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Trends in Pharmacological Sciences Nov 2016Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing... (Review)
Review
Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs.
Topics: Allostasis; Analgesics, Opioid; Animals; Brain; Down-Regulation; Drug Tolerance; Humans; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 27670390
DOI: 10.1016/j.tips.2016.08.002 -
Journal of Nippon Medical School =... Mar 2021The effectiveness and safety of antipsychotics have not been fully established in children and adolescents. Many antipsychotics approved for use in adults are prescribed... (Review)
Review
The effectiveness and safety of antipsychotics have not been fully established in children and adolescents. Many antipsychotics approved for use in adults are prescribed off-label to children and adolescents. We investigated the effectiveness and tolerability of antipsychotics for children and adolescents with schizophrenia and bipolar disorder. A literature review of the empirical evidence regarding the use of antipsychotics, particularly second-generation antipsychotics, in children and adolescents showed that these drugs were safe and effective for this population. Antipsychotics were similarly effective for treatment of schizophrenia and bipolar disorder in children and adolescents. When prescribing antipsychotics to this population, clinicians should consider adverse events and the discontinuation rate in treated patients. However, the current evidence shows a lack of consensus regarding the use of antipsychotics in children and adolescents.
Topics: Adolescent; Antipsychotic Agents; Bipolar Disorder; Child; Drug Tolerance; Female; Humans; Male; Safety; Schizophrenia, Childhood; Treatment Outcome; Withholding Treatment
PubMed: 32999174
DOI: 10.1272/jnms.JNMS.2021_88-108 -
MBio Jun 2023Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological...
Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological nutrient concentrations, pathogens encounter a relatively restrictive environment . We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically relevant mild nutrient stress (or "metabolic priming") triggers increased tolerance of a potent antimalarial drug. We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in metabolism or using a media formulation that simulates the human plasma environment. We determined that priming-induced tolerance was restricted to parasites that had newly invaded the host red blood cell, but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic tolerance, including translational repression and protein export. This finding suggests that regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently compared to the stable environment, priming-induced drug tolerance has ramifications for how results translate to studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to slow the evolution of resistance. There is a dire need for effective treatments against microbial pathogens. Yet, the continuing emergence of drug resistance necessitates a deeper knowledge of how pathogens respond to treatments. We have long appreciated the contribution of genetic evolution to drug resistance, but transient metabolic changes that arise in response to environmental factors are less recognized. Here, we demonstrate that short-term growth of malaria parasites in a nutrient-limiting environment triggers cellular changes that lead to better survival of drug treatment. We found that these strategies are similar to those employed by drug-tolerant parasites, which suggests that starvation "primes" parasites to survive and potentially evolve resistance. Since the environment of the human host is relatively nutrient restrictive compared to growth conditions in standard laboratory culture, this discovery highlights the important connections among nutrient levels, protective cellular pathways, and resistance evolution.
Topics: Humans; Plasmodium falciparum; Artemisinins; Malaria; Antimalarials; Drug Tolerance; Drug Resistance; Nutrients
PubMed: 37097173
DOI: 10.1128/mbio.00705-23 -
Physiology (Bethesda, Md.) Sep 2021Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut...
Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.
Topics: Analgesics, Opioid; Drug Tolerance; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Opioid Epidemic
PubMed: 34431418
DOI: 10.1152/physiol.00014.2021 -
Frontiers in Cellular and Infection... 2022Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is... (Review)
Review
Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is due to multiple reasons, including inadequate drug concentrations reaching at the site of infection and physiological changes of in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of that promotes drug tolerance in the host. Towards this end, multiple studies have converged on bacterial central carbon metabolism as a critical contributor to drug tolerance. In this review, we present the evidence that changes in central carbon metabolism can promote drug tolerance, depending on the environment surrounding . We posit that these metabolic pathways could be potential drug targets to stymie the development of drug tolerance and enhance the efficacy of current antimicrobial therapy.
Topics: Carbon; Drug Tolerance; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis, Lymph Node
PubMed: 36072222
DOI: 10.3389/fcimb.2022.958555 -
Trends in Microbiology Aug 2015During microbial production of solvent-like compounds, such as advanced biofuels and bulk chemicals, accumulation of the final product can negatively impact the... (Review)
Review
During microbial production of solvent-like compounds, such as advanced biofuels and bulk chemicals, accumulation of the final product can negatively impact the cultivation of the host microbe and limit the production levels. Consequently, improving solvent tolerance is becoming an essential aspect of engineering microbial production strains. Mechanisms ranging from chaperones to transcriptional factors have been used to obtain solvent-tolerant strains. However, alleviating growth inhibition does not invariably result in increased production. Transporters specifically have emerged as a powerful category of proteins that bestow tolerance and often improve production but are difficult targets for cellular expression. Here we review strain engineering, primarily as it pertains to bacterial solvent tolerance, and the benefits and challenges associated with the expression of membrane-localized transporters in improving solvent tolerance and production.
Topics: Bacteria; Biofuels; Drug Tolerance; Gene Expression; Membrane Transport Proteins; Metabolic Engineering; Solvents
PubMed: 26024777
DOI: 10.1016/j.tim.2015.04.008 -
Purinergic Signalling Jun 2023Cancer pain is the most prevalent symptom experienced by cancer patients. It substantially impacts a patient's long-term physical and emotional health, making it a... (Review)
Review
Cancer pain is the most prevalent symptom experienced by cancer patients. It substantially impacts a patient's long-term physical and emotional health, making it a pressing issue that must be addressed. Purinergic receptor P2X7 (P2X7R) is a widely distributed and potent non-selective ATP-gated ion channel that regulates tumor proliferation, chronic pain, and the formation of inflammatory lesions in the central nervous system. P2X7R plays an essential role in cancer pain and complications related to cancer pain including depression and opioid tolerance. This review focuses on the structure and distribution of P2X7R, its role in diverse tissues in cancer pain, and the application of P2X7R antagonists in the treatment of cancer pain to propose new ideas for cancer pain management.
Topics: Humans; Cancer Pain; Receptors, Purinergic P2X7; Analgesics, Opioid; Purinergic P2X Receptor Antagonists; Drug Tolerance; Neoplasms
PubMed: 36400869
DOI: 10.1007/s11302-022-09902-1 -
Pain Physician 2015Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient... (Review)
Review
Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient safety, and evaluate patient compliance using information that is not available with traditional urine drug testing (UDT). Blood testing does not need to be performed as frequently as UDT but provides extremely valuable information which can be used to more accurately evaluate patient compliance and assist with interpreting blood toxicology results commonly used in impairment or overdose cases. This narrative review presents the current evidence supporting the use of blood testing within the chronic pain management setting. In addition, this review aims to introduce and discuss the role of routine blood testing within the chronic pain management setting. Blood testing for the purpose of documenting opioid tolerance is a relatively novel tool for pain physicians and as such this review is not intended to be a comprehensive or exhaustive review of the scientific or medical literature. Prescribers must also be aware that this type of laboratory testing need only be administered to chronic pain patients receiving daily opioid therapy. Patients taking infrequent, low dose, or as needed medications are not anticipated to benefit from this type of test. Based on the complexity of both achieving acceptable outcomes with opioid treatment and the legal and societal issues at hand, we feel that the addition of blood concentration levels will become the standard of care in the near future.
Topics: Analgesics, Opioid; Chronic Pain; Drug Overdose; Drug Tolerance; Health Services Needs and Demand; Hematologic Tests; Humans; Pain Management; Patient Compliance; Substance Abuse Detection
PubMed: 25794214
DOI: No ID Found -
International Journal of Environmental... Feb 2022Humans have used opioids to suppress moderate to severe pain for thousands of years. However, the long-term use of opioids has several adverse effects, such as opioid... (Review)
Review
Humans have used opioids to suppress moderate to severe pain for thousands of years. However, the long-term use of opioids has several adverse effects, such as opioid tolerance, opioid-induced hyperalgesia, and addiction. In addition, the low efficiency of opioids in controlling neuropathic pain limits their clinical applications. Combining nonopioid analgesics with opioids to target multiple sites along the nociceptive pathway may alleviate the side effects of opioids. This study reviews the feasibility of reducing opioid side effects by regulating the transient receptor potential vanilloid 1 (TRPV1) receptors and summarizes the possible underlying mechanisms. Blocking and activating TRPV1 receptors can improve the therapeutic profile of opioids in different manners. TRPV1 and μ-opioid receptors are bidirectionally regulated by β-arrestin2. Thus, drug combinations or developing dual-acting drugs simultaneously targeting μ-opioid and TRPV1 receptors may mitigate opioid tolerance and opioid-induced hyperalgesia. In addition, TRPV1 receptors, especially expressed in the dorsal striatum and nucleus accumbens, participate in mediating opioid reward, and its regulation can reduce the risk of opioid-induced addiction. Finally, co-administration of TRPV1 antagonists and opioids in the primary action sites of the periphery can significantly relieve neuropathic pain. In general, the regulation of TRPV1 may potentially ameliorate the side effects of opioids and enhance their analgesic efficacy in neuropathic pain.
Topics: Analgesics, Opioid; Drug Tolerance; Humans; Neuralgia; Receptors, Opioid, mu; TRPV Cation Channels
PubMed: 35206575
DOI: 10.3390/ijerph19042387 -
Drug Delivery and Translational Research Jun 2024Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding... (Review)
Review
Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.
Topics: Humans; Anti-Bacterial Agents; Drug Delivery Systems; Animals; Drug Resistance, Microbial; Drug Resistance, Bacterial; Bacteria; Drug Tolerance
PubMed: 38341386
DOI: 10.1007/s13346-023-01513-6