RESUMEN
The direct blockade of CB1 cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB1 negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB1. We recently reported that GAT358, a CB1-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB1-allosteric mechanism of action. Whether a CB1-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted opioid side-effects remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine in male rats. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar spinal cord. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors in male mice. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception and reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 also produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal cord. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB1-NAM.
Asunto(s)
Analgésicos Opioides , Tolerancia a Medicamentos , Morfina , Ratas Sprague-Dawley , Receptor Cannabinoide CB1 , Síndrome de Abstinencia a Sustancias , Animales , Receptor Cannabinoide CB1/metabolismo , Masculino , Analgésicos Opioides/farmacología , Tolerancia a Medicamentos/fisiología , Regulación Alostérica/efectos de los fármacos , Ratones , Morfina/farmacología , Ratas , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Nocicepción/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 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 CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3â¯mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1â¯mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3â¯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 CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.
Asunto(s)
Tolerancia a Medicamentos , Morfina , Neuralgia , Paclitaxel , Receptor Cannabinoide CB2 , Células Receptoras Sensoriales , Animales , Masculino , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/genética , Femenino , Morfina/farmacología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Tolerancia a Medicamentos/fisiología , Ratones , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Nocicepción/efectos de los fármacos , Ratones Endogámicos C57BL , Caracteres Sexuales , Ratones Noqueados , Agonistas de Receptores de Cannabinoides/farmacologíaAsunto(s)
Tolerancia a Medicamentos , Hiperalgesia , Morfina , Morfina/farmacología , Morfina/efectos adversos , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Animales , Tolerancia a Medicamentos/fisiología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Ratones , Analgésicos Opioides/farmacología , HumanosRESUMEN
Opioid analgesics are widely used as a treatment option for pain management and relief. However, the misuse of opioid analgesics has contributed to the current opioid epidemic in the United States. Prescribed opioids such as morphine, codeine, oxycodone, and fentanyl are mu-opioid receptor (MOR) agonists primarily used in the clinic to treat pain or during medical procedures, but development of tolerance limits their utility for treatment of chronic pain. Here we explored the effects of biasing Gßγ signaling on tolerance development after chronic morphine treatment in vivo. We hypothesized that biasing Gßγ signaling with gallein could prevent activation of regulatory signaling pathways that result in tolerance to antinociceptive effects of MOR agonists. Gallein has been shown to bind to Gßγ and inhibit interactions of Gßγ with phospholipase-Cß3 (PLCß3) or G-protein-coupled receptor kinase 2 (GRK2) but not G-protein inwardly rectifying potassium (GIRK) channels. In mice, morphine-induced antinociception was evaluated in the 55°C warm water tail withdrawal assay. We used two paradigms for gallein treatment: administration during and after three times-daily morphine administration. Our results show that gallein cotreatment during repeated administration of morphine decreased opioid tolerance development and that gallein treatment in an opioid-tolerant state enhanced the potency of morphine. Mechanistically, our data suggest that PLCß3 is necessary for potentiating effects of gallein in an opioid-tolerant state but not in preventing the development of tolerance. These studies demonstrate that small molecules that target Gßγ signaling could reduce the need for large doses of opioid analgesics to treat pain by producing an opioid-sparing effect. SIGNIFICANCE STATEMENT: Biasing Gßγ signaling prevents tolerance to repeated morphine administration in vivo and potentiates the antinociceptive effects of morphine in an opioid-tolerant state. Mechanistically, phospholipase-Cß is necessary for potentiating effects of gallein in an opioid-tolerant state but not in preventing the development of tolerance. This study identifies a novel treatment strategy to decrease the development of tolerance to the analgesic effects of mu-opioid receptor agonists, which are necessary to improve pain treatment and decrease the incidence of opioid use disorder.
Asunto(s)
Analgésicos Opioides , Tolerancia a Medicamentos , Subunidades beta de la Proteína de Unión al GTP , Subunidades gamma de la Proteína de Unión al GTP , Ratones Endogámicos C57BL , Morfina , Nocicepción , Transducción de Señal , Animales , Morfina/farmacología , Tolerancia a Medicamentos/fisiología , Transducción de Señal/efectos de los fármacos , Ratones , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Masculino , Analgésicos Opioides/farmacología , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Nocicepción/efectos de los fármacos , Receptores Opioides mu/metabolismo , Receptores Opioides mu/agonistas , Fosfolipasa C beta/metabolismo , XantenosRESUMEN
Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.
Asunto(s)
Analgésicos Opioides , Tolerancia a Medicamentos , Hiperalgesia , Morfina , Plasticidad Neuronal , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T , Animales , Morfina/farmacología , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Tolerancia a Medicamentos/fisiología , Ratones , Analgésicos Opioides/farmacología , Masculino , Ratones Endogámicos C57BL , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through âº7 nicotinic acetylcholine receptors (nAChRs). Activating âº7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca2+ and peroxisome proliferator-activated receptor α (PPARâº)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that âº7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
Asunto(s)
Dolor Crónico , Receptores Nicotínicos , Ratas , Animales , Humanos , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Acetilcolina , Ratas Sprague-Dawley , Dimensión del Dolor/métodos , Tolerancia a Medicamentos/fisiología , Sustancia Gris Periacueductal/fisiología , Colinérgicos/farmacología , Receptores Nicotínicos/metabolismoRESUMEN
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
Asunto(s)
Analgésicos Opioides , Microglía , Humanos , Analgésicos Opioides/farmacología , Morfina/farmacología , Tolerancia a Medicamentos/fisiología , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológicoRESUMEN
Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund's adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT: The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.
Asunto(s)
Dolor Crónico , Hipersensibilidad , Neuralgia , Profármacos , Ratones , Masculino , Femenino , Animales , Morfina/farmacología , Morfina/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Tolerancia a Medicamentos/fisiología , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Adenosina TrifosfatoRESUMEN
The analgesic effect of opioids decreases over time due to the development of analgesic tolerance. We have shown that inhibition of the platelet-derived growth factor beta (PDGFR-ß) signaling eliminates morphine analgesic tolerance in rats. Although the PDGFR-ß and its ligand, the platelet-derived growth factor type B (PDGF-B), are expressed in the substantia gelatinosa of the spinal cord (SG) and in the dorsal root ganglia (DRG), their precise distribution within different cell types of these structures is unknown. Additionally, the impact of a tolerance-mediating chronic morphine treatment, on the expression and distribution of PDGF-B and PDGFR-ß has not yet been studied. Using immunohistochemistry (IHC), we found that in the spinal cord, PDGFR-ß and PDGF-B were expressed in neurons and oligodendrocytes and co-localized with the mu-opioid receptor (MOPr) in opioid naïve rats. PDGF-B was also found in microglia and astrocytes. Both PDGFR-ß and PDGF-B were detected in DRG neurons but not in spinal primary afferent terminals. Chronic morphine exposure did not change the cellular distribution of PDGFR-ß or PDGF-B. However, PDGFR-ß expression was downregulated in the SG and upregulated in the DRG. Consistent with our previous finding that morphine caused tolerance by inducing PDGF-B release, PDGF-B was upregulated in the spinal cord. We also found that chronic morphine exposure caused a spinal proliferation of oligodendrocytes. The changes in PDGFR-ß and PDGF-B expression induced by chronic morphine treatment suggest potential mechanistic substrates underlying opioid tolerance.
Asunto(s)
Analgésicos Opioides , Morfina , Ratas , Masculino , Animales , Morfina/farmacología , Analgésicos Opioides/farmacología , Analgésicos Opioides/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Proteínas Proto-Oncogénicas c-sis/farmacología , Ratas Sprague-Dawley , Ganglios Espinales/metabolismo , Tolerancia a Medicamentos/fisiología , Médula Espinal/metabolismoRESUMEN
A newly deorphanized G protein-coupled receptor, GPR171, is found to be highly expressed within the periaqueductal gray, a pain-modulating region in the brain. Our recent research has shown that a GPR171 agonist increases morphine antinociception in male mice and opioid signaling in vitro . The objective of this study was to evaluate the effects of combination treatment in females as well as whether chronic treatment can be used without exacerbating morphine-induced tolerance and withdrawal in female and male mice. Our results demonstrate that activation of GPR171 with an agonist attenuates morphine tolerance in both female and male mice on the tail-flick test, but not the hotplate test. Importantly, the GPR171 agonist in combination with morphine does not exacerbate morphine-induced tolerance and withdrawal during long-term morphine treatment. Taken together, these data suggest that the GPR171 agonist may be combined with morphine to maintain antinociception while reducing the dose of morphine and therefore reducing side effects and abuse liability. The outcome of this study is clearly an important step toward understanding the functional interactions between opioid receptors and GPR171 and developing safer therapeutics for long-term pain management.
Asunto(s)
Analgésicos Opioides , Morfina , Analgésicos Opioides/farmacología , Animales , Tolerancia a Medicamentos/fisiología , Femenino , Masculino , Ratones , Morfina/farmacología , Sustancia Gris Periacueductal/metabolismo , Receptores Acoplados a Proteínas G , Receptores Opioides , Receptores Opioides mu/agonistasRESUMEN
Non-small cell lung cancer (NSCLC) patients harboring activating mutations in epidermal growth factor receptor (EGFR) are sensitive to therapy with EGFR tyrosine kinase inhibitors (TKI). Despite remarkable clinical responses using EGFR TKI, surviving drug tolerant cells serve as a reservoir from which drug resistant tumors may emerge. This study addresses the need for improved efficacy of EGFR TKI by identifying targets involved in functional drug tolerance against them. To this aim, a high-throughput siRNA kinome screen was performed using two EGFR TKI-sensitive EGFR-mutant NSCLC cell lines in the presence/absence of the second-generation EGFR TKI afatinib. From the screen, Serine/Threonine/Tyrosine Kinase 1 (STYK1) was identified as a target that when downregulated potentiates the effects of EGFR inhibition in vitro. We found that chemical inhibition of EGFR combined with the siRNA-mediated knockdown of STYK1 led to a significant decrease in cancer cell viability and anchorage-independent cell growth. Further, we show that STYK1 selectively interacts with mutant EGFR and that the interaction is disrupted upon EGFR inhibition. Finally, we identified fibroblast growth factor 1 (FGF1) as a downstream effector of STYK1 in NSCLC cells. Accordingly, downregulation of STYK1 counteracted the afatinib-induced upregulation of FGF1. Altogether, we unveil STYK1 as a valuable target to repress the pool of surviving drug tolerant cells arising upon EGFR inhibition. Co-targeting of EGFR and STYK1 could lead to a better overall outcome for NSCLC patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Tolerancia a Medicamentos , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Afatinib/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Tolerancia a Medicamentos/genética , Tolerancia a Medicamentos/fisiología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Interferente Pequeño/genética , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of patients due to early molecular adaptation in cancer cells. A growing body of evidence suggests that a subpopulation of drug-tolerant persister cells-a reversible phenotype characterized by reduced drug sensitivity and decreased cell proliferation-maintains residual disease and may serve as a reservoir for resistant phenotypes. The survival of these residual tumor cells can be caused by reactivation of specific signaling pathways, phenotypic plasticity (i.e., transdifferentiation), epigenetic or metabolic reprogramming, downregulation of apoptosis as well as transcriptional remodeling. In this review, we discuss the molecular mechanisms that enable adaptive survival in drug-tolerant cells. We describe the main characteristics and dynamic nature of this persistent state, and highlight the current therapeutic strategies that may be used to interfere with the establishment of drug-tolerant cells, as an alternative to improve objective response to systemic therapies and delay the emergence of resistance to improve long-term survival.
Asunto(s)
Muerte Celular/genética , Tolerancia a Medicamentos/fisiología , Neoplasias/terapia , Línea Celular Tumoral , Proliferación Celular , HumanosRESUMEN
OBJECTIVES: The most notable adverse side effects of chronic morphine administration include tolerance and hyperalgesia. This study investigated the involvement of dorsal root ganglion (DRG) protein kinase CÉ (PKCÉ) expression during chronic morphine administration and also considered the relationship between DRG PKCÉ expression and the substance P- neurokinin1 receptor (SP- NK1R) activity. METHODS: Thirty-six animals were divided into six groups (n=6) in this study. In the morphine and sham groups, rats received 10 µg intrathecal (i.t.) morphine or saline for eight consecutive days, respectively. Behavioral tests were performed on days 1 and 8 before and after the first injections and then 48 h after the last injection (day 10). In the treatment groups, rats received NK1R antagonist (L-732,138, 25 µg) daily, either alone or 10 min before a morphine injection, Sham groups received DMSO alone or 10 min before a morphine injection. Animals were sacrificed on days 8 and 10, and DRG PKCÉ and SP expression were analyzed by western blot and immunohistochemistry techniques, respectively. RESULTS: Behavioral tests indicated that tolerance developed following eight days of chronic morphine injection. Hyperalgesia was induced 48 h after the last morphine injection. Expression of SP and PKCÉ in DRG significantly increased in rats that developed morphine tolerance on day 8 and hyperalgesia on day 10, respectively. NK1R antagonist (L-732,138) not only blocked the development of hyperalgesia and the increase of PKCÉ expression but also alleviated morphine tolerance. CONCLUSIONS: Our results provide evidence that DRG PKCÉ and SP-NK1R most likely participated in the generation of morphine tolerance and hyperalgesia. Pharmacological inhibition of SP-NK1R activity in the spinal cord suggests a role for NK1R and in restricting some side effects of chronic morphine. All experiments were performed by the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised1996) and were approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.MSP.REC.1396.130).
Asunto(s)
Hiperalgesia , Morfina , Animales , Tolerancia a Medicamentos/fisiología , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Irán , Morfina/efectos adversos , Ratas , Receptores de Neuroquinina-1/metabolismoRESUMEN
Secondary metabolites profoundly affect microbial physiology, metabolism and stress responses. Increasing evidence suggests that these molecules can modulate microbial susceptibility to commonly used antibiotics; however, secondary metabolites are typically excluded from standard antimicrobial susceptibility assays. This may in part account for why infections by diverse opportunistic bacteria that produce secondary metabolites often exhibit discrepancies between clinical antimicrobial susceptibility testing results and clinical treatment outcomes. In this Review, we explore which types of secondary metabolite alter antimicrobial susceptibility, as well as how and why this phenomenon occurs. We discuss examples of molecules that opportunistic and enteric pathogens either generate themselves or are exposed to from their neighbours, and the nuanced impacts these molecules can have on tolerance and resistance to certain antibiotics.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/fisiología , Tolerancia a Medicamentos/fisiología , Animales , Biopelículas/efectos de los fármacos , Humanos , SueloRESUMEN
The development of morphine tolerance in C57BL/6j mice was estimated by the analgesic effect in tail-flick and hot plate tests. Morphine hydrochloride (10 mg/kg body weight) was administered to animals twice for 5 days and once on the sixth day, saline or myelopeptides were injected 15 min before morphine administration (2 µg/kg body weight). In the tail-flick test, all studied myelopeptides suppressed the development of tolerance to morphine and did not show their own analgesic activity. In the hot plate test, only three myelopeptides (MP2, MP5, and MP6) were found to reduce the formation of morphine tolerance. MP1 significantly reduced the analgesic effect of morphine on days 1-3 of administration, but contributed to the preservation of the analgesic effect during the period of tolerance development.
Asunto(s)
Tolerancia a Medicamentos , Morfina/farmacología , Oligopéptidos/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Tolerancia a Medicamentos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Dolor/patología , Dimensión del DolorRESUMEN
Cancer-induced bone pain (CIBP) is considered to be one of the most difficult pain conditions to treat. Morphine, an analgesic drug, is widely used in clinical practice, and long-term use of morphine can lead to drug tolerance. Recent reports have suggested that inhibitors of epidermal growth factor receptor (EGFR) may have analgesic effects in cancer patients suffering from pain. Therefore, we sought to determine whether EGFR signaling was involved in morphine tolerance (MT) in a rat model of cancer-induced bone pain. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibias of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We observed sustained increased in the protein levels of EGFR, p-EGFR, ERK1/2, and p-ERK1/2 during the development of morphine tolerance in rats with cancer-induced bone pain by western blotting. The EGFR level was significantly increased in the MT and CIBP + MT groups, and EGFR was colocalized with markers of microglia and neurons in the spinal cords of rats. Inhibition of EGFR by a small molecule inhibitor markedly attenuated the degree of morphine tolerance and decreased the number of microglia, and the protein levels of EGFR, p-EGFR, ERK1/2, and p-ERK1/2 were also reduced. In summary, our results suggest that the activation of the EGFR signaling pathway in spinal microglia plays an important modulatory role in the development of morphine tolerance and that inhibition of EGFR may provide a new therapeutic option for cancer-induced bone pain.
Asunto(s)
Analgésicos Opioides/farmacología , Neoplasias Óseas/secundario , Dolor en Cáncer/tratamiento farmacológico , Tolerancia a Medicamentos/genética , Receptores ErbB/metabolismo , Microglía/metabolismo , Morfina/farmacología , Médula Espinal/metabolismo , Animales , Neoplasias Óseas/complicaciones , Dolor en Cáncer/etiología , Carcinoma 256 de Walker/complicaciones , Carcinoma 256 de Walker/secundario , Tolerancia a Medicamentos/fisiología , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Microglía/efectos de los fármacos , Fosforilación , Quinazolinas/farmacología , Ratas , Médula Espinal/efectos de los fármacos , Tibia , Tirfostinos/farmacologíaRESUMEN
The clinical application of opioids may be accompanied by a series of adverse consequences, such as opioid tolerance, opioid-induced hyperalgesia, opioid dependence or addiction. In view of this issue, clinicians are faced with the dilemma of treating various types of pain with or without opioids. In this review, we discuss that Src protein tyrosine kinase plays an important role in these adverse consequences, and Src inhibitors can solve these problems well. Therefore, Src inhibitors have the potential to be used in combination with opioids to achieve synergy. How to combine them together to maximize the analgesic effect while avoiding unnecessary trouble provides a topic for follow-up research.
Asunto(s)
Analgésicos Opioides/farmacología , Dolor Crónico/tratamiento farmacológico , Tolerancia a Medicamentos/fisiología , Hiperalgesia/inducido químicamente , Inhibidores de Proteínas Quinasas/farmacología , Trastornos Relacionados con Sustancias/etiología , Familia-src Quinasas/antagonistas & inhibidores , Analgésicos Opioides/metabolismo , Animales , Dolor Crónico/metabolismo , Humanos , Hiperalgesia/metabolismoRESUMEN
INTRODUCTION: Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract. METHODS: TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist). RESULTS: The inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR. CONCLUSION: The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs.
Asunto(s)
Analgésicos Opioides/farmacología , Tolerancia a Medicamentos/fisiología , Íleon/efectos de los fármacos , Íleon/metabolismo , Receptores de Cannabinoides/metabolismo , Animales , Cannabinoides/metabolismo , Diterpenos de Tipo Clerodano/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Morfina/farmacología , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Naloxona/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Síndrome de Abstinencia a Sustancias/metabolismoRESUMEN
BACKGROUND: A low level of response (low LR) to alcohol correlates with the later development of alcohol-related problems. Although some of the underpinnings of LR are understood, little is known about the potential relationship between LR and acute tolerance. The current analyses tested the hypothesis that a low LR will be explained in part by more intense acute tolerance to alcohol during a drinking session. METHODS: Data were generated through a reanalysis of data from 120 individuals who were 18- to 25-year-old, sex-matched pairs of low and high LR drinkers who at baseline did not meet criteria for an alcohol use disorder. Each subject participated in an oral alcohol challenge in which they consumed about 0.7 ml ethanol per kg and acute tolerance was measured as the differences in alcohol's effects at similar breath alcohol levels (BrACs) during the rising and falling breath alcohol concentration (BrAC) curve. Measures included aspects of the Subjective High Assessment Scale (SHAS) and body sway. RESULTS: Contrary to our hypothesis, but similar to results with other alcohol measures, acute tolerance was significantly attenuated in low LR compared with high LR individuals on most SHAS scores. Neither LR group demonstrated acute tolerance to alcohol for sleepiness or body sway. Men and women did not differ on any of these measures. CONCLUSION: These data do not support a role of acute tolerance in the low LR to alcohol as measured by subjective feelings of intoxication or body sway in these subjects, findings that were similar across males and females. In addition, consistent with the literature, the analyses demonstrated differences across measures such that acute tolerance was observed for most measures of subjective effects but not for body sway. Among the subjective effects, acute tolerance was observed for alcohol's intoxicating effect but not for feeling sleepy.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Intoxicación Alcohólica/diagnóstico , Tolerancia a Medicamentos/fisiología , Etanol/administración & dosificación , Adolescente , Adulto , Intoxicación Alcohólica/fisiopatología , Ataxia/inducido químicamente , Pruebas Respiratorias , Etanol/análisis , Femenino , Humanos , Masculino , Factores Sexuales , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.