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1.
Biomed Pharmacother ; 153: 113346, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076473

RESUMO

The I1 imidazoline receptor and its candidate protein imidazoline receptor antisera-selected (IRAS)/Nischarin are linked to µ opioid receptor (MOR) functions associated with MOR trafficking. We previously demonstrated that IRAS may play an important role in the development of morphine tolerance and physical dependence in vivo. However, the effects of IRAS on morphine psychological dependence are not fully understood. To extend these studies, we investigated the impact of IRAS on morphine dependence in conditioned place preference (CPP) experiments and explored the underlying mechanisms. Knockout of IRAS enhanced the acquisition and reinstatement of morphine-induced CPP. Conditional-knockout of IRAS in the nucleus accumbens (NAc) reproduced higher CPP, and overexpression of IRAS in the NAc rescued the increased morphine-induced CPP in IRAS-/- mice. IRAS-/- mice showed dramatic cAMP-dependent protein kinase (PKA) activation, upregulation of the phosphorylation of the AMPA receptor GluR1-S845 and NMDA receptor NR1-S897 in the NAc after CPP experiment. Moreover, knockout of IRAS induced an increase in spontaneous excitatory postsynaptic current (sEPSC) frequency and a decrease in the AMPA/NMDA ratio in the NAc after chronic morphine treatment. The selective AMPA receptor antagonist NBQX could inhibit morphine CPP in WT mice, while its effect was significantly reduced in IRAS-/- mice. Together, our results demonstrate that IRAS contributes to the regulation of morphine dependence and that the alteration of glutamatergic transmission in the NAc may participate in the effect of IRAS.


Assuntos
Dependência de Morfina , Morfina , Animais , Ácido Glutâmico/metabolismo , Receptores de Imidazolinas/metabolismo , Soros Imunes/metabolismo , Soros Imunes/farmacologia , Camundongos , Camundongos Knockout , Morfina/metabolismo , Morfina/farmacologia , Núcleo Accumbens , Receptores de AMPA/metabolismo , Recompensa
2.
Transl Psychiatry ; 12(1): 374, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36075888

RESUMO

Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.


Assuntos
Morfina , Núcleo Accumbens , Analgésicos Opioides/farmacologia , Animais , Humanos , Masculino , Morfina/farmacologia , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Ratos , Transcriptoma
3.
Biomed Pharmacother ; 153: 113436, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076552

RESUMO

S-nitrosothiols exert multiple effects on neural processes in the central and peripheral nervous system. This study shows that intravenous infusion of S-nitroso-L-cysteine (SNO-L-CYS, 1 µmol/kg/min) in anesthetized male Sprague Dawley rats elicits (a) sustained increases in minute ventilation, via increases in frequency of breathing and tidal volume, (b) a decrease in Alveolar-arterial (A-a) gradient, thus improving alveolar gas-exchange, (c) concomitant changes in arterial blood-gas chemistry, such as an increase in pO2 and a decrease in pCO2, (d) a decrease in mean arterial blood pressure (MAP), and (e) an increase in tail-flick (TF) latency (antinociception). Infusion of S-nitroso-D-cysteine (SNO-D-CYS, 1 µmol/kg/min, IV), did not elicit similar responses, except for a sustained decrease in MAP equivalent to that elicited by SNO-L-CYS. A bolus injection of morphine (2 mg/kg, IV) in rats receiving an infusion of vehicle elicited (a) sustained decreases in frequency of breathing tidal volume, and therefore minute ventilation, (b) a sustained decrease in MAP, (c) sustained decreases in pH, pO2 and maximal sO2 with sustained increases in pCO2 and A-a gradient, and (d) a sustained increase in TF latency. In rats receiving SNO-L-CYS infusion, morphine elicited markedly smaller changes in minute ventilation, arterial blood gas chemistry, A-a gradient and MAP. In contrast, the antinociceptive effects of morphine were enhanced in rats receiving the infusion of SNO-L-CYS. The morphine-induced responses in rats receiving SNO-D-CYS infusion were similar to vehicle-infused rats. These data are the first to demonstrate that infusion of an S-nitrosothiol, such as SNO-L-CYS, can stereoselectively ameliorate the adverse effects of morphine on breathing and alveolar gas exchange while promoting antinociception.


Assuntos
Analgesia , Morfina , Animais , Cisteína/análogos & derivados , Cisteína/farmacologia , Masculino , Morfina/farmacologia , Ratos , Ratos Sprague-Dawley , S-Nitrosotióis
4.
Addict Biol ; 27(5): e13214, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001431

RESUMO

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation.


Assuntos
Analgésicos Opioides , Usuários de Drogas , Animais , Autopsia , Humanos , Hipnóticos e Sedativos , Metadona , Morfina/farmacologia , Fumarato de Quetiapina/farmacologia , Ratos
5.
Addict Biol ; 27(5): e13212, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001437

RESUMO

The high-drinking-in-the-dark (HDID) lines of mice were selectively bred for achieving high blood alcohol levels in the drinking-in-the-dark (DID) task and have served as a unique genetic risk model for binge-like alcohol intake. However, little is known about their willingness to consume other addictive drugs. Here, we examined (a) whether the HDID-1 and HDID-2 lines of mice would voluntarily consume midazolam, methamphetamine, morphine and nicotine in a DID test and (b) whether the HDID lines differ from their founders, heterogeneous stock/Northport (HS/NPT), in consumption levels of these drugs at the concentrations tested. Separate groups of HDID-1, HDID-2 and HS/NPT mice were given 4 days of access to each drug, using the single-bottle, limited-access DID paradigm. Male and female mice of both HDID lines consumed all four offered drugs. We observed no genotype differences in 40 µg/ml methamphetamine intake, but significant differences in nicotine, midazolam and morphine intake. Both HDID lines drank significantly more (150 µg/ml) midazolam than their founders, providing strong support for a shared genetic contribution to binge ethanol and midazolam intake. HDID-2 mice, but not HDID-1 mice, consumed more morphine (700 µg/ml) and more nicotine across a range of concentrations than HS/NPT mice. These results demonstrate that the HDID mice can be utilized for tests of voluntary drug consumption other than ethanol and highlight potentially important differences between HDID lines in risk for elevated drug intake.


Assuntos
Metanfetamina , Nicotina , Consumo de Bebidas Alcoólicas/genética , Animais , Etanol , Feminino , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Midazolam/farmacologia , Morfina/farmacologia , Nicotina/farmacologia
6.
Addict Biol ; 27(5): e13220, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001441

RESUMO

Glutamate signalling through the N-methyl-d-aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein-protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR-dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse-like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Both IC87201 and ZL006 blocked morphine-induced CPP at doses that lacked intrinsic rewarding or aversive properties. Furthermore, in vivo fast-scan cyclic voltammetry (FSCV) was used to ascertain the impact of ZL006 on morphine-induced increases in dopamine (DA) efflux in the nucleus accumbens shell (NAc shell) evoked by electrical stimulation of the medial forebrain bundle (MFB). ZL006 attenuated morphine-induced increases in DA efflux at a dose that did not have intrinsic effects on DA transmission. We also employed multiple intravenous drug self-administration approaches to examine the impact of ZL006 on the reinforcing effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self-administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse-like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction.


Assuntos
Morfina , Recompensa , Animais , Proteína 4 Homóloga a Disks-Large , Morfina/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Núcleo Accumbens/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Recidiva
7.
Behav Brain Res ; 435: 114076, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36028000

RESUMO

Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6-9 days after surgery). Treatment with morphine (2 and 4 mg/kg) or CBD (30 mg/kg) induced a significant antinociceptive effect on evoked pain. The combination of CBD (30 mg/kg) and morphine (1 mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1 mg/Kg). Treatment with morphine (1 and 2 mg/kg) or CBD (30 mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30 mg/kg) and morphine (1 mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance. In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.


Assuntos
Canabidiol , Neuralgia , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Canabidiol/farmacologia , Constrição , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Ratos
8.
Front Immunol ; 13: 929222, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032146

RESUMO

Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation. In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2. Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1ß, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.


Assuntos
Analgesia , Canabinoides , Antígeno 96 de Linfócito , Receptor 4 Toll-Like , Canabinoides/farmacologia , Humanos , Lipopolissacarídeos , Antígeno 96 de Linfócito/antagonistas & inibidores , Morfina/farmacologia , Doenças Neuroinflamatórias , Manejo da Dor
9.
Neuropharmacology ; 217: 109202, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35917874

RESUMO

δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest that DORs promote the development of analgesic tolerance of µ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance. In this study, we generated Oprd1 conditional knockout (Oprd1-cKO) mice by crossing Advillin-Cre mice with Oprd1-floxed mice. DOR expression in the dorsal root ganglion was diminished in Oprd1-cKO mice. Systemic or intrathecal injection of the DOR agonist SNC-80 produced analgesia in wild-type (WT), but not Oprd1-cKO, mice. In contrast, intracerebroventricular injection of SNC-80 produced a similar analgesic effect in WT and Oprd1-cKO mice. However, morphine-induced analgesia, hyperalgesia, or analgesic tolerance did not differ between WT and Oprd1-cKO mice. Compared with WT mice, Oprd1-cKO mice showed increased mechanical and heat hypersensitivity after nerve injury or tissue inflammation. Furthermore, blocking DORs with naltrindole increased nociceptive sensitivity induced by nerve injury or tissue inflammation in WT, but not Oprd1-cKO, mice. In addition, naltrindole potentiated glutamatergic input from primary afferents to spinal dorsal horn neurons increased by nerve injury or CFA in WT mice; this effect was absent in Oprd1-cKO mice. Our findings indicate that DORs in primary sensory neurons are critically involved in the analgesic effect of DOR agonists but not morphine-induced analgesic tolerance. Presynaptic DORs at primary afferent central terminals constitutively inhibit inflammatory and neuropathic pain by restraining glutamatergic input to spinal dorsal horn neurons.


Assuntos
Dor Crônica , Morfina , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Dor Crônica/metabolismo , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Morfina/metabolismo , Morfina/farmacologia , Nociceptividade , Receptores Opioides/metabolismo , Receptores Opioides mu/agonistas , Células Receptoras Sensoriais/metabolismo
10.
Nat Neurosci ; 25(9): 1179-1190, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35982154

RESUMO

Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls µ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the µ-opioid receptor against overstimulation.


Assuntos
Analgésicos Opioides , Morfina , Analgésicos Opioides/farmacologia , Animais , Caenorhabditis elegans , Colesterol , Tolerância a Medicamentos , Proteínas de Membrana , Camundongos , Camundongos Knockout , Morfina/farmacologia , Receptores Opioides mu/genética
11.
Behav Brain Res ; 435: 114046, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-35933048

RESUMO

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10-20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6-5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia.


Assuntos
Analgesia , Morfina , Analgésicos Opioides/farmacologia , Animais , Constipação Intestinal , Morfina/farmacologia , Naloxona/farmacologia , Dor , Ratos
12.
Neurosci Lett ; 788: 136852, 2022 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-36028004

RESUMO

Despite advances in the treatment of human immunodeficiency virus (HIV), approximately one-half of people infected with HIV (PWH) experience neurocognitive impairment. Opioid use disorder (OUD) can exacerbate the cognitive and pathological changes seen in PWH. HIV increases inflammation and immune cell trafficking into the brain; however, less is known about how opioid use disorder affects the recruitment of immune cells. Accordingly, we examined the temporal consequences of HIV-1 Tat and/or morphine on the recruitment of endocytic cells (predominantly perivascular macrophages and microglia) in the dorsal striatum and hippocampus by infusing multi-colored, fluorescently labeled dextrans before and after exposure. To address this question, transgenic mice that conditionally expressed HIV-1 Tat (Tat+), or their control counterparts (Tat-), received three sequential intracerebroventricular (i.c.v.) infusions of Cascade Blue-, Alexa Fluor 488-, and Alexa Fluor 594-labeled dextrans, respectively infused 1 day before, 1-day after, or 13-days after morphine and/or Tat exposure. At the end of the study, the number of cells labeled with each fluorescent dextran were counted. The data demonstrated a significantly higher influx of newly-labeled cells into the perivascular space than into the parenchyma. In the striatum, Tat or morphine exposure increased the number of endocytic cells in the perivascular space, while only morphine increased the recruitment of endocytic cells into the parenchyma. In the hippocampus, morphine (but not Tat) increased the influx of dextran-labeled cells into the perivascular space, but there were too few labeled cells within the hippocampal parenchyma to analyze. Collectively, these data suggest that HIV-1 Tat and morphine act independently to increase the recruitment of endocytic cells into the brain in a region-specific manner.


Assuntos
Infecções por HIV , HIV-1 , Transtornos Relacionados ao Uso de Opioides , Animais , Corpo Estriado/metabolismo , Dextranos , Fluoresceínas , HIV-1/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Morfina/farmacologia , Ácidos Sulfônicos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
13.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36004465

RESUMO

Morphine is the most common drug of choice in clinical pain management; however, morphine tolerance presents a significant clinical challenge. The pathogenesis of morphine tolerance is known to be closely associated with angiotensin II receptor type 1 (AT1R) in microglia. As an AT1R antagonist, candesartan may serve an important role in regulating morphine tolerance. Therefore, the present study aimed to investigate the role of candesartan in morphine tolerance, and to explore the underlying mechanism. To meet this aim, BV2 microglial cells were treated with morphine or candesartan alone, or as a combination, and the expression levels of AT1R in BV2 cells were detected by reverse transcription­quantitative PCR (RT­qPCR) and western blotting. The levels of the inflammatory cytokines tumor necrosis factor­α, interleukin (IL)­1ß and IL­6 were subsequently detected by ELISA and western blotting. In addition, immunofluorescence analysis, western blotting and RT­qPCR were used to detect the expression levels of the BV2 cell activation marker, ionized calcium­binding adaptor molecule 1 (IBA­1). Western blotting was also used to detect the expression levels of peroxisome proliferator­activated receptor­Î³/AMP­activated protein kinase (PPARγ/AMPK) signaling pathway­associated proteins. Finally, the cells were treated with the PPARγ antagonist GW9662 and the AMPK inhibitor compound C to further explore the mechanism underlying the effects of candesartan on improving morphine tolerance. The expression levels of AT1R were revealed to be significantly increased following morphine induction; however, candesartan treatment inhibited the expression levels of AT1R, the levels of inflammatory cytokines and the protein expression levels of IBA­1 in morphine­induced BV2 cells in a dose­dependent manner. These processes may be associated with activation of the PPARγ/AMPK signaling pathway. Taken together, the present study revealed that treatment with candesartan reduced morphine­induced inflammatory response and cellular activation of BV2 cells via PPARγ/AMPK signaling.


Assuntos
Morfina , PPAR gama , Proteínas Quinases Ativadas por AMP/metabolismo , Benzimidazóis , Compostos de Bifenilo , Citocinas/metabolismo , Microglia/metabolismo , Morfina/farmacologia , PPAR gama/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Angiotensina/metabolismo , Transdução de Sinais , Tetrazóis
14.
Neuropharmacology ; 218: 109218, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35973602

RESUMO

The single nucleotide polymorphism (SNP) D398N (rs16969968) in CHRNA5, the gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChR), has been associated with both nicotine and opiate dependence in human populations. Expression of this SNP on presynaptic VTA dopaminergic (DA) neurons is known to cause a reduction in calcium signaling, leading to alterations in transmitter signaling and altered responses to drugs of abuse. To examine the impact of the Chrna5 SNP on opiate reward and underlying dopaminergic mechanisms, mice harboring two copies of the risk-associated allele (Chrna5 A/A) at a location equivalent to human rs16969968 were generated via CRISPR/cas9 genome editing. We sought to determine whether Chrna5 A/A mice show differences in sensitivity to rewarding properties of morphine using the conditioned place preference paradigm. When mice were tested two weeks after conditioning, female Chrna5 A/A mice showed significantly enhanced preference for the morphine-paired chamber relative to WT females, suggesting that this genotype may enhance opioid reward specifically in females. In contrast, Chrna5 genotype had no effect on locomotor sensitization in male or female mice. Relative to WT females, peak amplitude of ACh-gated currents recorded from VTA DA neurons in Chrna5 A/A females was potentiated 1 day after conditioning with morphine. Increased FOS expression was also observed in Chrna5 A/A mice relative to WT mice following exposure to the morphine CPP chamber. We propose that impaired α5 nAChR subunit function alters DA neuron response following repeated morphine exposures, and that this early cellular response could contribute to enhanced opiate reward two weeks after conditioning.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos , Animais , Feminino , Humanos , Masculino , Camundongos , Morfina/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Nicotina/farmacologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Recompensa
15.
Pharmacol Biochem Behav ; 218: 173431, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35850178

RESUMO

Ovarian hormones influence the activity of endogenous opioids, and exogenous administration of estradiol reduces opioid intake and opioid seeking in animal models of opioid reward and reinforcement. The purpose of this study was to examine the effects of ovarian hormones on the discriminative stimulus effects of morphine and naloxone-precipitated opioid withdrawal. To this end, separate groups of ovariectomized female rats were trained to discriminate the stimulus effects of either 3.0 or 10 mg/kg morphine, and substitution tests were conducted with estradiol or progesterone alone and in combination with morphine. At the conclusion of discrimination testing, rats were treated chronically with estradiol, progesterone, or their combination, and challenged with naloxone to measure opioid-like withdrawal symptoms. Finally, the effects of estradiol, progesterone, and their combination were examined on naloxone-precipitated withdrawal in morphine-dependent rats. Neither estradiol nor progesterone substituted for the morphine discriminative stimulus, but estradiol significantly increased the potency of morphine in rats trained to discriminate 10 mg/kg but not 3 mg/kg morphine. When administered chronically, neither hormone nor their combination produced an opioid-like withdrawal syndrome following a naloxone challenge. Acute administration of estradiol, but not progesterone or a combination of estradiol and progesterone, significantly reduced naloxone-precipitated weight loss in morphine-dependent rats. These data indicate that estradiol influences the behavioral effects of morphine, possibly by increasing endogenous tone at mu opioid receptors.


Assuntos
Dependência de Morfina , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias , Analgésicos Opioides/farmacologia , Animais , Estradiol/farmacologia , Feminino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Progesterona/farmacologia , Ratos , Receptores Opioides mu
16.
Life Sci ; 306: 120788, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35817166

RESUMO

AIMS: We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Pain behaviors were assessed by mechanical and thermal tests in rats. Cytokine and chemokine biomarkers in sciatic nerve and spinal cord were assessed by in situ qPCR. KEY FINDINGS: In the incisional pain assay, RAP-103 (0.01-1 mg/kg, i.p.) alone had no antiallodynic effect post-surgery. RAP-103 (0.5 mg/kg) when co-administered with morphine (0.5-5 mg/kg), reduced the ED50 of morphine from 3.19 mg/kg to 1.42 mg/kg. In a DPN model, rats exhibited persistent mechanical and cold allodynia. Oral administration of RAP-103 (0.5-0.02 mg/kg/day) resulted in a complete reversal of established hypersensitivity in DPN rats (P < .001), which gradually returned to pain hypersensitivity after the cessation of the treatment. The mRNA expression of cytokines, IL-1ß, TNFα; chemokines CCL2, CCL3; and chemokine receptors CCR2 and CCR5 in DPN rat sciatic nerve, but not spinal cord, were significantly increased. RAP-103 resulted in significant reductions in sciatic nerve expression of IL-1ß, TNFα and CCL3 in STZ-induced diabetic rats with trends toward lower levels for CCL2 and CCR5, while CCR2 was unchanged. SIGNIFICANCE: In acute pain, co-administration of RAP-103 with morphine provided the same antinociceptive effect with a reduced dose of morphine, reducing opioid side-effects and risks. RAP-103 by itself is an effective non-opioid antinociceptive treatment for diabetic neuropathic pain.


Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Neuralgia , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/metabolismo , Morfina/farmacologia , Morfina/uso terapêutico , NAD , Neuralgia/metabolismo , Peptídeos/uso terapêutico , Ratos , Receptores de Quimiocinas , Fator de Necrose Tumoral alfa
17.
Int J Mol Sci ; 23(14)2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35887364

RESUMO

Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP.


Assuntos
Analgesia , Dor Irruptiva , Dor do Câncer , Neoplasias , Receptores de Glutamato Metabotrópico , Analgesia/efeitos adversos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/efeitos adversos , Animais , Dor Irruptiva/tratamento farmacológico , Dor Irruptiva/etiologia , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Modelos Animais de Doenças , Camundongos , Morfina/farmacologia , Morfina/uso terapêutico , Neoplasias/tratamento farmacológico , Medição da Dor , Tálamo
18.
Neurosci Lett ; 786: 136774, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35809878

RESUMO

Opioid use disorder mainly results from functional defects in the brain reward loop, which includs the ventral tegmental area (VTA) and nucleus accumbens (NAc; consisting of shell and core, NAcS and NAcC). Reward effects contribute to opioid use disorder. RMTg M3 receptors play a role in opioid reward by regulating the γ-aminobutyric acid (GABA) neuron activity. Dopamine D1 receptors expressed on GABA neurons regulate opioid reward by mediating the dopamine neuron activity in the VTA. Therefore, we investigated the effect of activating M3 receptors by microinjecting pilocarpine into the RMTg along with activating D1 receptors by microinjecting SKF38393 into the VTA on morphine-induced reward effect, using the conditioned place preference (CPP) paradigm (locomotion was also recorded). We also investigated whether the activation of M3 receptors in the RMTg influenced dopamine release in the NAcS. The results showed that the inhibitory role of RMTg pilocarpine (60 µg/rat) infusions in morphine-induced CPP was reversed by VTA SKF38393 (4 µg/rat) infusions. Moreover, morphine (5 mg/kg, i.p.) increased dopamine release in the NAcS, which was blunted by microinjecting pilocarpine (60 µg/rat) into the RMTg. These results indicate that RMTg M3 receptors mediate morphine-induced reward effect, which is probably related to the dopamine activity within the VTA and NAcS. The relationship between RMTg M3 receptors and the mesolimbic dopamine system could be a potential direction for the treatment of opioid use disorder, but further verification through more comprehensive techniques is needed.


Assuntos
Morfina , Transtornos Relacionados ao Uso de Opioides , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Encéfalo , Colinérgicos/farmacologia , Dopamina/farmacologia , Neurônios Dopaminérgicos , Morfina/farmacologia , Núcleo Accumbens , Pilocarpina/farmacologia , Ratos , Receptores Muscarínicos , Recompensa , Área Tegmentar Ventral
19.
Drug Alcohol Depend ; 238: 109556, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35843139

RESUMO

Chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activation of chemokine receptors, especially CCR2, CCR5 and CXCR4, reduces opioid-induced analgesia by desensitizing OPRM1 receptors. Chemokine receptor antagonists (CRAs) enhance opioid analgesia, but knowledge about how CRAs impact adverse opioid effects remains limited. We examined effects of RAP-103, a multi-CRA orally active peptide analog of "DAPTA", on opioid-derived dependence, reinforcement, and respiratory depression in male rats and on changes in chemokine and OPRM1 (µ opioid) receptor levels in mesolimbic substrates during opioid abstinence. In rats exposed to chronic morphine (75 mg pellet x 7 d), daily RAP-103 (1 mg/kg, IP) treatment reduced the severity of naloxone-precipitated withdrawal responses. For self-administration (SA) studies, RAP-103 (1 mg/kg, IP) reduced heroin acquisition (0.1 mg/kg/inf) and reinforcing efficacy (assessed by motivation on a progressive-ratio reinforcement schedule) but did not impact sucrose intake. RAP-103 (1-3 mg/kg, IP) also normalized the deficits in oxygen saturation and enhancement of respiratory rate caused by morphine (5 mg/kg, SC) exposure. Abstinence from chronic morphine elicited brain-region specific changes in chemokine receptor protein levels. CCR2 and CXCR4 were increased in the ventral tegmental area (VTA), whereas CCR2 and CCR5 were reduced in the nucleus accumbens (NAC). Effects of RAP-103 (1 mg/kg, IP) were focused in the NAC, where it normalized morphine-induced deficits in CCR2 and CCR5. These results identify CRAs as potential biphasic function opioid signaling modulators to enhance opioid analgesia and inhibit opioid-derived dependence and respiratory depression.


Assuntos
Analgésicos Opioides , Insuficiência Respiratória , Analgésicos Opioides/farmacologia , Animais , Masculino , Morfina/farmacologia , Núcleo Accumbens , Peptídeos/metabolismo , Peptídeos/farmacologia , Ratos , Receptores de Quimiocinas/metabolismo , Receptores Opioides , Receptores Opioides mu , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico
20.
Brain Res ; 1792: 148033, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35905786

RESUMO

Maternal sleep-deprivation (MSD) has been shown to induce stress, hyperactivity, and risk taking behavior in the offspring; howbeit, it is not yet clear whether it may also affect vulnerability to psychostimulant abuse in the offspring. We aimed to determine whether MSD affects extinction and reinstatement of methamphetamine (METH) reward memory in the offspring and also to evaluate the possible role of dopamine D1-like and D2-like receptors in these processes. Thirty-day-old male offspring born to control and sleep-deprived dams (during the third week of pregnancy) were trained to acquire METH-induced place preference (2 mg/kg., i.p.). METH reward memory was then reinstated following an 8-day period of extinction. The offspring received SCH 23390 (0.03 or 0.1 mg/kg, i.p.) or sulpiride (20 or 60 mg/kg, i.p.) as antagonists of dopamine D1-like and D2-like receptors, respectively, either immediately after each daily extinction session or prior to the reinstatement session. MSD postponed METH extinction and facilitated METH reinstatement in the offspring. SCH 23390 facilitated METH extinction and decreased reinstatement of the extinguished METH preference. Sulpiride in the offspring from sleep-deprived dams facilitated METH extinction, but it did not affect reinstatement of the extinguished METH reward memory. It seems that MSD may enhance vulnerability to METH abuse in the offspring. Furthermore, both dopamine D1-like and D2-like receptors may mediate METH extinction in the offspring born to the sleep-deprived dams; however, only the dopamine D1 receptor may play an important role in reinstating the extinguished METH reward memory in the offspring.


Assuntos
Metanfetamina , Animais , Dopamina , Extinção Psicológica , Masculino , Metanfetamina/farmacologia , Morfina/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Recompensa , Privação do Sono , Sulpirida/farmacologia
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