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1.
Science ; 384(6700): eadn0886, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38843332

ABSTRACT

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express µ-opioid receptors (µORs). Disrupting µOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.


Subject(s)
Analgesics, Opioid , Oxycodone , Prefrontal Cortex , Pyramidal Cells , Receptors, Opioid, mu , Reward , Animals , Prefrontal Cortex/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Mice , Receptors, Opioid, mu/metabolism , Receptors, Opioid, mu/genetics , Oxycodone/pharmacology , Analgesics, Opioid/pharmacology , Pyramidal Cells/metabolism , Parabrachial Nucleus/metabolism , Male , Mice, Inbred C57BL , Substance Withdrawal Syndrome , Opioid-Related Disorders/metabolism , Connectome , Neurons/metabolism , Neurons/physiology , Transcriptome
2.
PeerJ ; 12: e17446, 2024.
Article in English | MEDLINE | ID: mdl-38827306

ABSTRACT

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.


Subject(s)
Crizotinib , Cytochrome P-450 CYP3A , Microsomes, Liver , Rats, Sprague-Dawley , Tramadol , Animals , Tramadol/pharmacology , Crizotinib/pharmacology , Rats , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Cytochrome P-450 CYP3A/metabolism , Male , Drug Interactions , Humans , Tandem Mass Spectrometry , Cytochrome P450 Family 2/metabolism , Cytochrome P450 Family 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Analgesics, Opioid/pharmacology
3.
Int J Nanomedicine ; 19: 4759-4777, 2024.
Article in English | MEDLINE | ID: mdl-38828199

ABSTRACT

Background: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia. Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA. Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001). Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.


Subject(s)
Analgesics, Opioid , Ganglia, Spinal , Morphine , Nanoparticles , Animals , Morphine/administration & dosage , Morphine/pharmacokinetics , Morphine/chemistry , Morphine/pharmacology , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Nanoparticles/chemistry , Rats , PC12 Cells , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacology , Male , Neuralgia/drug therapy , Mice , Lipids/chemistry , Proto-Oncogene Proteins/metabolism , Peripheral Nerves/drug effects , Mixed Function Oxygenases/metabolism , DNA-Binding Proteins , Liposomes
4.
Mol Pain ; 20: 17448069241260348, 2024.
Article in English | MEDLINE | ID: mdl-38828868

ABSTRACT

Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked prolongation of prostaglandin E2 (PGE2)-induced mechanical hyperalgesia, in vivo. In vitro, priming in nociceptors is characterized by a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. In the present in vitro study we tested the hypothesis that a mu-opioid receptor (MOR) agonist opioid analgesic, morphine, can produce priming by its direct action on nociceptors. We report that treatment of nociceptors with morphine, in vitro, produces a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. Our findings support the suggestion that opioids act directly on nociceptors to induce priming.


Subject(s)
Dinoprostone , Morphine , Nociceptors , Morphine/pharmacology , Animals , Nociceptors/drug effects , Nociceptors/metabolism , Dinoprostone/metabolism , Dinoprostone/pharmacology , Receptors, Opioid, mu/metabolism , Analgesics, Opioid/pharmacology , Male , Rats , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats, Sprague-Dawley , Dose-Response Relationship, Drug
5.
Pak J Pharm Sci ; 37(1): 53-63, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38741400

ABSTRACT

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.


Subject(s)
Anxiety , Ascorbic Acid , Behavior, Animal , Oxidative Stress , Sorghum , Tramadol , Animals , Tramadol/pharmacology , Oxidative Stress/drug effects , Male , Ascorbic Acid/pharmacology , Anxiety/prevention & control , Anxiety/chemically induced , Anxiety/drug therapy , Rats , Behavior, Animal/drug effects , Antioxidants/pharmacology , Brain/drug effects , Brain/metabolism , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Rats, Wistar , Analgesics, Opioid/pharmacology , Anti-Anxiety Agents/pharmacology , Maze Learning/drug effects
6.
Ann Med ; 56(1): 2329259, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38738380

ABSTRACT

Opioids are the most prescribed drugs for the alleviation of pain. Both clinical and preclinical studies have reported strong evidence for sex-related divergence regarding opioid analgesia. There is an increasing amount of evidence indicating that gonadal hormones regulate the analgesic efficacy of opioids. This review presents an overview of the importance of gonadal steroids in modulating opioid analgesic responsiveness and focuses on elaborating what is currently known regarding the underlyingmechanism. We sought to identify the link between gonadal hormones and the effect of oipiod antinociception.


Gonadal hormones contribute to the sexual dimorphism of opioid antinociception.Generally, oestradiol is a negative modulator of opioid analgesia via both non-genomic and genomic effects.Testosterone facilitates opioid analgesia mainly through the transcriptional activities of androgen receptors.Under normal physiological conditions, progestin and oestrogen exist in parallel and have a combined effect. However, progestin alone could promote opioid analgesia by increasing the expression of opioid receptors.


Subject(s)
Analgesics, Opioid , Gonadal Hormones , Pain , Analgesics, Opioid/pharmacology , Humans , Animals , Gonadal Hormones/metabolism , Male , Pain/drug therapy , Pain/metabolism , Female
7.
Addict Biol ; 29(5): e13403, 2024 May.
Article in English | MEDLINE | ID: mdl-38735880

ABSTRACT

Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse; however, it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl-experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 µg/kg/infusion) or saline for 10 days. After 24 h abstinence, VTA nuclei were isolated and prepared for sequencing on the 10× platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signalling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signalling. In glutamate neurons, we found enrichment of genes involved in cholinergic signalling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulated transcriptional repressor Bcl6, and upregulated transcription factor Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signalling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA that serves as the foundation for future mechanistic studies.


Subject(s)
Analgesics, Opioid , Fentanyl , Mice, Inbred C57BL , Ventral Tegmental Area , Animals , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism , Mice , Fentanyl/pharmacology , Male , Female , Analgesics, Opioid/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Self Administration , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Neurons/drug effects , Neurons/metabolism , Opioid-Related Disorders/genetics
8.
Cells ; 13(10)2024 May 14.
Article in English | MEDLINE | ID: mdl-38786059

ABSTRACT

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.


Subject(s)
Analgesics, Opioid , Astrocytes , Neurons , Prenatal Exposure Delayed Effects , Signal Transduction , Synapses , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Animals , Synapses/metabolism , Synapses/drug effects , Female , Pregnancy , Mice , Analgesics, Opioid/pharmacology , Analgesics, Opioid/adverse effects , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/metabolism , Neurons/metabolism , Neurons/drug effects , Neurons/pathology , Signal Transduction/drug effects , Buprenorphine/pharmacology , Cells, Cultured , Mice, Inbred C57BL
9.
Biomed Pharmacother ; 175: 116665, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38701564

ABSTRACT

Opioid receptor agonists are often used when cancer patients undergo surgery or analgesic treatment. As analgesics in clinical care, opioids can provide intraoperative or to chronic cancer pain relief. Immune function plays an important role in anti-cancer therapy, with cellular immunity, comprised principally of T-lymphocytes and natural killer cells, representing the primary anti-cancer immune response. However, it remains unclear whether immune function is further affected with the use of opioids in already immunocompromised cancer patients. This article provides a review of the effects of commonly used clinical opioids, including morphine, oxycodone, fentanyl and tramadol, on immune function in cancer patients. It provides a summary of current evidence regarding the immunomodulatory effects of opioids in the cancer setting and mechanisms underlying these interactions.


Subject(s)
Analgesics, Opioid , Neoplasms , Humans , Analgesics, Opioid/therapeutic use , Analgesics, Opioid/pharmacology , Neoplasms/immunology , Neoplasms/drug therapy , Cancer Pain/drug therapy , Cancer Pain/immunology , Animals , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Immune System/drug effects
10.
Sci Rep ; 14(1): 12082, 2024 05 27.
Article in English | MEDLINE | ID: mdl-38802422

ABSTRACT

Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the internal mechanisms. This is even true for those neural networks designed to emulate mechanistic models, which simply learn a mapping between the inputs and outputs of mechanistic models, ignoring the underlying processes. Using a mechanistic model studying the pharmacological interaction between opioids and naloxone as a proof-of-concept example, we demonstrated that by reorganizing the neural networks' layers to mimic the structure of the mechanistic model, it is possible to achieve better training rates and prediction accuracy relative to the previously proposed black-box neural networks, while maintaining the interpretability of the mechanistic simulations. Our framework can be used to emulate mechanistic models in a large parameter space and offers an example on the utility of increasing the interpretability of deep learning networks.


Subject(s)
Deep Learning , Naloxone , Neural Networks, Computer , Systems Biology , Systems Biology/methods , Naloxone/pharmacology , Humans , Pharmacology/methods , Analgesics, Opioid/pharmacology , Computer Simulation
11.
Neuropharmacology ; 254: 109972, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38710443

ABSTRACT

Opioid use disorder (OUD) is a chronic condition associated with long-lasting molecular and behavioral changes. Animals with prolonged access to opioids develop behaviors similar to human OUD. Identifying associated molecular changes can provide insight to underpinnings that lead to or maintain OUD. In pilot studies, we identified several miRNA targets that are altered by the administration of oxycodone. We selected mir182 for follow up as it was recently shown to be dysregulated in plasma of men administered oxycodone. In addition, mir182 is increased in reward-related brain regions of male rats following exposure to various addictive substances. The present study utilizes a long-access oxycodone self-administration paradigm to examine changes in mir182 and its mRNA targets associated with neuroplasticity, which may be involved in the maintenance of OUD-like phenotype in rats. Male rats were trained to self-administer oxycodone (0.1 mg/kg/infusion, i. v.) for 6 h daily sessions for 12 days. Each animal had a yoked saline control that received matched saline infusions. Animals were then tested on a progressive ratio schedule to measure motivation to obtain a single infusion of oxycodone. Drug seeking was measured following 28 days of forced abstinence using a 90-min cued/test. RTqPCR was utilized to measure mir182 and mRNA targets related to neuroplasticity (wnt3, plppr4, pou3f3, tle4, cacna2d, and bdnf) from the nucleus accumbens. Data revealed that animals responded on a continuum for oxycodone. When divided into two groups termed high- and low responders, animals diverged during self-administration acquisition and maintained differences in behavior and gene expression throughout the study. mir182 was upregulated in the nucleus accumbens of both high and low responders and negatively correlated with tle4, which showed a strong negative correlation with reinstatement behavior. mRNA target levels were correlated with behaviors associated with increased severity of OUD behavior in male rats.


Subject(s)
MicroRNAs , Neuronal Plasticity , Oxycodone , Self Administration , Animals , Male , Oxycodone/administration & dosage , Oxycodone/pharmacology , Neuronal Plasticity/drug effects , Rats , MicroRNAs/metabolism , MicroRNAs/genetics , Individuality , Rats, Sprague-Dawley , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacology , Opioid-Related Disorders/genetics , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/genetics
12.
Nature ; 630(8015): 141-148, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38778097

ABSTRACT

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (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 drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, 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.


Subject(s)
Dopaminergic Neurons , Fentanyl , Nucleus Accumbens , Receptors, Opioid, mu , Reinforcement, Psychology , Substance Withdrawal Syndrome , Ventral Tegmental Area , Animals , Fentanyl/pharmacology , Receptors, Opioid, mu/metabolism , Mice , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiology , Male , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Substance Withdrawal Syndrome/metabolism , Nucleus Accumbens/metabolism , Nucleus Accumbens/drug effects , Dopamine/metabolism , Optogenetics , Central Amygdaloid Nucleus/metabolism , Central Amygdaloid Nucleus/drug effects , Central Amygdaloid Nucleus/physiology , Female , Mice, Inbred C57BL , Opioid-Related Disorders/metabolism , Analgesics, Opioid/pharmacology , Analgesics, Opioid/administration & dosage
13.
Behav Brain Res ; 469: 115065, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38782097

ABSTRACT

Acetaminophen (paracetamol) is one of the most popular analgesics for the management of fever and pain but few reports have investigated its antidepressant-like effect. Moreover, the role of the opioidergic pathway has been indicated in depression pathophysiology. This study aimed to examine the involvement of the opioid receptors in the antidepressant-like effect of acetaminophen after acute and sub-chronic administration using mice forced swimming test (FST). Our finding showed that administration of acetaminophen (50 and 100 mg/kg, i.p.) 30 min before the FST produced an antidepressant effect which was reduced by naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). Moreover, we observed that acetaminophen in higher doses (200 and 400 mg/kg) was ineffective. Also, the response of the non-effective dose of acetaminophen (25 mg/kg) was potentiated by the non-effective dose of morphine (0.1 mg/kg) in the FST that was antagonized by naloxone. Also, in contrast to morphine (10 mg/kg), acetaminophen (100 mg/kg, i.p.) induced neither tolerance to the anti-immobility behavior nor withdrawal syndrome after repeated administration. In addition, RT-PCR showed that hippocampal mu- and kappa-opioid receptor mRNA expression increased in mice after repeated administration of acetaminophen; however, morphine therapy for 6 days did not affect kappa-opioid receptor expression. Our findings demonstrated that acetaminophen in lower doses but not high doses revealed an antidepressant-like activity without inducing tolerance and withdrawal syndromes. Moreover, the observed effect of acetaminophen may be via altering the opioid system, particularly hippocampal mu- and kappa-receptors.


Subject(s)
Acetaminophen , Antidepressive Agents , Dose-Response Relationship, Drug , Naloxone , Narcotic Antagonists , Animals , Acetaminophen/pharmacology , Acetaminophen/administration & dosage , Male , Mice , Antidepressive Agents/pharmacology , Antidepressive Agents/administration & dosage , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Narcotic Antagonists/administration & dosage , Swimming , Depression/drug therapy , Depression/metabolism , Morphine/pharmacology , Morphine/administration & dosage , Hippocampus/drug effects , Hippocampus/metabolism , Disease Models, Animal , Analgesics, Opioid/pharmacology , Analgesics, Opioid/administration & dosage , Analgesics, Non-Narcotic/pharmacology , Analgesics, Non-Narcotic/administration & dosage , Receptors, Opioid/metabolism , Receptors, Opioid/drug effects , Receptors, Opioid, mu/metabolism , Receptors, Opioid, mu/drug effects
14.
Bioorg Chem ; 148: 107489, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38797065

ABSTRACT

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.


Subject(s)
Receptors, Opioid, mu , Animals , Structure-Activity Relationship , Mice , Receptors, Opioid, mu/metabolism , Receptors, Opioid, mu/antagonists & inhibitors , Humans , Molecular Structure , Thiophenes/chemistry , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/therapeutic use , Male , Dose-Response Relationship, Drug , Analgesics, Opioid/pharmacology , Analgesics, Opioid/chemistry , Narcotic Antagonists/pharmacology , Narcotic Antagonists/chemistry , Morphine/pharmacology
15.
Neuropharmacology ; 255: 110002, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38754577

ABSTRACT

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.


Subject(s)
Analgesics, Opioid , Fentanyl , Rats, Sprague-Dawley , Animals , Fentanyl/pharmacology , Fentanyl/analogs & derivatives , Male , Female , Analgesics, Opioid/pharmacology , Rats , Reinforcement, Psychology , Dose-Response Relationship, Drug , Self Administration , Respiratory Insufficiency/chemically induced , Pain Measurement/drug effects , Pain Measurement/methods
16.
ACS Chem Neurosci ; 15(11): 2091-2098, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38747710

ABSTRACT

Xylazine (also known as "tranq") is a potent nonopioid veterinary sedative that has recently experienced a surge in use as a drug adulterant, most often combined with illicitly manufactured fentanyl. This combination may heighten the risk of fatal overdose. Xylazine has no known antidote approved for use in humans, and age-adjusted overdose deaths involving xylazine were 35 times higher in 2021 than 2018. In April 2023, the Biden Administration declared xylazine-laced fentanyl an emerging drug threat in the United States. In 2022, the Drug Enforcement Agency (DEA) reported nearly a quarter of seized fentanyl powder contained xylazine. This dramatic increase in prevalence has solidified the status of xylazine as an emerging drug of abuse and an evolving threat to public health. The following narrative review outlines the synthesis, pharmacokinetics, pharmacodynamics, and adverse effects of xylazine, as well as the role it may play in the ongoing opioid epidemic.


Subject(s)
Xylazine , Xylazine/pharmacology , Humans , Animals , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/chemistry , Fentanyl/pharmacology , Fentanyl/chemistry , Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacology , Drug Overdose/epidemiology
17.
Eur J Pharmacol ; 975: 176648, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38759706

ABSTRACT

Opioids are used for pain relief in patients suffering from acute myocardial ischemia or infarction. Clinical and laboratory studies demonstrate that morphine treated patients or the experimental animal model suffering acute myocardial ischemia and reperfusion, may worsen myocardial viability. As transient receptor potential vanilloid 1 (TRPV1) plays important roles in pain sensation and cardio-protection, we query whether opioids may exacerbate myocardial viability via interaction with TRPV1 activity in the pain relief. We found the co-expressions of TRPV1 and opioid µ, δ and κ receptors in adult rat cardiomyocytes. Intravenous injection of morphine (0.3 mg/kg) at 20 min after induction of myocardial ischemia, in the rat model of acute myocardial ischemia and reperfusion, induced significant reduction of phosphorylated TRPV1 (p-TRPV1) in the ventricular myocardium and increase in serum cardiac troponin I (cTnI), compared with the ischemia/reperfusion controls (all P < 0.05). The effects of morphine were completely reversed by selective opioid µ, δ and κ receptor antagonists. While significant upregulation of p-TRPV1 (P < 0.05) and improvement of ±dP/dt max (all P < 0.05) were detected in the animals giving the same dose of morphine before induction of myocardial ischemia. The changes in p-TRPV1 correlate with the alterations of cTnI (r = -0.5840, P = 0.0283) and ±dP/dt max (r = 0.8084, P = 0.0005 and r = -0.8133, P = 0.0004, respectively). The findings of this study may indicate that potentiation and attenuation of TRPV1 sensitivity correlate with the improvement of the cardiac performance and the aggravation of myocardial viability, respectively, by giving morphine before and during myocardial ischemia and reperfusion.


Subject(s)
Morphine , Myocardial Reperfusion Injury , Rats, Sprague-Dawley , TRPV Cation Channels , Animals , TRPV Cation Channels/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/drug therapy , Morphine/pharmacology , Phosphorylation/drug effects , Male , Rats , Time Factors , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Analgesics, Opioid/pharmacology , Receptors, Opioid/metabolism , Troponin I/metabolism , Troponin I/blood , Myocardium/metabolism , Myocardium/pathology
18.
Genes Brain Behav ; 23(2): e12894, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38597363

ABSTRACT

Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up-down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h2 = 0.23-0.40). All strains displayed oxycodone-induced analgesia that peaked at 15-30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h2 = 0.10-0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone-induced analgesia.


Subject(s)
Analgesia , Opioid-Related Disorders , Rats , Animals , Oxycodone/pharmacology , Analgesics, Opioid/pharmacology
19.
Biol Pharm Bull ; 47(4): 872-877, 2024.
Article in English | MEDLINE | ID: mdl-38658360

ABSTRACT

The formalin test is one approach to studying acute pain in rodents. Similar to formalin, injection with glutamate and veratrine can also produce a nociceptive response. This study investigated whether opioid-related compounds could suppress glutamate- and veratrine-induced nociceptive responses in mice at the same dose. The administration of morphine (3 mg/kg), hydromorphone (0.4 mg/kg), or fentanyl (0.03 mg/kg) suppressed glutamate-induced nociceptive response, but not veratrine-induced nociceptive response at the same doses. However, high doses of morphine (10 mg/kg), hydromorphone (2 mg/kg), or fentanyl (0.1 mg/kg) produced a significant reduction in the veratrine-induced nociceptive response. These results indicate that high doses are required when using morphine, hydromorphone, or fentanyl for sodium channel-related neuropathic pain, such as ectopic activity. As a result, concerns have arisen about overdose and abuse if the dose of opioids is steadily increased to relieve pain. In contrast, trimebutine (100 mg/kg) and fentanyl analog isobutyrylfentanyl (iBF; 0.1 mg/kg) suppressed both glutamate- and veratrine-induced nociceptive response. Furthermore, nor-isobutyrylfentanyl (nor-iBF; 1 mg/kg), which is a metabolite of iBF, suppressed veratrine-induced nociceptive response. Besides, the optimal antinociceptive dose of iBF, unlike fentanyl, only slightly increased locomotor activity and did not slow gastrointestinal transit. Cancer pain is a complex condition driven by inflammatory, neuropathic, and cancer-specific mechanisms. Thus, iBF may have the potential to be a superior analgesic than fentanyl.


Subject(s)
Analgesics, Opioid , Fentanyl , Animals , Fentanyl/pharmacology , Fentanyl/analogs & derivatives , Male , Mice , Analgesics, Opioid/pharmacology , Glutamic Acid/metabolism , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Analgesics/pharmacology , Analgesics/therapeutic use , Pain Measurement/drug effects , Pain Measurement/methods , Morphine/pharmacology
20.
FASEB J ; 38(8): e23603, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38648368

ABSTRACT

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.


Subject(s)
Analgesics, Opioid , Dysbiosis , Fentanyl , Gastrointestinal Microbiome , Intestinal Mucosa , Mice, Inbred C57BL , Morphine , Animals , Morphine/pharmacology , Mice , Dysbiosis/chemically induced , Dysbiosis/microbiology , Gastrointestinal Microbiome/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/microbiology , Male , Fentanyl/pharmacology , Analgesics, Opioid/pharmacology , Brain-Gut Axis/drug effects , Fecal Microbiota Transplantation , Pancreatitis-Associated Proteins/metabolism , Akkermansia/drug effects , Antimicrobial Peptides/pharmacology , Bacteroidetes/drug effects
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