-
Frontiers in Neural Circuits 2024Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and... (Review)
Review
Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.
Topics: Humans; Quality of Life; Animals; Smell; Opioid Peptides; Olfactory Tubercle; Olfaction Disorders
PubMed: 38872907
DOI: 10.3389/fncir.2024.1408189 -
Scientific Reports Jun 2024Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive...
Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist, used to treat drug addiction. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI seizures can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and/or seizures post-TBI. TBI was induced by a modified Marmarou Weight-Drop (WD) method on 4-week-old C57BL/6J male mice. Mice were placed in two groups: non-telemetry assessing the acute effects or in telemetry monitoring for interictal events and spontaneous seizures both following TBI and naltrexone. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation, neurodegeneration and fiber track integrity at 8 days and 3 months post-TBI. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. Our results show an increase in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. Video-EEG revealed increased interictal events in TBI mice, with 71% mice developing post-traumatic seizures (PTS). Naltrexone treatment ameliorated neuroinflammation, neurodegeneration, reduced interictal events and prevented seizures in all TBI mice, which makes naltrexone a promising candidate against PTS, TBI-associated neuroinflammation and epileptogenesis in a WD model of TBI.
Topics: Animals; Naltrexone; Male; Mice; Disease Models, Animal; Seizures; Brain Injuries, Traumatic; Mice, Inbred C57BL; Neuroprotective Agents; Receptors, Opioid, mu; Electroencephalography; Cytokines
PubMed: 38867062
DOI: 10.1038/s41598-024-63942-8 -
Genes, Brain, and Behavior Jun 2024Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is...
Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.
Topics: Animals; Female; Arvicolinae; Receptors, Opioid, mu; Pair Bond; Maternal Behavior; Nucleus Accumbens; Pregnancy; Receptors, Oxytocin; Receptors, Opioid, kappa; Gyrus Cinguli; Preoptic Area; Receptors, Dopamine D1
PubMed: 38861664
DOI: 10.1111/gbb.12906 -
BioRxiv : the Preprint Server For... Jun 2024Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field...
Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HTR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HTR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HTR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HTR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, . Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including , and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.
PubMed: 38854027
DOI: 10.1101/2024.05.28.596205 -
Biomedicine & Pharmacotherapy =... Jun 2024Cannabinoid CB agonists show therapeutic efficacy without unwanted CB-mediated side effects. The G protein-biased CB receptor agonist LY2828360 attenuates the...
Cannabinoid CB receptors in primary sensory neurons are implicated in CB agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.
Cannabinoid CB agonists show therapeutic efficacy without unwanted CB-mediated side effects. The G protein-biased CB receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB agonists. Anti-allodynic effects of structurally distinct CB agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB mice and in mice lacking CB receptors in CX3CR1 expressing microglia/macrophages (CX3CR1; CB), but were absent in mice lacking CB receptors in peripheral sensory neurons (Advillin; CB). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB and CX3CR1; CB mice with established paclitaxel-induced neuropathy but was absent in male (or female) Advillin; CB mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB mice, but not Advillin; CB mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB or CX3CR1; CB mice of either sex. Our findings have potential clinical implications.
PubMed: 38850666
DOI: 10.1016/j.biopha.2024.116879 -
Journal of Molecular Biology Jun 2024Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of...
Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of autophagy is linked to a variety of diseases ranging from organ-specific illnesses like cardiomyopathy to systemic illnesses such as cancer or metabolic syndromes. Given the variety of autophagic functions within a cell and tissue, regulation of autophagy is complex and contains numerous positive and negative feedback loops. While our knowledge of mechanisms for cargo selectivity has significantly improved over the last decade, our understanding of signaling routes activating individual autophagy pathways remains rather sparse. In this resource study, we report on a well-characterized chemical library containing 77 GPCR-targeting ligands that was used to systematically analyze LC3B-based autophagy as well as ER-phagy flux upon compound treatment. Upon others, compounds TC-G 1004, BAY 60-6583, PSNCBAM-1, TC-G 1008, LPA2 Antagonist 1, ML154, JTC-801 and ML-290 targeting adenosine receptor A2a (ADORA2A), adenosine receptor A2b (ADORA2B), cannabinoid receptor 1 (CNR1), G-protein coupled receptor 39 (GPR39), lysophosphatidic acid receptor 2 (LPAR2), neuropeptide S receptor 1 (NPSR1), opioid related nociceptin receptor 1 (OPRL1), and relaxin receptor 1 (RXFP1), respectively, were hit compounds for general autophagy flux. From these compounds, only JTC-801 markly increased ER-phagy flux. In addition, the global impact of these selected hit compounds were analyzed by TMT-based mass spectrometry and demonstrated the differential impact of targeting GPCRs on autophagy-associated proteins. This chemical screening exercise indicates to a significant cross-talk between GPCR signaling and regulation of autophagy pathways.
PubMed: 38848865
DOI: 10.1016/j.jmb.2024.168643 -
Translational Perioperative and Pain... 2024This editorial discusses the status and issues related to perioperative opioid usage monitoring and waste. Opioid detection of wasted material is briefly discussed also....
This editorial discusses the status and issues related to perioperative opioid usage monitoring and waste. Opioid detection of wasted material is briefly discussed also. Flowlytics from Invistics is a digital system to monitor opioid usage and waste in medical facilities. Opioid waste in medical facilities has a two-person witness procedure. Easy to use detection of wasted materials needs to be developed in the future. It is unclear whether the strategies used in medical facilities should be recommended for opioid disposal in the public to reduce opioid diversion. Relevant studies are needed.
PubMed: 38846450
DOI: 10.31480/2330-4871/185 -
Cureus May 2024Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R ( and gene products,... (Review)
Review
Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R ( and gene products, respectively). Both subtypes have recently been cloned and their crystal structures have been published. As a result, highly selective S1R and S2R agonist and antagonist ligands are now available. Unlike the confusion generated from prior use of non-selective 'sigma' compounds, these tool compounds have begun to add clarity about the function of sigma receptors in health and disease. The discovery of compounds with high-affinity (nM range) S1R/S2R or S2R/S1R subtype selectivity (>100-fold), and selectivity over off-target sites (>1,000-fold) has brought the study of sigma receptor pharmacology into the modern era. Computer modeling has contributed to a better understanding of the binding processes, structural requirements for chemical synthesis, and potential therapeutic uses. Several lines of evidence converge on pain as a therapeutic target for S1R-antagonists (as single mechanism or as part of a multi-mechanistic approach). We highlight here some compounds reported over the past few years that have promise for use as analgesics, specifically some mono-mechanistic S1R-antagonists, and some that are 'bispecific', i.e., have more than one mechanism of action, for example, complementary action of the mu-opioid receptor (MOR). We concentrate on some compounds that are further along in development, in particular, some of the bispecific S1R-antagonist/MOR-agonist compounds.
PubMed: 38846228
DOI: 10.7759/cureus.59837 -
Neurobiology of Disease Aug 2024Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and...
BACKGROUND
Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates.
METHODS
A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity.
RESULTS
MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits.
CONCLUSIONS
Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.
Topics: Humans; Multiple System Atrophy; Parkinson Disease; Male; Female; Middle Aged; Aged; Brain; Magnetic Resonance Imaging; Iron; Neurotransmitter Agents; Brain Mapping
PubMed: 38830476
DOI: 10.1016/j.nbd.2024.106549