Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 17.888
Filtrar
1.
ACS Chem Neurosci ; 12(16): 3124-3139, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34351126

RESUMO

The clinical treatment of chronic postoperative pain (CPSP) remains challenging. The side effects of chronic morphine treatment limit its clinical application. MEL-0614, a novel endomorphin analogue that is highly selective and agonistic for µ opioid receptor (MOR), produces a more powerful analgesic effect than that of morphine. In this study, we explored the difference in antinociceptive tolerance and related mechanisms between MEL-0614 and morphine in CPSP induced in a skin/muscle incision and retraction (SMIR) mice model. We found that acute administration of MEL-0614 (1, 3, 5, and 10 nmol, i.t.) produced a dose-dependent analgesic effect that was superior to that of morphine in the SMIR mice model. Long-term MEL-0614 treatment (10 nmol, i.t.) did not induce tolerance compared with morphine. Notably, tolerance induced by morphine could be greatly prevented and/or inhibited via cross-administration or coadministration between MEL-0614 and morphine. In addition, MEL-0614 accelerated the recovery of postoperative pain, whereas morphine aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. In addition, MEL-0614 did not activate microglia and the P2X7R signaling pathway and showed reduced expression iba1 and P2X7R compared with that observed after morphine administration. Release of inflammatory factors was induced by continued administration of morphine during SMIR surgery, but MEL-0614 did not promote the activation of inflammatory factors. Our results showed that MEL-0614 has superior analgesic effects in CPSP and leads to tolerance to a lesser degree than morphine. Further, MEL-0614 may be used as a promising treatment option for the long-term treatment in CPSP.


Assuntos
Morfina , Dor Pós-Operatória , Analgésicos Opioides/farmacologia , Animais , Tolerância a Medicamentos , Camundongos , Morfina/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Receptores Opioides mu , Receptores Purinérgicos P2X7 , Transdução de Sinais
2.
Life Sci ; 283: 119866, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352257

RESUMO

AIMS: Morphine, a commonly used drug for anesthesia, affects lipid metabolism in different tissues, but the mechanism is currently unclear. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme responsible for the first step of triglyceride (TG) hydrolysis. Here we aim to investigate whether ATGL phosphorylation is involved in morphine-induced TG accumulation. MAIN METHODS: Oil red O staining and TG content analysis were used to detect the effect of morphine on lipid storage. A series of ATGL phosphoamino acid site mutant plasmids were constructed by gene synthesis and transfected to HL-1 cells to evaluate the phosphorylation levels of ATGL phosphoamino acid in morphine-treated HL-1 cells with immunoprecipitation and immunoblotting assay. KEY FINDINGS: Morphine acute treatment induced excessive accumulation of TG and decreased the phosphorylation level of ATGL Ser406 in HL-1 cells. Of note, the phosphorylation positive mutation of ATGL Ser406 to aspartic acid effectively reversed morphine-induced excessive accumulation of TG in HL-1 cells. SIGNIFICANCE: This discovery will help to fully understand the lipid regulation function of morphine in a new scope. In addition, it will expand the phosphorylation research of ATGL more comprehensively and provide powerful clues for lipid metabolism regulation.


Assuntos
Lipase/metabolismo , Morfina/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Masculino , Camundongos , Morfina/farmacocinética , Miocárdio/patologia , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos
3.
Environ Sci Pollut Res Int ; 28(38): 52675-52688, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34453251

RESUMO

We aimed to review the literature to find the specific effect of opioids on the activity of cholinesterase (ChE) enzyme which plays a substantial role in the functioning of cholinergic system. Literature search was performed by two independent reviewers in order to find relevant articles about the changes in the activity of ChE in mice or rat following opioid administration. Based on findings from literature review, opioid administration is able to induce cholinergic modulation via decreasing or increasing the activity of ChE enzyme. However, the degree of variation of ChE in various brain regions is different. No gender differences was reported in the effect of opioids on ChE activity. Although chronic opioid administration may decrease enzyme function, ChE activity might be unchanged following opioid withdrawal using naloxone or the development of tolerance. Opioid type affects whether or not naloxone can reverse the changes of ChE. Direct inhibitory action of morphine and the other opioid ligands believed responsible for the decrease in the ChE activity. Moreover, the potency of codeine to induce allosteric enhancement of acetylcholine receptor signaling might be involved in the cholinergic modulation of codeine and other opioids. Animal studies on rat and mice showed that opioids may change the activity of ChE. These changes can pertain an increase or decrease in enzyme activity; as there might be no change. The type of opioid used may have an effect on the cholinergic modulation. It is beneficial to conduct cross-sectional and cohort studies on addicted individuals, especially opium abusers, to find the precise association of opioids with alterations in human acetyl cholinesterase or butyrylcholinesterase. Simulation studies can also examine the structure-function relationships and provide important details to better understand the mechanism of action of opioid compounds on ChE activity. In addition, understanding how opioids impact ChE activity may help perform proper interventions for drug abstinence.


Assuntos
Analgésicos Opioides , Butirilcolinesterase , Animais , Codeína , Estudos Transversais , Camundongos , Morfina/farmacologia , Ratos
4.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299631

RESUMO

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague-Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.


Assuntos
Analgésicos Opioides/farmacologia , Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley
5.
J Physiol ; 599(15): 3771-3797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142718

RESUMO

KEY POINTS: While respiratory complications following opioid use are mainly mediated via activation of mu opioid receptors, long-latency off-target signalling via innate immune toll-like receptor 4 (TLR4) may impair other essential elements of breathing control such as respiratory motor plasticity. In adult rats, pre-treatment with a single dose of morphine blocked long-term facilitation (LTF) of phrenic motor output via a long-latency TLR4-dependent mechanism. In the phrenic motor nucleus, morphine triggered TLR4-dependent activation of microglial p38 MAPK - a key enzyme that orchestrates inflammatory signalling and is known to undermine phrenic LTF. Morphine-induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. Therefore, we suggest minimizing TLR-4 signalling may improve breathing stability during opioid therapy. ABSTRACT: Opioid-induced respiratory dysfunction is a significant public health burden. While respiratory effects are mediated via mu opioid receptors, long-latency off-target opioid signalling through innate immune toll-like receptor 4 (TLR4) may modulate essential elements of breathing control, particularly respiratory motor plasticity. Plasticity in respiratory motor circuits contributes to the preservation of breathing in the face of destabilizing influences. For example, respiratory long-term facilitation (LTF), a well-studied model of respiratory motor plasticity triggered by acute intermittent hypoxia, promotes breathing stability by increasing respiratory motor drive to breathing muscles. Some forms of respiratory LTF are exquisitely sensitive to inflammation and are abolished by even a mild inflammation triggered by TLR4 activation (e.g. via systemic lipopolysaccharides). Since opioids induce inflammation and TLR4 activation, we hypothesized that opioids would abolish LTF through a TLR4-dependent mechanism. In adult Sprague Dawley rats, pre-treatment with a single systemic injection of the prototypical opioid agonist morphine blocks LTF expression several hours later in the phrenic motor system - the motor pool driving diaphragm muscle contractions. Morphine blocked phrenic LTF via TLR4-dependent mechanisms because pre-treatment with (+)-naloxone - the opioid inactive stereoisomer and novel small molecule TLR4 inhibitor - prevented impairment of phrenic LTF in morphine-treated rats. Morphine triggered TLR4-dependent activation of microglial p38 MAPK within the phrenic motor system - a key enzyme that orchestrates inflammatory signalling and undermines phrenic LTF. Morphine-induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. We suggest minimizing TLR-4 signalling may improve breathing stability during opioid therapy by restoring endogenous mechanisms of plasticity within respiratory motor circuits.


Assuntos
Morfina , Nervo Frênico , Receptor 4 Toll-Like , Animais , Hipóxia , Morfina/farmacologia , Plasticidade Neuronal , Ratos , Ratos Sprague-Dawley , Medula Espinal
6.
J Equine Vet Sci ; 102: 103459, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34119202

RESUMO

The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded experimental design was used. Five adult healthy horses two males and three females with a mean body weight of 380 ± 45 Kg (335-425 kg), were studied. Treatments consisted of romifidine 30 µg/kg (R30) or 60 µg/kg (R60) combined with morphine 0.1 mg/kg with a washout interval of 72 hours, administered through an epidural catheter placed at the first intercoccygeal space. Heart rate (HR) and respiratory rate (fR), pH, blood gases, arterial blood pressures (mmHg), and threshold for electrical noxious stimulation was evaluated for 120 minutes and after 240 minutes of epidural injection. Data were collected before injections and every 15 minutes for 120 minutes, and at 240 minutes of epidural administration. Significant sedation occurred in both treatments with no statistically significant difference between them. There were significant changes in fR and HR from baseline but no difference between treatments. Arterial blood pressures were significantly lower in R60 treatment from 75 up to 120 minutes post epidural injection. Analgesia was considered moderate for both treatments lasting longer with romifidine at 60 µg/kg. Epidurally administered romifidine and morphine combination in horses produces dose-dependent sedation, arterial hypotension, and antinociceptive effects.


Assuntos
Analgésicos , Morfina , Animais , Feminino , Cavalos , Imidazóis/farmacologia , Masculino , Morfina/farmacologia , Estudos Prospectivos
7.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071269

RESUMO

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30-180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.


Assuntos
Analgésicos Opioides/química , Destreza Motora/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Vortioxetina/farmacologia , Analgesia/métodos , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Fenclonina/química , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Naloxona/química , Dor/tratamento farmacológico , Fentolamina/química , Piperazinas/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , alfa-Metiltirosina/química
8.
Molecules ; 26(11)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071603

RESUMO

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-ß-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.


Assuntos
Oligopeptídeos/genética , Peptídeos Opioides/química , Receptores Opioides mu/metabolismo , Dor Aguda/tratamento farmacológico , Analgésicos , Animais , Comportamento Animal , Células CHO , Cricetinae , Cricetulus , Cicloeptanos/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Morfina/química , Morfina/farmacologia , Movimento/efeitos dos fármacos , Naloxona/farmacologia , Naltrexona/farmacologia , Manejo da Dor , Piperidinas/farmacologia
9.
Aging (Albany NY) ; 13(9): 12766-12779, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952717

RESUMO

Pain in hepatocellular carcinoma (HCC) is a frequent cause of low quality of life, and morphine is routinely used as a first-line opiate analgesic in HCC. Morphine may exert not only analgesic effects but also anti-cancer effects via unknown mechanisms. Here we show that morphine can inhibit HCC cell proliferation. We further show that DEAD-box helicase 49 (DDX49) is up-regulated in HCC tumors, and that knocking down the DDX49 gene decreases tumor formation in vivo and in vitro, as well as reduces tumor metastasis in vivo. Morphine decreases DDX49 expression in HCC cells. Our results suggest that DDX49 contributes to HCC, and that morphine may exert anti-cancer effects by down-regulating it.


Assuntos
Dor do Câncer/tratamento farmacológico , Carcinoma Hepatocelular/terapia , RNA Helicases DEAD-box/genética , Neoplasias Hepáticas/terapia , Morfina/farmacologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Dor do Câncer/etiologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante/métodos , RNA Helicases DEAD-box/antagonistas & inibidores , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hepatectomia , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Morfina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1093-G1104, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908261

RESUMO

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.


Assuntos
Motilidade Gastrointestinal/fisiologia , Hiperalgesia/fisiopatologia , Morfina/farmacologia , Constipação Induzida por Opioides/fisiopatologia , Animais , Ciclo-Oxigenase 2/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Hiperalgesia/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Constipação Induzida por Opioides/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
11.
eNeuro ; 8(3)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33782102

RESUMO

About half the people infected with human immunodeficiency virus (HIV) have neurocognitive deficits that often include memory impairment and hippocampal deficits, which can be exacerbated by opioid abuse. To explore the effects of opioids and HIV on hippocampal CA1 pyramidal neuron structure and function, we induced HIV-1 transactivator of transcription (Tat) expression in transgenic mice for 14 d and co-administered time-release morphine or vehicle subcutaneous implants during the final 5 d (days 9-14) to establish steady-state morphine levels. Morphine was withheld from some ex vivo slices during recordings to begin to assess the initial pharmacokinetic consequences of opioid withdrawal. Tat expression reduced hippocampal CA1 pyramidal neuronal excitability at lower stimulating currents. Pyramidal cell firing rates were unaffected by continuous morphine exposure. Behaviorally, exposure to Tat or high dosages of morphine impaired spatial memory Exposure to Tat and steady-state levels of morphine appeared to have largely independent effects on pyramidal neuron structure and function, a response that is distinct from other vulnerable brain regions such as the striatum. By contrast, acutely withholding morphine (from morphine-tolerant ex vivo slices) revealed unique and selective neuroadaptive shifts in CA1 pyramidal neuronal excitability and dendritic plasticity, including some interactions with Tat. Collectively, the results show that opioid-HIV interactions in hippocampal area CA1 are more nuanced than previously assumed, and appear to vary depending on the outcome assessed and on the pharmacokinetics of morphine exposure.


Assuntos
HIV-1 , Região CA1 Hipocampal/metabolismo , HIV-1/metabolismo , Hipocampo/metabolismo , Morfina/farmacologia , Células Piramidais/metabolismo , Aprendizagem Espacial , Transativadores , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
12.
eNeuro ; 8(2)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33707203

RESUMO

Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G-protein-dependent feedback pathways, mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G-protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABABR-dependent and D2R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D2R and GABABR in VTA DA neurons. Ablation of GABABR or D2R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABABR or D2R activation. D2R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABABR ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D2R nor GABABR ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G-protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction.


Assuntos
Cocaína , Área Tegmentar Ventral , Animais , Cocaína/farmacologia , Neurônios Dopaminérgicos , Feminino , Proteínas de Ligação ao GTP , Masculino , Camundongos , Morfina/farmacologia
13.
Eur J Pharmacol ; 899: 174007, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705801

RESUMO

G-protein-biased agonists with reduced ß-arrestin-2 activation are being investigated as safer alternatives to clinically-used opioids. ß-arrestin-2 has been implicated in the mechanism of opioid-induced antinociceptive tolerance. Opioid-induced analgesic tolerance is classically considered as centrally-mediated, but recent reports implicate nociceptive dorsal root ganglia neurons as critical mediators in this process. Here, we investigated the role of ß-arrestin-2 in the mechanism of opioid tolerance in dorsal root ganglia nociceptive neurons using ß-arrestin-2 knockout mice and the G-protein-biased µ-opioid receptor agonist, TRV130. Whole-cell current-clamp electrophysiology experiments revealed that 15-18-h overnight exposure to 10 µM morphine in vitro induced acute tolerance in ß-arrestin-2 wild-type but not knockout neurons. Furthermore, in wild-type neurons circumventing ß-arrestin-2 activation by overnight treatment with 200 nM TRV130 attenuated tolerance. Similarly, acute morphine tolerance in vivo in ß-arrestin-2 knockout mice was prevented in the warm-water tail-withdrawal assay. Treatment with 30 mg/kg TRV130 s.c. also inhibited acute antinociceptive tolerance in vivo in wild-type mice. Alternately, in ß-arrestin-2 knockout neurons tolerance induced by 7-day in vivo exposure to 50 mg morphine pellet was conserved. Likewise, ß-arrestin-2 deletion did not mitigate in vivo antinociceptive tolerance induced by 7-day exposure to 25 mg or 50 mg morphine pellet in both female or male mice, respectively. Consequently, these results indicated that ß-arrestin-2 mediates acute but not chronic opioid tolerance in dorsal root ganglia neurons and to antinociception in vivo. This suggests that opioid-induced antinociceptive tolerance may develop even in the absence of ß-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Gânglios Espinais/efeitos dos fármacos , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Receptores Opioides mu/agonistas , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , beta-Arrestina 2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Masculino , Camundongos Knockout , Neurônios/metabolismo , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Fatores de Tempo , beta-Arrestina 2/deficiência , beta-Arrestina 2/genética
14.
Integr Cancer Ther ; 20: 1534735421995237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33660537

RESUMO

PURPOSE: Morphine is often used for the treatment of moderate and severe cancer pain, but long-term use can lead to morphine tolerance. Methods for effectively inhibiting morphine tolerance and the related mechanism of action are of great significance for the treatment of cancer pain. Previous studies have shown that electroacupuncture (EA) can inhibit the occurrence of morphine tolerance, but the mechanism is not yet clear. The aim of the present study was to explore the signaling pathway by which EA attenuates the development of bone cancer pain (BCP)-morphine tolerance (MT). MATERIALS AND METHODS: Changes in the paw withdrawal threshold (PWT) of rats with bone cancer pain-morphine tolerance were observed in a study of EA combined with intrathecal injection of a PI3K inhibitor (LY294002) or agonist (insulin-like growth factor-1 [IGF-1]). We also tested the protein expression of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated c-Jun NH2-terminal kinase 1/2 (p-JNK1/2), and ß-arrestin2 in the L4-6 spinal dorsal horn of rats. RESULTS: The protein expression of p-PI3K, p-Akt, p-JNK1/2, and ß-arrestin2 was upregulated in the L4-6 spinal dorsal horn of rats with bone cancer pain and bone cancer pain-morphine tolerance. EA delayed the occurrence of morphine tolerance in rats with bone cancer pain and downregulated the protein expression of p-PI3K, p-Akt, p-JNK1/2, and ß-arrestin2 in the L4-6 spinal dorsal horn of rats with bone cancer pain-morphine tolerance. Intrathecal injection of LY294002 attenuated the development of morphine tolerance and downregulated the protein expression of p-Akt, p-JNK1/2, and ß-arrestin2 in the spinal dorsal horn of rats with bone cancer pain-morphine tolerance. In addition, the inhibitory effect of EA on morphine tolerance was reversed by IGF-1. CONCLUSION: The mechanism underlying the ability of EA to attenuate morphine tolerance may be associated with inhibition of the PI3K/Akt/JNK1/2 signaling pathway.


Assuntos
Dor do Câncer , Eletroacupuntura , Neoplasias , Animais , Dor do Câncer/tratamento farmacológico , Morfina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Corno Dorsal da Medula Espinal/metabolismo
15.
Psychopharmacology (Berl) ; 238(4): 1193-1211, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33655408

RESUMO

INTRODUCTION: The classical effects of exogenous opioids, such as morphine, are predominantly mediated through µ-opioid receptors. The chronic use of morphine induces anxiety-like behavior causing functional changes in the mesolimbic dopaminergic system. The mixed µ/κ-agonist, nalbuphine, used either as an analgesic or as an adjuvant with morphine, produces different and opposite effects. However, whether nalbuphine can be used to antagonize morphine-induced anxiety and dopaminergic alterations is not fully known. OBJECTIVE: This study aimed to compare acute and chronic effects of nalbuphine on morphine-induced anxiety and dopaminergic alterations in rats. METHODS: Male adult Wistar albino rats were made opioid-dependent by administering increasing doses of morphine (5-25 mg/kg; i.p.; b.i.d.). Withdrawal was induced by naloxone (1 mg/kg, i.p.), 4 h after the last morphine injection. Anxiety-like behavior was measured using Activity Monitor (Coulbourn Instruments, Inc. USA). Thereafter, the animals were sacrificed and the brain dissected out and the level of cAMP and the transcriptional and translational expression of TH was measured. Nalbuphine was co-administered with morphine, acutely and chronically, at various doses (0.1, 0.3, 1.0, 3.0 mg/kg, i.p.). RESULTS: Morphine-dependent rats showed a significant higher anxiety and cAMP levels and a significant decrease in the expression of TH. Co-administration of chronic doses of nalbuphine attenuates the higher anxiety, cAMP levels, and upregulates the TH expressions; however, the acute nalbuphine treatment does not attenuate the morphine-induced side effects. CONCLUSION: Therefore, nalbuphine might have an important role in attenuating the anxiety and the effects of the dopaminergic pathway and may have potential in the treatment of opioid addiction.


Assuntos
Analgésicos Opioides/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Dopamina/metabolismo , Morfina/farmacologia , Nalbufina/farmacologia , Síndrome de Abstinência a Substâncias/psicologia , Animais , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Transtornos Relacionados com Narcóticos/psicologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Neurosci Lett ; 751: 135801, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33705932

RESUMO

Lidocaine hydrochloride (LC-HCl) and morphine hydrochloride (Mor-HCl) are two kinds of most prevalently used anesthetics. However, their influences on electrical excitability of hippocampal neuronal networks and hippocampal brain slices were rarely studied. Previously, our group have assessed the influence of acetylcholine, alcohol and temperature change on the excitability of neural networks with the so-called Voltage Threshold Measurement Method (VTMM) based on microelectrode array (MEA). In this paper, we will study the influence of LC-HCl and Mor-HCl on the electrical excitability of neural networks and the morphological features of neurons, and discuss the relations between the changes of electrical excitability of neural networks and the morphological changes of neurons. The results of VTMM showed: The voltage threshold (VTh) of hippocampal neuronal networks and hippocampal brain slices first increased and then decreased as the LC-HCl concentration increased. The VTh of hippocampal neuronal networks and hippocampal brain slices increased as the Mor-HCl concentration increased. The results of HCS experiments showed: The neurite length change of cultured hippocampal neuronal networks increased first and then decreased with increased LC-HCl concentration, but decreased as the Mor-HCl concentration increased. The combined analysis of VTMM and HCS experiments showed that under effects of the two drugs, the VTh and the hippocampal neurite length were strongly negatively correlated.


Assuntos
Hipocampo/efeitos dos fármacos , Lidocaína/farmacologia , Morfina/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Anestésicos Locais/farmacologia , Animais , Células Cultivadas , Interações Medicamentosas , Hipocampo/citologia , Hipocampo/fisiologia , Potenciais da Membrana , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley
17.
FASEB J ; 35(3): e21407, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33583084

RESUMO

The obesity epidemic has increased type II diabetes mellitus (T2DM) across developed countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia-reperfusion (I-R) injury, and refractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opioid receptor stimulus may overcome diabetes mellitus-induced cardiac dysfunction via membrane/mitochondrial-dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I-R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochondrial function. T2DM induced 25% weight gain, hyperglycemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca2+ -induced swelling, and cell death were all evident. Morphine administration for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I-R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contractile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short-term, but high-dose morphine administration in diabetic patients undergoing or recovering from acute ischemic cardiovascular events.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Morfina/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Humanos , Camundongos , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/etiologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
18.
Behav Brain Funct ; 17(1): 1, 2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33612106

RESUMO

BACKGROUND: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 µg/0.5 µL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. RESULTS: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 µg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. CONCLUSIONS: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.


Assuntos
Benzoatos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Morfina/farmacologia , Entorpecentes/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Animais , Benzoatos/administração & dosagem , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Glicina/administração & dosagem , Glicina/farmacologia , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Recompensa
19.
Neurosci Lett ; 748: 135735, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33592307

RESUMO

Opioid agonists are used in clinic for pain management, however this application is challenged by development of tolerance and dependence following prolonged exposure. Various approaches have been suggested to address this concern, however, there is still no consensus among the researchers. Neural processing of sleep and nociception are co-regulated through shared brain regions having bidirectional interplays. Thus, we aimed to investigate whether application of REM sleep deprivation (REM-SD) could affect morphine analgesic tolerance and dependence. To this end, adult male rats underwent sleep deprivation during light and dark phases (LSD and DSD, respectively) using the inverted flower pot method and then tolerance and dependence was induced by repeated injection of morphine for 7 days (10 mg/kg, daily, i.p.). Results indicated that REM-SD delays the development of tolerance to morphine during both phases; however this effect was more potent following LSD. Moreover, LSD decreased the baseline thermal threshold and total withdrawal score. One possible hypothesis for our observations is REM-SD-induced attenuation of orexin system which is still controversial among the researchers. Other stronger possibilities might be down-regulation of opioid receptors in response to sleep loss experience. Finally, it seems that modification of sleep periods may assist to decrease the severity of opioid tolerance and dependence.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Dor/tratamento farmacológico , Privação do Sono/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Tolerância a Medicamentos/fisiologia , Masculino , Morfina/farmacologia , Ratos Wistar , Receptores Opioides/efeitos dos fármacos , Privação do Sono/tratamento farmacológico
20.
Neurosci Lett ; 749: 135742, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607203

RESUMO

Prescription opioids are powerful pain-controlling medications that have both benefits and potentially serious risks. Morphine is one of the preferred analgesics that are widely used to treat chronic pain. However, chronic morphine exposure has been found to cause both functional and structural changes in several brain regions, including the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and hippocampus (HPC), which lead to addictive behavior. Caveolin-1 (Cav-1), a scaffolding protein of membrane lipid rafts (MLRs), has been shown to organize GPCRs and multiple synaptic signaling proteins within the MLRs to regulate synaptic signaling and neuroplasticity. Previously, we showed that in vitro morphine treatment significantly elevates Cav-1 expression and causes neuroplasticity changes. In this study, we confirmed that chronic morphine exposure can significantly increase Cav-1 expression (P < 0.05) and microtubule-associated protein (MAP-2)-positive neuronal dendritic growth in the hippocampus. Moreover, the rewarding effect and dendritic growth in the HPC induced by chronic morphine exposure were significantly inhibited by hippocampal Cav-1 knockdown. Together, these data suggest that Cav-1 in the hippocampus plays an essential role in the neuroplasticity changes that underlie morphine addiction behaviors.


Assuntos
Caveolina 1/metabolismo , Hipocampo/metabolismo , Morfina/farmacologia , Plasticidade Neuronal/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Dependência de Morfina/metabolismo , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Interferência de RNA/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...