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BioRxiv : the Preprint Server For... Sep 2023After injury, mammalian spinal cords develop scars to seal off the damaged area and prevent further injury. However, excessive scarring can hinder neural regeneration...
After injury, mammalian spinal cords develop scars to seal off the damaged area and prevent further injury. However, excessive scarring can hinder neural regeneration and functional recovery (1, 2). These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate the extent of scar formation. Previous research on scar formation has primarily focused on the role of astrocytes, but recent evidence suggests that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain types of injury, becoming a core component of scars (3-7). However, the mechanisms regulating ependymal proliferation in both healthy and injured conditions remain unclear. Here, we uncover an intercellular kappa (κ) opioid signaling pathway that controls endogenous ependymal proliferation. Specifically, we detect expression of the κ opioid receptor, OPRK1, in a functionally under-characterized cell type called cerebrospinal fluid-contacting neurons (CSF-cNs). We also discover a neighboring cell population that express the cognate ligand, prodynorphin (PDYN). Importantly, OPRK1 activation excites CSF-cNs, and systemic administration of a κ antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, injecting a κ agonist reduces the proliferation induced by dorsal hemisection. Altogether, our data suggest a regulatory mechanism whereby PDYN cells tonically release κ opioids to stimulate CSF-cNs, which in turn suppress ependymal proliferation. This endogenous pathway provides a mechanistic basis for the potential use of κ opiates in modulating scar formation and treating spinal cord injuries.
PubMed: 38883735
DOI: 10.1101/2023.09.07.556726 -
The Korean Journal of Pain Jul 2024Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to...
BACKGROUND
Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. Biguanide-type drugs such as metformin (MET) are effective for neuroprotection and can be beneficial for addressing opioid tolerance in the treatment of chronic pain. It has been proposed that analgesic tolerance to NSAIDs is mediated by the endogenous opioid system. According to the cross-tolerance between NSAIDs, especially sodium salicylate (SS), and opiates, especially morphine, the objective of this study was to investigate whether MET administration can reduce tolerance to the anti-nociceptive effects of SS.
METHODS
Fifty-six male Wistar rats were used in this research (weight 200-250 g). For induction of tolerance, SS (300 mg/kg) was injected intraperitoneally for 7 days. During the examination period, animals received MET at doses of 50, 75, or 100 mg/kg for 7 days to evaluate the development of tolerance to the analgesic effect of SS. The hot plate test was used to evaluate the drugs' anti-nociceptive properties.
RESULTS
Salicylate injection significantly increased hot plate latency as compared to the control group, but the total analgesic effect of co-treatment with SS + Met50 was stronger than the SS group. Furthermore, the effect of this combination undergoes less analgesic tolerance over time.
CONCLUSIONS
It can be concluded that MET can reduce the analgesic tolerance that is induced by repeated intraperitoneal injections of SS in Wister rats.
PubMed: 38881281
DOI: 10.3344/kjp.24066 -
The Journal of Adolescent Health :... Jul 2024
Topics: Humans; Buprenorphine; Opioid-Related Disorders; Adolescent; Opiate Substitution Treatment; Health Services Accessibility; Narcotic Antagonists; Injections
PubMed: 38880557
DOI: 10.1016/j.jadohealth.2024.04.010 -
British Journal of Anaesthesia Jul 2024Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate...
Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation.
Topics: Humans; Intubation, Intratracheal; Rocuronium; Neuromuscular Nondepolarizing Agents; Sugammadex; Androstanols; Benzodiazepines; Fentanyl; Analgesics, Opioid; Naloxone; Rapid Sequence Induction and Intubation
PubMed: 38879265
DOI: 10.1016/j.bja.2024.04.005 -
Regional Anesthesia and Pain Medicine Jun 2024The population undergoing cardiac surgery confronts challenges from uncontrolled post-sternotomy pain, with possible adverse effects on outcome. While the parasternal...
Rectus sheath block added to parasternal block may improve postoperative pain control and respiratory performance after cardiac surgery: a superiority single-blinded randomized controlled clinical trial.
BACKGROUND
The population undergoing cardiac surgery confronts challenges from uncontrolled post-sternotomy pain, with possible adverse effects on outcome. While the parasternal block can improve analgesia, its coverage may be insufficient to cover epigastric area. In this non-blinded randomized controlled study, we evaluated the analgesic and respiratory effect of adding a rectus sheath block to a parasternal block.
METHODS
58 patients undergoing cardiac surgery via median sternotomy were randomly assigned to receive parasternal block with rectus sheath block (experimental) or parasternal block with epigastric exit sites of chest drains receiving surgical infiltration of local anesthetic (control). The primary outcome of this study was pain at rest at extubation. We also assessed pain scores at rest and during respiratory exercises, opiate consumption and respiratory performance during the first 24 hours after extubation.
RESULTS
The median (IQR) maximum pain scores (on a 0-10 Numeric Rate Scale (NRS)) at extubation were 4 (4, 4) in the rectus sheath group and 5 (4, 5) in the control group (difference 1, p value=0.03). Rectus sheath block reduced opioid utilization by 2 mg over 24 hours (IC 95% 0.0 to 2.0; p<0.01), reduced NRS scores at other time points, and improved respiratory performance at 6, 12, and 24 hours after extubation.
CONCLUSION
The addition of a rectus sheath block with a parasternal block improves analgesia for cardiac surgery requiring chest drains emerging in the epigastric area.
TRIAL REGISTRATION NUMBER
NCT05764616.
PubMed: 38876800
DOI: 10.1136/rapm-2024-105430 -
The International Journal on Drug Policy Jun 2024In this essay we want to foreground a question: what happens to 'addiction' when we take seriously cultural scripts informing its trajectories? Can this bring us to...
In this essay we want to foreground a question: what happens to 'addiction' when we take seriously cultural scripts informing its trajectories? Can this bring us to unthink addiction as problematic notion and move it onto new paradigms that fit better the now acknowledged fluidity and pluralistic episteme of 'addiction' and more broadly of chronic life conditions? Indeed, 'addiction' has become a pivotal concept in the contemporary world. A powerful diagnostic framework in interpreting human behaviour, for some 'addiction' has become the 'new normal' with chronic relations with different things such as food, sex, gambling, and mind-altering substances touching upon the lifestyle of a majority of individuals, making everyone 'addicts in practice'. Perhaps this has something to do with the constituent force that 'habit' - as in 'addiction' - has in defining our present and future. Though 'addiction' goes beyond the question of mind-altering drugs, the politics of 'addiction' is intimately tied to substances such as opioids and opiates, cocaine, cannabis, and psychedelics that have been the object of durable systemic political control and security repression. Contextually the line between licit/illicit substances is softening and blurring, the 'dual' purpose that drugs serve is now recognised in scientific and popular analysis moving the question of 'addiction' beyond the medicine/drug dichotomy. Yet, culture is generally absent in understanding 'addiction.' When it is referred to, this happens in diminutive terms limited to Anglo-American modern culture. Culture matters and it matters with different weights and measures as it moves across the world. There are cultural environments of health informed by practices and epistemologies of well-being that have evolved in lines opposites from or only intersecting with the Anglo-American, and generally Western, world. Exploring these spaces and cultural scripts enables our scholarship on drugs and 'addiction' to move the barycentre of discussion towards novel considerations around the historical trajectories and potential futures of our diagnostic terms and policy interventions.
PubMed: 38875879
DOI: 10.1016/j.drugpo.2024.104473 -
Journal of Neuroimmune Pharmacology :... Jun 2024The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the...
The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the emerging public health challenge of understanding and treating POE children. We examined two scenarios using preclinical models: offspring exposed to oxycodone (OXY) in utero (IUO) and acute postnatal OXY (PNO). We hypothesized exposure to OXY during pregnancy primes offspring for neurodevelopmental deficits and severity of deficits is dependent on timing of exposure. Notable findings include reduced head size and brain weight in offspring. Molecular analyses revealed significantly lower levels of inflammasome-specific genes in the prefrontal cortex (PFC). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) highlighted the enrichment of genes associated with mitochondrial and synapse dysfunction in POE offspring. Western blot analysis validated IPA predictions of mitochondrial dysfunction in PFC-derived synaptosomes. Behavioral studies identified significant social deficits in POE offspring. This study presents the first comparative analysis of acute PNO- and IUO-offspring during early adolescence finding acute PNO-offspring have considerably greater deficits. The striking difference in deficit severity in acute PNO-offspring suggests that exposure to opioids in late pregnancy pose the greatest risk for offspring well-being.
Topics: Animals; Oxycodone; Pregnancy; Female; Prenatal Exposure Delayed Effects; Male; Analgesics, Opioid; Behavior, Animal; Rats; Rats, Sprague-Dawley; Neurodevelopmental Disorders; Prefrontal Cortex
PubMed: 38874861
DOI: 10.1007/s11481-024-10129-7 -
Advances in Neurobiology 2024It has become apparent that endogenous opioids act not only as neurotransmitters and neuromodulators, but have multiple functions in the body. Activation of the opioid...
It has become apparent that endogenous opioids act not only as neurotransmitters and neuromodulators, but have multiple functions in the body. Activation of the opioid system by opiate drugs is associated with a risk of cancer development through direct stimulation of tumor cell proliferation and through immunosuppression. In contrast, the endogenous peptide opioid [Met]-enkephalin, now commonly referred to as Opioid Growth Factor (OGF), negatively regulates cell proliferation in a wide number of cells during development, homeostasis, and neoplasia. This action is mediated through the opioid growth factor receptor, originally designated the zeta (ζ) opioid receptor. Further, contrary to the traditional notion of opiates as immunosuppressive, endogenous OGF has been shown to possess a number of positive immunomodulatory properties and may provide a beneficial effect in cancer by augmenting the activity of cells involved in both innate and acquired immunity. Taken together, the evidence supports consideration of opioid peptides such as OGF as new strategies for cancer therapy.
Topics: Animals; Humans; Cell Proliferation; Enkephalin, Methionine; Neoplasms; Opioid Peptides; Receptors, Opioid
PubMed: 38874718
DOI: 10.1007/978-3-031-45493-6_4 -
Addiction Science & Clinical Practice Jun 2024The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as... (Randomized Controlled Trial)
Randomized Controlled Trial
The identification and treatment of alcohol problems in primary care (iTAPP) study: protocol for a stepped wedge cluster randomized control trial testing the 15-method in a primary care setting.
BACKGROUND
The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as specialized treatment for mild to moderate alcohol dependence in Sweden. A feasibility study of the 15-method in Danish primary care found the method acceptable and feasible.
AIMS
To evaluate the effectiveness of the 15-method in a Danish primary care setting in (1) lowering the proportion of patients exceeding the Danish low-risk alcohol consumption limit of ten standard units per week and a maximum of four standard units on a single day for men and women, and (2) increasing the likelihood of alcohol use being addressed during a consultation in general practice. Further, the rate of prescribed pharmacological treatment for alcohol problems (Disulfiram, Naltrexone, Acamprosate, and Nalmefene) will be measured along with the use of the biomarkers Alanine Transaminase and Gamma-Glutamyl Transferase.
METHODS
Stepped wedge cluster randomized controlled trial in sixteen general practices in the Region of Southern Denmark. Following a three-month baseline, the practices are randomly assigned to launch dates in one of four clusters. General practitioners and nurses receive three hours of training in the 15-method before launch. Patient questionnaires will collect data on alcohol consumption levels among patients affiliated with the practices. The healthcare professionals will register consultations in which alcohol is addressed in their patient filing system. Pharmacological treatment rates and the use of biomarkers will be collected through Danish national registries. The study follows the Medical Research Council's guidelines for developing and evaluating complex interventions.
DISCUSSION
From the patient's perspective, the 15-method may help identify alcohol-related problems at an earlier stage with flexible treatment offers in a familiar setting. For healthcare professionals, it addresses a traditionally challenging topic by equipping them with concrete tools, communication training, and clear treatment directives. From a societal perspective, primary care holds a unique position to identify hazardous and harmful alcohol use across different age groups, with potential public health and economic benefits through early identification and intervention.
TRIAL REGISTRATION
Clinicaltrials.gov NCT05916027. Retrospectively registered 22 June 2023.
Topics: Humans; Primary Health Care; Denmark; Naltrexone; Alcoholism; Male; Female; Alcohol Deterrents; Disulfiram; Acamprosate; Adult; Taurine; Alanine Transaminase; gamma-Glutamyltransferase; Middle Aged; Mass Screening; Randomized Controlled Trials as Topic
PubMed: 38872214
DOI: 10.1186/s13722-024-00474-6 -
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