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Mu Opioid Receptor-Positive Neurons in the Dorsal Raphe Nucleus Are Impaired by Morphine Abstinence.Biological Psychiatry Dec 2023Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the...
BACKGROUND
Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, using both molecular and behavioral approaches, we tested the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence.
METHODS
MOR-Cre mice were exposed to chronic morphine and then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence. We studied DRN-MOR neurons of abstinent mice using 1) viral translating ribosome affinity for transcriptome profiling, 2) fiber photometry to measure neuronal activity, and 3) an opto-intracranial self-stimulation paradigm applied to DRN-MOR neurons to assess responses related to addiction vulnerability including persistence to respond, motivation to obtain the stimulation, self-stimulation despite punishment, and cue-induced reinstatement.
RESULTS
DRN-MOR neurons of abstinent animals showed a downregulation of genes involved in ion conductance and MOR-mediated signaling, as well as altered responding to acute morphine. Opto-intracranial self-stimulation data showed that abstinent animals executed more impulsive-like and persistent responses during acquisition and scored higher on addiction-like criteria.
CONCLUSIONS
Our data suggest that protracted abstinence to chronic morphine leads to reduced MOR function in DRN-MOR neurons and abnormal self-stimulation of these neurons. We propose that DRN-MOR neurons have partially lost their reward-facilitating properties, which in turn may lead to increased propensity to perform addiction-related behaviors.
Topics: Mice; Animals; Morphine; Dorsal Raphe Nucleus; Receptors, Opioid, mu; Analgesics, Opioid; Neurons
PubMed: 37393045
DOI: 10.1016/j.biopsych.2023.06.024 -
European Journal of Pharmacology Jan 2024The use of morphine in clinical medicine is severely constrained by tolerance. Therefore, it is essential to examine pharmacological therapies that suppress the...
BACKGROUND
The use of morphine in clinical medicine is severely constrained by tolerance. Therefore, it is essential to examine pharmacological therapies that suppress the development of morphine tolerance. Amiloride suppressed the expression of inflammatory cytokines by inhibiting microglial activation. Microglia play a crucial role in the establishment of morphine tolerance. Thus, we anticipated that amiloride might suppress the development of morphine tolerance. During this investigation, we assessed the impact of amiloride on mouse morphine tolerance.
METHODS
Mice received morphine (10 mg/kg, s.c.) twice daily with intrathecally injected amiloride (0.3 μg/5 μl, 1 μg/5 μl, and 3 μg/5 μl) for nine continuous days. To assess morphine tolerance, mice underwent the tail-flick and hot plate tests. BV-2 cells were used to investigate the mechanism of amiloride. By using Western blotting, real-time PCR, and immunofluorescence labeling methods, the levels of acid-sensing ion channels (ASICs), nuclear factor kappa B (NF-kB) p65, p38 mitogen-activated protein kinase (MAPK) proteins, and neuroinflammation-related cytokines were determined.
RESULTS
The levels of ASIC3 in the spinal cord were considerably increased after long-term morphine administration. Amiloride was found to delay the development of tolerance to chronic morphine assessed via tail-flick and hot plate tests. Amiloride reduced microglial activation and downregulated the cytokines IL-1β and TNF-a by inhibiting ASIC3 in response to morphine. Furthermore, amiloride reduced p38 MAPK phosphorylation and inhibited NF-κB expression.
CONCLUSIONS
Amiloride effectively reduces chronic morphine tolerance by suppressing microglial activation caused by morphine by inhibiting ASIC3.
Topics: Mice; Animals; Morphine; Analgesics, Opioid; Amiloride; Neuroinflammatory Diseases; NF-kappa B; Microglia; Cytokines; Spinal Cord
PubMed: 37918499
DOI: 10.1016/j.ejphar.2023.176173 -
Annals of Medicine Dec 2024Many clinical trials have demonstrated the benefits of intraoperative systemic lidocaine administration in major abdominal surgeries. We tested the hypothesis that... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Many clinical trials have demonstrated the benefits of intraoperative systemic lidocaine administration in major abdominal surgeries. We tested the hypothesis that systemic lidocaine is associated with an enhanced early quality of recovery in patients following laparoscopic colorectal resection.
PATIENTS AND METHODS
We randomly allocated 126 patients scheduled for laparoscopic colorectal surgery in a 1:1 ratio to receive either lidocaine (1.5 mg kg bolus over 10 min, followed by continuous infusion at 2 mg kg h until the end of surgery) or identical volumes and rates of saline. The primary outcome was the Quality of Recovery-15 score assessed 24 h after surgery. Secondary outcomes were areas under the pain numeric rating scale curve over time, 48-h morphine consumption, and adverse events.
RESULTS
Compared with saline, systemic lidocaine improved the Quality of Recovery-15 score 24 h postoperatively, with a median difference of 4 (95% confidence interval: 1-6; = 0.015). Similarly, the area under the pain numeric rating scale curve over 48 h at rest and on movement was reduced in the lidocaine group ( = 0.004 and < 0.001, respectively). However, these differences were not clinically meaningful. Lidocaine infusion reduced the intraoperative remifentanil requirements but not postoperative 48-h morphine consumption ( < 0.001 and = 0.34, respectively). Additionally, patients receiving lidocaine had a quicker and earlier return of bowel function, as indicated by a shorter time to first flatus (log-rank < 0.001), yet ambulation time was similar between groups (log-rank test, = 0.11).
CONCLUSIONS
In patients undergoing laparoscopic colorectal surgery, intraoperative systemic lidocaine resulted in statistically but not clinically significant improvements in quality of recovery (see Graphical Abstract). Chinese Clinical Trial Registry; ChiCTR1900027635.
Topics: Humans; Lidocaine; Anesthetics, Local; Colorectal Surgery; Analgesics, Opioid; Pain, Postoperative; Double-Blind Method; Laparoscopy; Morphine
PubMed: 38346397
DOI: 10.1080/07853890.2024.2315229 -
Neuropharmacology Nov 2023Chronic morphine tolerance is a repulsive barrier to the clinical treatment of pain. Whereas the underlying molecular mechanisms of morphine tolerance remain unknown....
Tumor necrosis factor-α-induced protein 8-like 2 alleviates morphine antinociceptive tolerance through reduction of ROS-mediated apoptosis and MAPK/NF-κB signaling pathways.
Chronic morphine tolerance is a repulsive barrier to the clinical treatment of pain. Whereas the underlying molecular mechanisms of morphine tolerance remain unknown. Here, we proposed that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is an essential control point regarding the progression of chronic morphine antinociceptive tolerance. We found that TIPE2 levels in the lumbar spinal cord were significantly downregulated in the morphine tolerance mouse model. Specifically, decreased TIPE2 by morphine tolerance was primarily expressed in spinal neurons, while increased expression of spinal TIPE2 distinctly attenuated the chronic morphine antinociceptive tolerance and tolerance-associated hyperalgesia. We also observed that increased expression of spinal TIPE2 significantly reduced morphine tolerance-induced neuronal ROS production and apoptosis, along with the activation of MAPKs and NF-κB signaling pathways. Moreover, the increased TIPE2 expression inhibited neuronal activation and glial reactivity in the spinal dorsal horn after chronic morphine exposure. Additionally, TIPE2 overexpression in cultured SH-SY5Y cells significantly suppressed ROS production and apoptosis in response to morphine challenge. Therefore, we can conclude that the upregulation of spinal TIPE2 may attenuate the morphine antinociceptive tolerance via TIPE2-dependent downregulation of neuronal ROS, inhibition of neuronal apoptosis, suppression of MAPKs and NF-κB activation. TIPE2 may be a potential strategy for preventing morphine tolerance in the future studies and clinical settings.
Topics: Humans; Mice; Animals; Morphine; NF-kappa B; Tumor Necrosis Factor-alpha; Reactive Oxygen Species; Neuroblastoma; Spinal Cord Dorsal Horn; Spinal Cord; Signal Transduction; Analgesics; Apoptosis; Intracellular Signaling Peptides and Proteins
PubMed: 37451333
DOI: 10.1016/j.neuropharm.2023.109667 -
Journal of Neurochemistry Mar 2024Despite the advent of combination anti-retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV-associated neurocognitive...
Despite the advent of combination anti-retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV-associated neurocognitive disorders (HAND). HAND can be worsened by co-morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV-1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co-exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co-exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety-like, novelty-seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase-positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context-dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty-seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time-dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV-1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.
Topics: Humans; Mice; Animals; Morphine; Exploratory Behavior; HIV-1; Dopamine; 3,4-Dihydroxyphenylacetic Acid; Mice, Transgenic; Analgesics, Opioid; Homovanillic Acid; HIV Infections; Neurotransmitter Agents; tat Gene Products, Human Immunodeficiency Virus
PubMed: 38308495
DOI: 10.1111/jnc.16057 -
Neuromodulation : Journal of the... Jan 2024Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being... (Review)
Review
OBJECTIVE
Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being stimulation of the dorsal columns; however, certain neuropathic pain areas involve dermatomes that are suboptimally covered by SCS. Stimulation of the spinal nerve roots has the advantage of targeting one or several dermatomes at the same time. The aim of this systematic review is to investigate the efficacy of spinal nerve root stimulation (SNRS) for chronic pain disorders.
MATERIALS AND METHODS
A detailed literature review was performed through the Ovid Embase and MEDLINE data bases in addition to reference searching. Gray literature was included by searching through common search engines using a simplified search strategy. Studies included were focused on adult patients (aged >18 years), diagnosis of chronic pain syndrome (including but not limited to complex regional pain syndrome, persistent spinal pain syndrome, neuropathic pain secondary to trauma or infection, postherpetic pain, and cancer pain). Patients must have undergone SNRS insertion, with ≥six months of documented pain intensity scores on follow-up.
RESULTS
A total of 40 studies underwent full text review, and 13 articles were included in final analysis. Mean preoperative pain intensity was 8.14 ± 0.74 on the visual analog scale, whereas mean postoperative pain intensity at one year was 3.18 ± 1.44. Of 119 patients, 83 (70%) achieved ≥50% reduction in pain intensity after SNRS, whereas 36 (30%) achieved <50% reduction in pain intensity. Only three studies assessed changes in analgesia medication dose and reported morphine equivalent doses varied by case series. Overall, there was a trend toward a reduction in analgesia medications in the postoperative period.
CONCLUSIONS
SNRS led to a mean 44% reduction in pain intensity, with a low level of certainty. In addition, there is some evidence to suggest that using SNRS is associated with reduced use of analgesics, including morphine and gabapentin.
Topics: Adult; Humans; Chronic Pain; Analgesics; Spinal Nerve Roots; Spinal Cord Stimulation; Morphine; Neuralgia
PubMed: 37642627
DOI: 10.1016/j.neurom.2023.07.008 -
The Knee Aug 2023Multimodal pain management regimens and intraosseous infusion of morphine are two novel techniques that show promise in decreasing postoperative pain and opioid...
BACKGROUND
Multimodal pain management regimens and intraosseous infusion of morphine are two novel techniques that show promise in decreasing postoperative pain and opioid consumption following total knee arthroplasty. However, no study has analyzed the intraosseous infusion of a multimodal pain management regimen in this patient population. The purpose of our investigation was to examine the intraosseous administration of a multimodal pain regimen comprised of morphine and ketorolac during total knee arthroplasty with regard to immediate and 2-week postoperative pain, opioid pain medication intake, and nausea levels.
METHODS
In this prospective cohort study with comparisons to a historical control group, 24 patients were prospectively enrolled to receive an intraosseous infusion of morphine and ketorolac dosed according to age-based protocols while undergoing total knee arthroplasty. Immediate and 2-week postoperative Visual Analog Score (VAS) pain scores, opioid pain medication intake, and nausea levels were recorded and compared against a historical control group that received an intraosseous infusion of morphine alone.
RESULTS
During the first four postoperative hours, patients who received the multimodal intraosseous infusion experienced lower VAS pain scores and required less breakthrough intravenous pain medication than those patients in our historical control group. Following this immediate postoperative period, there were no additional differences between groups in terms of pain levels or opioid consumption, and there were no differences in nausea levels between groups at any time.
CONCLUSIONS
Our multimodal intraosseous infusion of morphine and ketorolac dosed according to age-based protocols improved immediate postoperative pain levels and reduced opioid consumption in the immediate postoperative period for patients undergoing total knee arthroplasty.
Topics: Humans; Analgesics, Opioid; Morphine; Ketorolac; Arthroplasty, Replacement, Knee; Prospective Studies; Infusions, Intraosseous; Pain, Postoperative; Nausea
PubMed: 37399631
DOI: 10.1016/j.knee.2023.06.002 -
The Pharmacogenomics Journal Jun 2024The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide...
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Topics: Humans; Morphine; Male; Female; Cancer Pain; Middle Aged; Analgesics, Opioid; Delayed-Action Preparations; Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Morphine Derivatives; Adult; Pharmacogenomic Variants; Toll-Like Receptor 2
PubMed: 38824169
DOI: 10.1038/s41397-024-00339-w -
Aging Jun 2024Morphine tolerance refers to gradual reduction in response to drug with continuous or repeated use of morphine, requiring higher doses to achieve same effect.
BACKGROUND
Morphine tolerance refers to gradual reduction in response to drug with continuous or repeated use of morphine, requiring higher doses to achieve same effect.
METHODS
The morphine tolerance dataset GSE7762 profiles, obtained from gene expression omnibus (GEO) database, were used to identify differentially expressed genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) was applied to explore core modules of DEGs related to morphine tolerance. Core genes were input into Comparative Toxicogenomics Database (CTD). Animal experiments were performed to validate role of Tsc22d3 in morphine tolerance and its relationship with ferroptosis-related pathway.
RESULTS
500 DEGs were identified. DEGs were primarily enriched in negative regulation of brain development, neuronal apoptosis processes, and neurosystem development. Core gene was identified as Tsc22d3. Tsc22d3 gene-associated miRNAs were mmu-miR-196b-5p and mmu-miR-196a-5p. Compared to Non-morphine tolerant group, Tsc22d3 expression was significantly upregulated in Morphine tolerant group. Tsc22d3 expression was upregulated in Morphine tolerant+Tsc22d3_OE, expression of HIF-1alpha, GSH, GPX4 in GPX4 ferroptosis-related pathway showed a more pronounced decrease. As Tsc22d3 expression was downregulated in Morphine tolerant+Tsc22d3_KO, expression of HIF-1alpha, GSH, GPX4 in GPX4 ferroptosis-related pathway exhibited a more pronounced increase. Upregulation of Tsc22d3 in Morphine tolerant+Tsc22d3_OE led to a more pronounced increase in expression of apoptosis proteins (P53, Caspase-3, Bax, SMAC, FAS). The expression of inflammatory factors (IL6, TNF-alpha, CXCL1, CXCL2) showed a more pronounced increase with upregulated Tsc22d3 expression in Morphine tolerant+Tsc22d3_OE.
CONCLUSIONS
Tsc22d3 is highly expressed in brain tissue of morphine-tolerant mice, activating ferroptosis pathway, enhancing apoptosis, promoting inflammatory responses in brain cells.
Topics: Animals; Ferroptosis; Morphine; Mice; Phospholipid Hydroperoxide Glutathione Peroxidase; Drug Tolerance; Male; MicroRNAs; Signal Transduction; Mice, Inbred C57BL
PubMed: 38843390
DOI: 10.18632/aging.205903 -
Neuroreport Dec 2023The interaction between the μ opioid receptor (MOR) and β-arrestin2 serves as a model for addressing morphine tolerance. A peptide was designed to alleviate morphine...
The interaction between the μ opioid receptor (MOR) and β-arrestin2 serves as a model for addressing morphine tolerance. A peptide was designed to alleviate morphine tolerance through interfering with the interaction of MOR and β-arrestin2. We developed a peptide derived from MOR. The MOR-TAT-pep peptide was expressed in E. coli Bl21(DE3) and purified. The effects of MOR-TAT-pep in alleviating morphine tolerance was examined through behavior tests. The potential mechanism was detected by Western blotting, Mammalian Two-Hybrid and other techniques. The pretreatment with MOR-TAT-pep prior to morphine usage led to an enhanced analgesic effectiveness of morphine and a significant reduction in the development of morphine tolerance. The peptide directly interacted with β-arrestin2 during morphine treatment and deceased the membrane recruitment of β-arrestin2. MOR-TAT-pep effectively suppressed the increase of β-arrestin2 induced by morphine. The MOR-TAT-pep could alleviate morphine tolerance through inhibition of β-arrestin2.
Topics: Animals; Morphine; Analgesics, Opioid; beta-Arrestin 1; Receptors, Opioid, mu; Escherichia coli; Peptides; Mammals
PubMed: 37942736
DOI: 10.1097/WNR.0000000000001963