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Biomedicine & Pharmacotherapy =... Jul 2024The lysine-specific demethylase 1 (KDM1A) is reported to be a regulator in learning and memory. However, the effect of KDM1A in oxycodone rewarding memory has yet to be...
The lysine-specific demethylase 1 (KDM1A) is reported to be a regulator in learning and memory. However, the effect of KDM1A in oxycodone rewarding memory has yet to be studied. In our study, rewarding memory was assessed by using conditioned place preference (CPP) in male mice. Next generation sequencing and chromatin immunoprecipitation-PCR were used to explore the molecular mechanisms. Oxycodone significantly decreased PP1α mRNA and protein levels in hippocampal neurons. Oxycodone significantly increased KDM1A and H3K4me1 levels, while significantly decreased H3K4me2 levels in a time- and dose-dependent manner. Behavioral data demonstrated that intraperitoneal injection of ORY-1001 (KDM1A inhibitor) or intra-hippocampal injection of KDM1A siRNA/shRNA blocked the acquisition and expression of oxycodone CPP and facilitated the extinction of oxycodone CPP. The decrease of PP1α was markedly blocked by the injection of ORY-1001 or KDM1A siRNA/shRNA. Oxycodone-induced enhanced binding of CoRest with KDM1A and binding of CoRest with the PP1α promoter was blocked by ORY-1001. The level of H3K4me2 demethylation was also decreased by the treatment. The results suggest that oxycodone-induced upregulation of KDM1A via demethylation of H3K4me2 promotes the binding of CoRest with the PP1α promoter, and the subsequent decrease in PP1α expression in hippocampal neurons may contribute to oxycodone reward.
Topics: Animals; Male; Epigenesis, Genetic; Mice; Oxycodone; Histone Demethylases; Hippocampus; Reward; Conditioning, Psychological; Mice, Inbred C57BL; Histones; Neurons; Memory
PubMed: 38870630
DOI: 10.1016/j.biopha.2024.116931 -
PloS One 2024Insomnia symptoms are negatively related to opioid use disorder (OUD) treatment outcomes, possibly reflecting the influence of sleep on neurofunctional domains...
OBJECTIVES
Insomnia symptoms are negatively related to opioid use disorder (OUD) treatment outcomes, possibly reflecting the influence of sleep on neurofunctional domains implicated in addiction. Moreover, the intersection between OUD recovery and sleep represents an area well-suited for the development of novel, personalized treatment strategies. This study assessed the prevalence of clinically significant insomnia symptoms and characterized its neurofunctional correlates among a clinical sample of adults with OUD receiving buprenorphine.
METHODS
Adults (N = 129) receiving buprenorphine for OUD from an outpatient clinic participated in a cross-sectional survey. Participants completed an abbreviated version of NIDA's Phenotyping Assessment Battery, which assessed 6 neurofunctional domains: sleep, negative emotionality, metacognition, interoception, cognition, and reward. Bivariate descriptive statistics compared those with evidence of clinically significant insomnia symptoms (Insomnia Severity Index [ISI] score of ≥11) to those with minimal evidence of clinically significant insomnia symptoms (ISI score of ≤10) across each of the neurofunctional domains.
RESULTS
Roughly 60% of participants reported clinically significant insomnia symptoms (ISI score of ≥11). Experiencing clinically significant insomnia symptoms was associated with reporting greater levels of depression, anxiety, post-traumatic stress, stress intolerance, unhelpful metacognition, and interoceptive awareness (ps<0.05). Participants with evidence of clinically significant insomnia were more likely to report that poor sleep was interfering with their OUD treatment and that improved sleep would assist with their treatment (ps<0.05).
CONCLUSIONS
Insomnia was prevalent among adults receiving buprenorphine for OUD. Insomnia was associated with neurofunctional performance, which may impact OUD treatment trajectories. Our findings indicate potential targets in the development of personalized treatment plans for patients with co-morbid insomnia and OUD. To inform the development of novel treatment strategies, more research is needed to understand the potential mechanistic links between sleep disturbances and substance use.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Male; Female; Adult; Opioid-Related Disorders; Buprenorphine; Cross-Sectional Studies; Middle Aged; Cognition; Sleep; Opiate Substitution Treatment; Interoception; Reward
PubMed: 38870144
DOI: 10.1371/journal.pone.0304461 -
Scandinavian Journal of Trauma,... Jun 2024
Topics: Humans; Emergency Medical Services; Analgesics, Opioid; Nalbuphine; Analgesia; Pain Management
PubMed: 38867316
DOI: 10.1186/s13049-024-01227-9 -
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 -
Communications Medicine Jun 2024Opioid use in the United States and abroad is an endemic part of society with yearly increases in overdose rates and deaths. In response, the use of the safe and...
BACKGROUND
Opioid use in the United States and abroad is an endemic part of society with yearly increases in overdose rates and deaths. In response, the use of the safe and effective reversal agent, naloxone, is being fielded and used by emergency medical technicians at a greater rate. There is evidence that repeated dosing of a naloxone nasal spray is becoming more common. Despite this we lack repeated dosing guidelines as a function of the amount of opiate the patient has taken.
METHODS
To measure repeat dosing guidelines, we construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdose scenarios. We run a single patient through multiple goal directed resuscitation protocols and measure total naloxone administered.
RESULTS
Here we show that naloxone is highly effective at reversing the respiratory symptoms of the patient and recommend dosing requirements as a function of the fentanyl amount administered. We show that for increasing doses of fentanyl, naloxone requirements also increase. The rescue dose displays a nonlinear response to the initial opioid dose. This nonlinear response is largely logistic with three distinct phases: onset, rapid acceleration, and a plateau period for doses above 1.2 mg.
CONCLUSIONS
This paper investigates the total naloxone dose needed to properly reverse respiratory depression associated with fentanyl overdose. We show that the current guidelines for a rescue dose may be much lower than required.
PubMed: 38866911
DOI: 10.1038/s43856-024-00536-5 -
Journal of Medical Internet Research Jun 2024Telemedicine has the potential to remove geographic and temporal obstacles to health care access. Whether and how telemedicine can increase health care access for...
BACKGROUND
Telemedicine has the potential to remove geographic and temporal obstacles to health care access. Whether and how telemedicine can increase health care access for underserved populations remains an open question. To address this issue, we integrated facilitated telemedicine encounters for the management of hepatitis C virus (HCV), a highly prevalent condition among people with opioid use disorder (OUD), into opioid treatment programs (OTPs). In New York State, OTPs are methadone-dispensing centers that provide patient-centered, evidence-based treatment for OUD. We investigated the integration and impact of facilitated telemedicine into OTP workflows in these settings.
OBJECTIVE
This study aims to understand OTP staff experiences with integrating facilitated telemedicine for HCV treatment into OTPs, including best practices and lessons learned.
METHODS
We conducted semistructured interviews with 45 OTP staff members (13 clinical, 12 administrative, 6 physicians, and 14 support staff members) at least one year after the implementation of facilitated telemedicine for HCV management. We used hermeneutic phenomenological analysis to understand OTP staff experiences.
RESULTS
We identified 4 overarching themes illustrating the successful integration of facilitated telemedicine for HCV care into OTPs. First, integration requires an understanding of the challenges, goals, and values of the OTP. As OTP staff learned about new, highly effective HCV therapies, they valued an HCV cure as a "win" for their patients and were excited about the potential to eliminate a highly prevalent infectious disease. Second, the integration of facilitated telemedicine into OTPs fosters social support and reinforces relationships between patients and OTP staff. OTP staff appreciated the ability to have "eyes on" patients during telemedicine encounters to assess body language, a necessary component of OUD management. Third, participants described high levels of interprofessional collaboration as a care team that included the blurring of lines between disciplines working toward a common goal of improving patient care. Study case managers were integrated into OTP workflows and established communication channels to improve patient outcomes. Fourth, administrators endorsed the sustained and future expansion of facilitated telemedicine to address comorbidities.
CONCLUSIONS
OTP staff were highly enthusiastic about facilitated telemedicine for an underserved population. They described high levels of collaboration and integration comparable to relevant integrative frameworks. When situated within OTPs, facilitated telemedicine is a high-value application of telemedicine that provides support for underserved populations necessary for high-quality health care. These experiences support sustaining and scaling facilitated telemedicine in comparable settings and evaluating its ability to address other comorbidities.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02933970; https://clinicaltrials.gov/study/NCT02933970.
Topics: Humans; Telemedicine; Hepatitis C; Qualitative Research; Female; Male; Opioid-Related Disorders; Adult; New York; Opiate Substitution Treatment; Middle Aged
PubMed: 38865703
DOI: 10.2196/53049 -
Upsala Journal of Medical Sciences 2024Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses...
BACKGROUND
Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated.
METHODS
A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS).
RESULTS
Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations.
CONCLUSION
Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
Topics: Humans; Hypnotics and Sedatives; Analgesics; Male; Female; Middle Aged; Aged; Intensive Care Units; Prospective Studies; Adult; Midazolam; Critical Care; Dexmedetomidine; Fentanyl; Critical Illness; Propofol; Clonidine; Ketamine; Morphine; Aged, 80 and over; Dose-Response Relationship, Drug; Thiopental; Acetaminophen
PubMed: 38863729
DOI: 10.48101/ujms.v129.10560 -
Journal of Hospice and Palliative Care Jun 2024This case report explores the challenges and complexities associated with opioid management of cancer pain, emphasizing the importance of early involvement of a hospice...
This case report explores the challenges and complexities associated with opioid management of cancer pain, emphasizing the importance of early involvement of a hospice consultation team and the adoption of a multidisciplinary approach to care. A 56-year-old man with advanced pancreatic cancer experienced escalating pain and inappropriate opioid prescriptions, highlighting the shortcomings of traditional pain management approaches. Despite procedural intervention by the attending physician and increased opioid dosages, the patient's condition deteriorated. Subsequently, the involvement of a hospice consultation team, in conjunction with collaborative psychiatric care, led to an overall improvement. The case underscores the necessity of early hospice engagement, psychosocial assessments, and collaborative approaches in the optimization of patient-centered palliative care.
PubMed: 38863562
DOI: 10.14475/jhpc.2024.27.2.77 -
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 -
Biomedicine & Pharmacotherapy =... Jul 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.
Topics: Animals; Paclitaxel; Male; Receptor, Cannabinoid, CB2; Female; Morphine; Sensory Receptor Cells; Drug Tolerance; Mice; Neuralgia; Nociception; Mice, Inbred C57BL; Sex Characteristics; Mice, Knockout; Cannabinoid Receptor Agonists
PubMed: 38850666
DOI: 10.1016/j.biopha.2024.116879