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2.
Psychopharmacology (Berl) ; 238(10): 2895-2903, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34247265

RESUMO

RATIONALE: Social support and opioid replacement therapy are commonly used to treat opioid withdrawal. OBJECTIVE: The present study tested the hypothesis that social housing and buprenorphine administration can restore wheel running depressed by morphine withdrawal in rats. RESULTS: Experiment 1 assessed disruptive side effects of buprenorphine and found that administration of low doses (3.2, 10, & 32 µg/kg, s.c.) had no impact on voluntary wheel running. Experiment 2 assessed the impact of social housing and acute buprenorphine administration (10 µg/kg) on morphine withdrawal. Two 75 mg morphine pellets were implanted for 3 days to induce dependence. Removal of the morphine pellets caused a decrease in body weight, increase in wet dog shakes, and depression of wheel running during the normally active dark phase of the circadian cycle. Social housing restored wheel running and reduced the number of wet dog shakes but did not affect body weight. Administration of buprenorphine restored wheel running depressed by morphine withdrawal for 2 days in individually housed rats and produced time-dependent changes in socially housed rats: Depression of wheel running in the 3 h following administration and restoration of running subsequently compared to saline-treated controls. CONCLUSIONS: The impact of buprenorphine and social housing to reduce the effect of morphine withdrawal in rats is consistent with the use of opioid substitution therapy and psychotherapy/social support to treat opioid withdrawal in humans. These data provide further validation for the clinical relevance for the use of wheel running to assess spontaneous opioid withdrawal.


Assuntos
Buprenorfina , Atividade Motora , Síndrome de Abstinência a Substâncias , Animais , Habitação , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Ratos , Síndrome de Abstinência a Substâncias/tratamento farmacológico
3.
J Neurochem ; 158(2): 373-390, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950542

RESUMO

The adverse side effects of opioids, especially antinociceptive tolerance, limit their clinical application. A recent study reported that platelet-derived growth factor receptor ß (PDGFRß) blockage selectively inhibited morphine tolerance. Autophagy has been reported to contribute to the cellular and behavioral responses to morphine. However, little is known about the relationship between PDGFRß and autophagy in the mechanisms of morphine tolerance. In this study, rats were intrathecally administered with morphine twice daily for 7 days to induce antinociceptive tolerance, which was evaluated using a tail-flick latency test. By administration autophagy inhibitor 3-Methyladenine, PDGFRß inhibitor imatinib, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 hydrochloride and minocycline hydrochloride, western blot, immunofluorescence, and transmission electron microscopy techniques were used to elucidate the roles of PDGFRß, autophagy, and related signaling pathways in morphine tolerance. This study demonstrated for the first time that spinal PDGFRß in microglia promotes autophagy in gamma-aminobutyric acid (GABA) interneurons through activating p38 MAPK pathway during the development of morphine tolerance, which suggest a potential strategy for preventing the development of morphine tolerance clinically, thereby improving the use of opioids in pain management.


Assuntos
Autofagia/genética , Tolerância a Medicamentos/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Neurônios/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Mesilato de Imatinib/farmacologia , Imidazóis/farmacologia , Injeções Espinhais , Masculino , Minociclina/farmacologia , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Medição da Dor/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Sci Rep ; 11(1): 6355, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737657

RESUMO

Using two-sensor electrochemical recordings in freely moving rats, we examined the relationship between physiological and drug-induced oxygen fluctuations in the brain and periphery. Animals chronically implanted with oxygen sensors in the nucleus accumbens (NAc) and subcutaneous (SC) space were subjected to several mildly arousing stimuli (sound, tail-pinch and social interaction) and intravenous injections of cocaine and heroin. Arousing stimuli induced rapid increases in NAc oxygen levels followed by and correlated with oxygen decreases in the SC space. Therefore, cerebral vasodilation that increases cerebral blood flow and oxygen entry into brain tissue results from both direct neuronal activation and peripheral vasoconstriction, which redistributes arterial blood from periphery to the brain. The latter factor could also explain a similar pattern of oxygen responses found in the substantia nigra reticulata, suggesting hyperoxia as a global phenomenon with minor structural differences during early time intervals following the stimulus onset. While arousing stimuli and cocaine induced similar oxygen responses in the brain and SC space, heroin induced a biphasic down-up brain oxygen fluctuation associated with a monophasic oxygen decrease in the SC space. Oxygen decreases occurred more rapidly and stronger in the SC space, reflecting a drop in blood oxygen levels due to respiratory depression.


Assuntos
Encéfalo/fisiopatologia , Cocaína/efeitos adversos , Heroína/efeitos adversos , Neurônios/efeitos dos fármacos , Oxigênio/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Cocaína/farmacologia , Heroína/farmacologia , Humanos , Entorpecentes/efeitos adversos , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fenômenos Fisiológicos/efeitos dos fármacos , Ratos , Ratos Long-Evans , Vigília/efeitos dos fármacos , Vigília/fisiologia
5.
Int J Dev Neurosci ; 81(3): 238-248, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33534920

RESUMO

Early life stress (ELS) disrupts brain development and subsequently affects physical and psychological health. ELS has been associated with an increased risk of relapse and inadequate treatment response in addicted patients. The current study was designed to find the effect of ELS on the rewarding effect of morphine and cannabinoid and their interaction. Pregnant female Wistar rats were used in this study. On postnatal day 2 (PND2), pups were separated from their mothers for 3 hr daily. This procedure was repeated every day at the same time until PND 14. The control group was kept in the standard nesting way with their mothers. The adult male offspring of maternal separated (MS) and standard nested (SN) rats were used. Using conditioned place preference task (CPP), the rewarding effect of morphine (0.75, 1.25, 2.5, and 5 mg/kg) was evaluated in both MS and SN groups. Besides, the rewarding effect of cannabinoids was investigated using the administration of CB1 receptor agonist (ACPA, 0.25, 0.5, 1 µg/rat) and inverse agonist (AM-251, 30, 60, and 90 ng/rat) in the nucleus accumbens (NAc). To evaluate the interaction between NAc cannabinoidergic system and morphine, the noneffective dose of ACPA and AM-251 were administered with a noneffective dose of morphine (0.75 mg/kg) on both MS and SN animals. Obtained results indicated that MS groups had a leftward shift in the rewarding effect of morphine and conditioned with low doses of morphine. However, they had a rightward shift in the rewarding effect of cannabinoids. In addition, coadministration of noneffective doses of morphine and ACPA potentiate conditioning in both MS and SN groups. Previous evidence shows that ELS induced changes in the brain, especially in the reward circuits. Here, we demonstrated that MS animals are more sensitive to the rewarding effect of morphine compared with SN animals. In addition, ELS disrupts the cannabinoid system and affect the rewarding effect of cannabinoids.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Privação Materna , Morfina/farmacologia , Entorpecentes/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Interações Medicamentosas , Feminino , Masculino , Ratos , Ratos Wistar , Recompensa
6.
Neuropsychobiology ; 80(2): 147-157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33611320

RESUMO

BACKGROUND: Investigations into neurochemical mechanisms of opioid addiction are difficult due to the complexity of behavior and multiplicity of involved neurotransmitter and hormonal systems. The aim of this study was to examine the benefits of structured analysis of these mechanisms using the framework of the neurochemical model Functional Ensemble of Temperament (FET) and the example of maternal behavior under the condition of opium consumption in pregnancy. The FET differentiates between (a) endurance, (b) speed of integration, and (c) emotionality aspects of behavior suggesting that these systems are differentially regulated by (a) serotonin-neuropeptides-brain-derived neurotrophic factor (BDNF), (b) dopamine-GABA, and (c) opioid receptor systems, correspondingly. The FET also suggests that mu-opioid receptors (MORs) binding the endorphines (including opium's ingredient morphine) have a stronger association with regulation endurance, whereas delta-OR have a stronger association with integration of behavior and kappa-OR - with the perceptual mobilization seen in anxiety. To test the predictions of this model, we compared the impact of massive MOR dysregulation on 3 behavioral aspects of behavior and on serotonin, BDNF, and corticosterone levels. METHODS: The study used 24 female white Wistar rats which were randomly divided into (1) control group: pregnant rats without any intervention; (2) opium-exposed group: animals that were exposed to opium during pregnancy and after the delivery until the end of the study. At the end of the study, the levels of BDNF, serotonin (5-HT) in the hippocampus of the mother's brain, and serum corticosterone, as well as 12 aspects of the maternal behavior were evaluated. The differences between control and experimental groups were assessed using the t test for independent samples. RESULTS: The BDNF and serotonin concentrations in the hippocampus of the mother rats which were exposed to opium were lower than in the control group; the mean corticosterone in exposed mothers was higher than in the control group. Behaviorally, opium-consuming mothers showed lower endurance in 4 distinct behavioral categories (nesting, feeding, grooming, and retrieval) than the mothers in the control group. Ease of integration of behavior was affected to a lesser degree, showing a significant effect only in 1 out of 5 applied measures. Self-grooming, seen as an emotionality-related aspect of behavior, was not affected. CONCLUSION: Opium exposure during pregnancy in our experiment primarily reduced the endurance of rat's maternal behavior, but the speed of integration of behavioral acts was less affected. This negative impact of opium on endurance was associated with a decrease of BDNF and serotonin levels in the hippocampus and an increase in corticosterone level in opium-consuming mothers. There is no effect of opium exposure on self-grooming behavior. This pattern supports the FET hypothesis about the role of 5-HT and BDNF in endurance, differential regulation of endurance, integrative and emotionality aspects of behavior, and differential association of the MOR system with endurance aspects, in comparison with kappa- and delta opioid receptors.


Assuntos
Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Hipocampo/metabolismo , Comportamento Materno/fisiologia , Entorpecentes/farmacologia , Ópio , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Entorpecentes/administração & dosagem , Gravidez , Ratos , Ratos Wistar
7.
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
8.
Psychopharmacology (Berl) ; 238(4): 1183-1192, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33484299

RESUMO

RATIONALE: Oxycodone is one of the most commonly prescribed and most frequently abused opioid analgesics, yet little is known regarding individual vulnerabilities to oxycodone abuse. The synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) has been shown to produce a "high-responder" phenotype characterized by increased drug intake and responding during periods of signaled drug unavailability (e.g., during post-infusion timeouts) in ~ 40% of male Sprague-Dawley rats. This phenotype also transfers to other psychostimulants (e.g., cocaine and methamphetamine), but it is unknown whether this phenotype transfers to other (non-stimulant) drugs of abuse. OBJECTIVES: The present study aimed to (1) reestablish the "high-responder" phenotype in male Sprague-Dawley rats (n = 11) that acquired self-administration of MDPV (0.032 mg/kg/inf) on a fixed ratio 1 (FR1) schedule of reinforcement and (2) compare full dose-response curves for MDPV and oxycodone self-administration under an FR5 schedule of reinforcement. RESULTS: MDPV was ~ 3-fold more potent at maintaining peak levels of behavior and resulted in greater overall drug intake than oxycodone. High levels of timeout responding were noted in a subset of rats that acquired MDPV self-administration ("high-responders", n = 5), and the FR5 dose-response curve for MDPV was shifted upward for these rats relative to their "low-responder" (n = 6) counterparts. "High-responders" also self-administered more infusions of oxycodone under an FR5 schedule of reinforcement than "low-responders"; however, this was not coupled with increased levels of timeout responding. CONCLUSIONS: The present data suggest that a subset of individuals with a history of using synthetic cathinones may be particularly vulnerable to the abuse of oxycodone.


Assuntos
Benzodioxóis/farmacologia , Condicionamento Operante/efeitos dos fármacos , Entorpecentes/farmacologia , Oxicodona/farmacologia , Pirrolidinas/farmacologia , Autoadministração , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Esquema de Reforço
9.
Artigo em Inglês | MEDLINE | ID: mdl-32791167

RESUMO

Substance addiction is a chronic and complicated disease involving genetic and environmental factors. Coregulated by the above factors, perturbations of the gut microbiome have been shown to have an essential role in the development of many neuropsychiatric disorders, including addiction. However, shifts in the gut microbiome during different stages of morphine addiction remain uncharacterized. In the present study, we harvested fecal samples from mice at the acquisition (both the control and morphine groups), extinction and reinstatement stages of morphine-induced conditioned place preference (CPP). Gut microbiome profiles were detected with 16S ribosomal RNA gene sequencing. We observed an increase in community richness following morphine conditioning, and it decreased after 4 weeks of abstinence. The abundance of Verrucomicrobia increased and Bacteroides decreased at the acquisition of morphine-induced CPP, while a recovery trend was found at the extinction stage. Several discriminative genera were identified for the characterization of different stages of morphine CPP. Functional analysis of taxa with differential abundance between CPP stages was mainly enriched in the pathways of amino acid metabolism. Taken together, our findings will extend the association between dysbiosis of the gut microbiome and the opioid-induced rewarding or reinforcing behaviors.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Recompensa
10.
Behav Brain Res ; 399: 113052, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33279638

RESUMO

Incubation of eggs is a critical component of parental care in avian species. However, we do not fully understand the neuroendocrine mechanisms underlying this vital behavior. While prolactin is clearly involved, it alone cannot explain the fine-tuning of incubation behavior. The present experiments explored the possibility that incubation is reinforced through a hedonic system in which contact with eggs elicited an opiate-mediated reinforcing state. Blockade of opiate receptors with naloxone reduced time ring neck doves (Streptopelia risoria) spent on the nest, possibly by uncoupling the opiate-receptor mediated hedonic experience of contact with eggs from nest-sitting behavior. Likewise, activation of opiate receptors with morphine also reduced time spent on the nest, possibly by activating an opiate-receptor mediated hedonic experience, hence rendering the eliciting behavior (contact with eggs) unnecessary. Taken together, the results suggest that the opiate system may play a previously unrecognized role in facilitating incubation through reinforcement.


Assuntos
Columbidae/fisiologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Comportamento de Nidação/fisiologia , Peptídeos Opioides/fisiologia , Prazer/fisiologia , Receptores Opioides/efeitos dos fármacos , Reforço Psicológico , Animais , Columbidae/metabolismo , Feminino , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Comportamento de Nidação/efeitos dos fármacos , Peptídeos Opioides/metabolismo , Comportamento Paterno/efeitos dos fármacos , Comportamento Paterno/fisiologia , Prazer/efeitos dos fármacos , Recompensa , Fatores de Tempo
11.
J Neurosci ; 41(2): 354-365, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33219004

RESUMO

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.SIGNIFICANCE STATEMENT Relapse to heroin use is one of the major obstacles in the treatment of opiate addiction. Triggers for relapse are modulated by environmental challenges such as caloric restriction. Elucidating the brain mechanisms that underlie relapse is critical for evidence-based treatment development. Here we demonstrate a critical role for the input from the paraventricular thalamus (PVT), a hub for cortical, sensory, and limbic information, to the nucleus accumbens shell (an area known to be important for reward and motivation) in the augmentation of heroin seeking in food-restricted rats. Our findings highlight a previously unknown role for the PVT in heroin seeking following a period of abstinence.


Assuntos
Córtex Cerebral/fisiologia , Comportamento de Procura de Droga/efeitos dos fármacos , Privação de Alimentos , Dependência de Heroína/psicologia , Vias Neurais/fisiologia , Núcleo Accumbens/fisiologia , Tálamo/fisiologia , Animais , Comportamento Aditivo/fisiopatologia , Clozapina/farmacologia , Heroína/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Ratos , Ratos Long-Evans , Recidiva , Autoadministração , Síndrome de Abstinência a Substâncias/psicologia
12.
Behav Brain Res ; 399: 113021, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33227244

RESUMO

Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Alcaloides de Triptamina e Secologanina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Sprague-Dawley , Alcaloides de Triptamina e Secologanina/administração & dosagem
13.
Behav Brain Res ; 397: 112924, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-32976861

RESUMO

Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor antagonists on the expression and extinction of morphine-induced CPP. To induce morphine CPP, adult male Wistar rats received a daily subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Different doses of SCH23390 (0.25, 1 or 4 µg/0.5 µl saline), as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 µg/0.5 µl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the CA1 region in the expression and extinction phases 1 h before CPP evaluation. Conditioning scores and locomotor activities were recorded during the tests. Results indicated that the injection of the antagonists into the CA1 region dose-dependently attenuated the expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in the expression phases. Furthermore, microinjections of SCH23390 and sulpiride shortened the extinction phase of the morphine-induced CPP without changing the locomotor activity. The results indicated the involvement of D1- and D2-like receptors within the CA1 region in the expression and extinction of rewarding properties of morphine.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Sulpirida/farmacologia
14.
Behav Brain Res ; 397: 112953, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33031872

RESUMO

Opioid abuse is a major health problem. The objective of the present study was to evaluate the potentially disruptive side effects and therapeutic potential of a novel antagonist (D24M) of the mu-/delta-opioid receptor (MOR/DOR) heterodimer in male rats. Administration of high doses of D24M (1 & 10 nmol) into the lateral ventricle did not disrupt home cage wheel running. Repeated twice daily administration of increasing doses of morphine (5-20 mg/kg) over 5 days depressed wheel running and induced antinociceptive tolerance measured with the hot plate test. Administration of D24M had no effect on morphine tolerance, but tended to prolong morphine antinociception in non-tolerant rats. Spontaneous morphine withdrawal was evident as a decrease in body weight, a reduction in wheel running and an increase in sleep during the normally active dark phase of the circadian cycle, and an increase in wheel running and wakefulness in the normally inactive light phase. Administration of D24M during the dark phase on the third day of withdrawal had no effect on wheel running. These data provide additional evidence for the clinical relevance of home cage wheel running as a method to assess spontaneous opioid withdrawal in rats. These data also demonstrate that blocking the MOR/DOR heterodimer does not produce disruptive side effects or block the antinociceptive effects of morphine. Although administration of D24M had no effect on morphine withdrawal, additional studies are needed to evaluate withdrawal to continuous morphine administration and other opioids in rats with persistent pain.


Assuntos
Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Sono/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Sprague-Dawley , Corrida
15.
Pharmacol Biochem Behav ; 200: 173077, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33316293

RESUMO

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species' strengths as model systems and can inform experimental design in studies of opioid withdrawal.


Assuntos
Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversos , Dor/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Fentanila/farmacologia , Humanos , Hiperalgesia/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/efeitos adversos , Entorpecentes/farmacologia , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/tratamento farmacológico
16.
Behav Brain Res ; 400: 113045, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33309750

RESUMO

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABAB receptor. Similarly to all GABAB PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Moduladores GABAérgicos/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores de GABA-B , Anfetamina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Moduladores GABAérgicos/administração & dosagem , Masculino , Camundongos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem
17.
Pharmacol Biochem Behav ; 199: 173061, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33164848

RESUMO

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48 h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.


Assuntos
Heroína/administração & dosagem , Metadona/administração & dosagem , Entorpecentes/administração & dosagem , Autoadministração , Administração por Inalação , Animais , Comportamento Animal/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Heroína/farmacologia , Masculino , Metadona/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Wistar
18.
Clin Epigenetics ; 12(1): 170, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168052

RESUMO

BACKGROUND: Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine. RESULTS: Using mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels. CONCLUSIONS: Morphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance. Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.


Assuntos
Histonas/efeitos dos fármacos , Morfina/farmacologia , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Entorpecentes/farmacologia , Complexo Repressor Polycomb 2/genética , Animais , Ciclo Celular/efeitos dos fármacos , Metilação de DNA , Regulação para Baixo , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Epigênese Genética , Feminino , Expressão Gênica , Genoma/genética , Histonas/genética , Camundongos , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Regiões Promotoras Genéticas/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
19.
Neuropharmacology ; 181: 108351, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33031806

RESUMO

The widely abused prescription opioid oxycodone is a mu-opioid receptor (MOP-r) agonist and addiction to such opioids is a relapsing disorder. The human MOP-r gene (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G, which affects risk of severe opioid use disorders. A112G (G/G) knock-in mice are models of human A118G carriers. We examined oxycodone self-administration (SA) in male and female G/G versus wild type (A/A) mice in SA sessions and in relapse-like behavior. Adult male and female G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, FR1) for 10 consecutive days. Following 10-day home cage drug free withdrawal, the mice were re-exposed to oxycodone SA for a further 10 days. MOP-r receptor mRNA in various brain regions were examined immediately after the last re-exposure session. We found that G/G mice had greater oxycodone SA than A/A mice in the initial and in re-exposure sessions. Mice of both genotypes had greater oxycodone intake during the re-exposure period than during the initial exposure. We also detected differences in MOP-r gene expression due to genotype, sex and oxycodone SA history in the dorsal striatum, hippocampus, and prefrontal cortex. These studies may improve our understanding of MOP-r-agonist self-exposure and relapse in human carriers of the A118G SNP.


Assuntos
Entorpecentes/farmacologia , Oxicodona/farmacologia , Receptores Opioides mu/genética , Animais , Corpo Estriado/efeitos dos fármacos , Feminino , Técnicas de Introdução de Genes , Genótipo , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Entorpecentes/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Oxicodona/administração & dosagem , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Autoadministração , Caracteres Sexuais , Abuso de Substâncias por Via Intravenosa , Síndrome de Abstinência a Substâncias/psicologia
20.
Neuropharmacology ; 181: 108350, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33027625

RESUMO

Opioid addiction is a brain disease that severely harms society and personal health. Although the tremendous numbers of patients worldwide and emerged negative events, effective treatments for opioid addiction are still lacking. Neuropeptide Y (NPY) is one of the main orexigenic peptides that play vital roles in food intake and energy metabolism. However, increasing evidence indicates that NPY may have great potential in mediating reward effects and drug dependence. In the present study, we assessed the expression changes of NPY in the nucleus accumbens at different timepoints following morphine conditioned place preference (CPP) and investigated the functional importance of potential NPY changes. Our results showed that NPY expression significantly decreased in the nucleus accumbens shell (AcbSh) immediately after chronic morphine exposure. Subsequently, it increased rapidly at first and then gradually returned to normal levels. Further data indicated that these NPY changes were involved in morphine reward memory, demonstrated by a reduction in the extinction period after blocking of the Y5 receptor by L-152,804 in the AcbSh and a prolonged duration of the extinction period following the application of NPY. More importantly, the additional results revealed that L-152,804 also remarkably suppressed the reinstatement of morphine CPP. Together, our results indicate that a complicated plasticity of the NPY pathway in AcbSh occurs following morphine CPP, and this plasticity plays an important role in modulating morphine reward memory. These findings may enhance our understanding of the role of the NPY system in opioid addiction and indicate a promising target for opioid addiction treatment.


Assuntos
Dependência de Morfina/psicologia , Morfina/farmacologia , Entorpecentes/farmacologia , Neuropeptídeo Y/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Recompensa
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