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Current Opinion in Supportive and... Jun 2017Pain management presents a major challenge in neonatal care. Newborn infants who require medical treatment can undergo frequent invasive procedures during a critical... (Review)
Review
PURPOSE OF REVIEW
Pain management presents a major challenge in neonatal care. Newborn infants who require medical treatment can undergo frequent invasive procedures during a critical period of neurodevelopment. However, adequate analgesic provision is infrequently and inconsistently provided for acute noxious procedures because of limited and conflicting evidence regarding analgesic efficacy and safety of most commonly used pharmacological agents. Here, we review recent advances in the measurement of infant pain and discuss clinical trials that assess the efficacy of pharmacological analgesia in infants.
RECENT FINDINGS
Recently developed measures of noxious-evoked brain activity are sensitive to analgesic modulation, providing an objective quantitative outcome measure that can be used in clinical trials of analgesics.
SUMMARY
Noxious stimulation evokes changes in activity across all levels of the infant nervous system, including reflex activity, altered brain activity and behaviour, and long-lasting changes in infant physiological stability. A multimodal approach is needed if we are to identify efficacious and well tolerated analgesic treatments. Well designed clinical trials are urgently required to improve analgesic provision in the infant population.
Topics: Acetaminophen; Administration, Cutaneous; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Brain; Humans; Infant, Newborn; Morphine; Pain; Pain Management; Pain Measurement; Randomized Controlled Trials as Topic
PubMed: 28375883
DOI: 10.1097/SPC.0000000000000270 -
International Journal of Molecular... Nov 2023Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for...
Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves.
Topics: Animals; Mice; Analgesics; Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Tolerance; Interleukins; Morphine; Pruritus
PubMed: 38003738
DOI: 10.3390/ijms242216548 -
Molecular Therapy : the Journal of the... May 2023Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons,...
Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.
Topics: Mice; Animals; Antagomirs; Morphine; MicroRNAs; Brain; Extracellular Vesicles
PubMed: 37012704
DOI: 10.1016/j.ymthe.2023.03.030 -
The Journal of Neuroscience : the... Apr 2023The paraventricular nucleus of the thalamus (PVT) is involved in drug addiction-related behaviors, and morphine is a widely used opioid for the relief of severe pain....
The paraventricular nucleus of the thalamus (PVT) is involved in drug addiction-related behaviors, and morphine is a widely used opioid for the relief of severe pain. Morphine acts via opioid receptors, but the function of opioid receptors in the PVT has not been fully elucidated. Here, we used electrophysiology to study neuronal activity and synaptic transmission in the PVT of male and female mice. Activation of opioid receptors suppresses the firing and inhibitory synaptic transmission of PVT neurons in brain slices. On the other hand, the involvement of opioid modulation is reduced after chronic morphine exposure, probably because of desensitization and internalization of opioid receptors in the PVT. Overall, the opioid system is essential for the modulation of PVT activities. Opioid receptors modulate the activities and synaptic transmission in the PVT by suppressing the firing rate and inhibitory synaptic inputs. These modulations were largely diminished after chronic morphine exposure.
Topics: Male; Female; Mice; Animals; Analgesics, Opioid; Receptors, Opioid; Paraventricular Hypothalamic Nucleus; Thalamus; Synaptic Transmission; Morphine
PubMed: 36898836
DOI: 10.1523/JNEUROSCI.1766-22.2023 -
Journal of Proteome Research Jul 2023Substance use disorders are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of...
Substance use disorders are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based quantitative proteomics, along with a data-independent acquisition analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveal cocaine and morphine differentially alter diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between the phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome. The proteomics data in this study are available via ProteomeXchange with identifier PXD042043.
Topics: Mice; Animals; Cocaine; Nucleus Accumbens; Morphine; Proteome; Analgesics, Opioid
PubMed: 37311105
DOI: 10.1021/acs.jproteome.3c00126 -
Bioengineered Dec 2021Morphine tolerance poses a great challenge for clinicians, whose pathogenesis has a close connection with microglial activation and neuroinflammation. Dihydroartemisinin...
Morphine tolerance poses a great challenge for clinicians, whose pathogenesis has a close connection with microglial activation and neuroinflammation. Dihydroartemisinin (DHA) that derives from artemisinin, may serve as a potential anti-inflammatory drug. In this study, the effects as well as the underlying mechanism of DHA on suppressing microglial activation and neuroinflammation were explored. The microglial cell line BV-2 cells were induced by morphine and treated with DHA or minocycline. With the application of CCK-8, the cell viability was detected. Western blot was employed to assess the expressions of Ki67, IBa-1, and TLR4 and quantitative real-time PCR (qRT-PCR) was adopted to evaluate miRNA-16 (miR-16) expression. With the adoption of ELISA kits and qRT-PCR, the release of inflammatory cytokines was evaluated. Besides, luciferase reporter assay was applied to testify the binding relationship between miR-16 and TLR4. NF-κB expression was measured by immunofluorescence. DHA reduced cell viability and decreased protein expression of Ki67 and IBa-1 in morphine-induced BV-2 cells. Additionally, DHA contributed to the declined release of pro-inflammatory cytokines. miR-16 was down-regulated by morphine but was up-regulated by DHA concentration-dependently in BV-2 cells. The inhibition of miR-16 partly abolished the inhibitory effects of DHA on morphine-induced microglial activation and neuroinflammation. Moreover, TLR4 was found to be bound to miR-16, and the inhibitory effect of DHA on TLR4/NF-κB was partly reversed by miR-16 inhibition. In conclusion, DHA remarkably suppressed microglial activation and neuroinflammation through regulating miR-16-mediated TLR4/NF-κB signaling. This study may provide a new solution to improve clinical analgesic efficacy of morphine.
Topics: Animals; Artemisinins; Cell Line; Gene Expression Regulation; Inflammation; Mice; Microglia; Morphine; Nerve Tissue Proteins
PubMed: 34854364
DOI: 10.1080/21655979.2021.1982311 -
Canadian Journal of Anaesthesia =... Oct 2017
Topics: Analgesics, Opioid; Blood-Brain Barrier; Brain; Morphine
PubMed: 28721688
DOI: 10.1007/s12630-017-0932-y -
European Journal of Pharmacology May 2020Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the...
Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Topics: Animals; Central Nervous System Stimulants; Disease Models, Animal; Drug Administration Schedule; Drug Tolerance; Humans; Hyperalgesia; Injections, Spinal; Male; Morphine; Morphine Derivatives; Nociception; Pain Measurement; Rats; Spinal Cord; Substance P
PubMed: 32112778
DOI: 10.1016/j.ejphar.2020.173021 -
European Journal of Clinical... Jun 2015The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are... (Review)
Review
OBJECTIVES
The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are responsible for this variation.
METHODS
A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL, and Cochrane library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined.
RESULTS
Twenty-eight studies were identified. After quality assessment, 20 studies were included. Only 10 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups, but greatest in critically ill neonates (both preterm and term) and infants. In critically ill patients, the CV was 16-97% in preterm neonates, 24-87% in term neonates, 35 and 134% in infants, 39 and 55% in children, and 74% in adolescents. The CV was 37 and 44% respectively in non-critically ill neonates and infants. The mean clearance was higher in children (32 and 52 ml min(-1) kg(-1)) than in neonates (2 to 16 ml min(-1) kg(-1)).
CONCLUSIONS
Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.
Topics: Child; Critical Illness; Humans; Individuality; Morphine
PubMed: 25845657
DOI: 10.1007/s00228-015-1843-x -
Peptides May 2019Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the... (Review)
Review
Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, most studies have examined the role of glia activation within the spinal cord. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This review attempts to summarize what is known regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance. These data, together, provide information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.
Topics: Analgesics, Opioid; Chronic Pain; Drug Tolerance; Humans; Inflammation Mediators; Morphine; Opioid-Related Disorders; Periaqueductal Gray; Spinal Cord; Toll-Like Receptor 4
PubMed: 30890355
DOI: 10.1016/j.peptides.2019.01.003