system, and has been implicated in the pathophysiology of several neurological and psychiatric disorders. Several in vivo and ex vivo studies have shown that Sig-1R activation exerts unique neuroprotective effects. However, the underlying mechanisms remain unclear. To date, no study has yet demonstrated the association between Sig-1R activation and ferroptosis in patients with SCI. However, the present study found that Sig-1R activation effectively promoted the recovery of motor function in mice after spinal cord injury, attenuated neuronal apoptosis, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited ferroptosis in spinal cord tissues following SCI in mice. Ferroptosis and IRE1α were significantly upregulated after spinal cord injury, while sigma-1 receptor agonists were able to facilitate this result through the elimination of inositol-requiring enzyme-1 alpha (IRE1α)-mediated neuronal ferroptosis. Therefore, sigma-1 receptor activation could attenuate ferroptosis after SCI by reducing IRE1α and improving functional recovery after SCI, potentially representing a new therapeutic strategy for treating SCI.
Topics: Spinal Cord Injuries; Animals; Receptors, sigma; Ferroptosis; Sigma-1 Receptor; Mice; Protein Serine-Threonine Kinases; Mice, Inbred C57BL; Neurons; Endoribonucleases; Male; Recovery of Function; Apoptosis; Spinal Cord
PubMed: 38763502
DOI: 10.1016/j.brainres.2024.149011 -
Time-dependent ligand-receptor binding kinetics and functionality in a heterodimeric receptor model.Biochemical Pharmacology Jul 2024GPCRs heteromerize both in CNS and non-CNS regions. The cell uses receptor heteromerization to modulate receptor functionality and to provide fine tuning of receptor...
GPCRs heteromerize both in CNS and non-CNS regions. The cell uses receptor heteromerization to modulate receptor functionality and to provide fine tuning of receptor signaling. In order for pharmacologists to explore these mechanisms for therapeutic purposes, quantitative receptor models are needed. We have developed a time-dependent model of the binding kinetics and functionality of a preformed heterodimeric receptor involving two drugs. Two cases were considered: both or only one of the drugs are in excess with respect to the total concentration of the receptor. The latter case can be applied to those situations in which a drug causes unwanted side effects that need to be reduced by decreasing its concentration. The required efficacy can be maintained by the allosteric effects mutually exerted by the two drugs in the two-drug combination system. We discuss this concept assuming that the drug causing unwanted side effects is an opioid and that analgesia is the therapeutic effect. As additional points, allosteric modulation by endogenous compounds and synthetic bivalent ligands was included in the study. Receptor heteromerization offers a mechanistic understanding and quantification of the pharmacological effects elicited by combinations of two drugs at different doses and with different efficacies and cooperativity effects, thus providing a conceptual framework for drug combination therapy.
Topics: Ligands; Kinetics; Protein Binding; Receptors, G-Protein-Coupled; Humans; Models, Biological; Allosteric Regulation; Time Factors; Protein Multimerization
PubMed: 38763260
DOI: 10.1016/j.bcp.2024.116299 -
Scientific Reports May 2024To investigate the association between three selected pain polymorphisms and clinical, functional, sensory-related, psychophysical, psychological or cognitive variables...
To investigate the association between three selected pain polymorphisms and clinical, functional, sensory-related, psychophysical, psychological or cognitive variables in a sample of women with fibromyalgia (FMS). One hundred twenty-three (n = 123) women with FMS completed demographic (age, height, weight), clinical (years with pain, intensity of pain at rest and during daily living activities), functional (quality of life, physical function), sensory-related (sensitization-associated and neuropathic-associated symptoms), psychophysical (pressure pain thresholds), psychological (sleep quality, depressive and anxiety level) and cognitive (pain catastrophizing, kinesiophobia) variables. Those three genotypes of the OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 single nucleotide polymorphisms were obtained by polymerase chain reactions from no-stimulated whole saliva collection. No significant differences in demographic, clinical, functional, sensory-related, psychophysical, psychological and cognitive variables according to OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680 genotype were identified in our sample of women with FMS. A multilevel analysis did not either reveal any significant gene-to-gene interaction between OPRM1 rs1799971 x HTR1B rs6296, OPRM1 rs1799971 x COMT rs4680 and HTR1B rs6296 x COMT rs4680 for any of the investigated outcomes. This study revealed that three single nucleotide polymorphisms, OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680, mostly associated with chronic pain were not involved in phenotyping features of FMS. Potential gene-to-gene interaction and their association with clinical phenotype in women with FMS should be further investigated in future studies including large sample sizes.
Topics: Humans; Fibromyalgia; Female; Catechol O-Methyltransferase; Receptors, Opioid, mu; Polymorphism, Single Nucleotide; Middle Aged; Adult; Receptor, Serotonin, 5-HT1B; Phenotype; Genotype; Genetic Predisposition to Disease; Quality of Life
PubMed: 38760456
DOI: 10.1038/s41598-024-62240-7 -
Experimental Biology and Medicine... 2024Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal...
Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.
Topics: Animals; Lacrimal Apparatus; Tears; Naltrexone; Rats, Sprague-Dawley; Male; Diabetes Mellitus, Experimental; Rats; Aquaporin 5; Administration, Topical; Dry Eye Syndromes
PubMed: 38756167
DOI: 10.3389/ebm.2024.10175 -
Scientific Reports May 2024Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and...
Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
Topics: Animals; Male; Mice; Acetaminophen; Amidohydrolases; Analgesics; Arachidonic Acids; Benzoquinones; Glycerides; Periaqueductal Gray; Transcriptome
PubMed: 38750093
DOI: 10.1038/s41598-024-61791-z -
Journal of Medicinal Chemistry Jun 2024There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study...
Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.
There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds , , and . Compound (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound was 10-fold selective for α9α10 over α9 nAChR. Compounds , , and inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.
Topics: Animals; Humans; Male; Mice; Analgesics; Inflammation; Mice, Knockout; Nicotinic Agonists; Pain; Piperazines; Receptors, Nicotinic; Salts; Structure-Activity Relationship; Iodides
PubMed: 38748608
DOI: 10.1021/acs.jmedchem.3c02429