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1.
Pharmacol Biochem Behav ; 219: 173451, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35995262

RESUMO

The disruptive effects of pain on quality of life are greater in men than in women, but the disruptive effects of opioid administration and withdrawal tend to be greater in women. These sex differences in pain, acute opioid effects, and opioid withdrawal tend to be opposite to sex differences reported in laboratory rats. We hypothesized that sex differences in humans and rats would more closely align if animal research measured quality of life as opposed to traditional evoked behaviors of pain (e.g., nociceptive reflexes) and opioid withdrawal (e.g., wet dog shakes). The present study assessed quality of life in adult female and male rats by measuring voluntary wheel running in the rat's home cage. Hindpaw inflammation induced by administration of Complete Freund's Adjuvant (CFA) into the right hindpaw caused a greater depression of wheel running in male compared to female rats. Twice daily injections of high morphine doses (5-20 mg/kg) and the subsequent morphine withdrawal caused a greater depression of wheel running in female compared to male rats. These sex differences are consistent with human data that shows the impact of pain on quality of life is greater in men than women, but the negative effects of opioid administration and withdrawal are greater in women. The present data indicate that the clinical significance of animal research would be enhanced by shifting the endpoint from pain and opioid evoked behaviors to measures of quality of life such as voluntary wheel running.


Assuntos
Morfina , Síndrome de Abstinência a Substâncias , Analgésicos Opioides/efeitos adversos , Animais , Feminino , Humanos , Masculino , Morfina/efeitos adversos , Atividade Motora , Entorpecentes/farmacologia , Dor , Qualidade de Vida , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
2.
Neuropharmacology ; 209: 109018, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35240132

RESUMO

The aim of the current study was to test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through overlapping neural systems. The reported experiments focussed on noradrenaline (NA) and corticotrophin-releasing factor (CRF) because of their known involvement in both opioid withdrawal and memory consolidation. Male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin and received injections of 3 mg/kg naloxone (NLX) to precipitate withdrawal. NLX was preceded by 0.1-0.6 mg/kg lofexidine (LOF) (alpha-2 adrenergic agonist) or 10-20 mg/kg antalarmin (ANT) (CRF1 receptor antagonist), and all injections were administered immediately after (i.e., post-training method) the sample phase of the spontaneous object recognition memory task. The same procedure was repeated 7 days after removal of the mini-pumps. To establish conditioned withdrawal, heroin-exposed rats were confined for 2 h in a context (CS+) following injections of 3 mg/kg NLX and in another context (CS-) following vehicle injections. Seven days after removal of mini-pumps, the effects of immediate post-sample exposure to the CS+ (and CS-) preceded by 0.6 mg/kg LOF or 20 mg/kg ANT were assessed. It was found both LOF and ANT blocked the enhancement of object memory by post-sample NLX administration and by exposure to the CS+. These results suggest that pharmacological and psychological withdrawal impact memory storage by activating overlapping NA and CRF systems.


Assuntos
Consolidação da Memória , Síndrome de Abstinência a Substâncias , Hormônio Adrenocorticotrópico/farmacologia , Analgésicos Opioides/farmacologia , Animais , Hormônio Liberador da Corticotropina/farmacologia , Heroína/farmacologia , Masculino , Naloxona/farmacologia , Entorpecentes/farmacologia , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina
3.
Neuropharmacology ; 206: 108938, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34982972

RESUMO

Morphine tolerance (MT) caused by the long-term use of morphine is a major medical problem. The molecular mechanism of morphine tolerance remains elusive. Here, we established a morphine tolerance model in rats and verified whether the long noncoding RNA (lncRNA) MRAK159688 is involved in morphine tolerance and its specific molecular mechanism. We show the significant upregulation of MRAK159688 expression in the spinal cord of morphine-tolerant rats. Overexpression of MRAK159688 by a lentivirus reduces the analgesic efficacy of morphine and induces pain behavior. Downregulation of MRAK159688 using a small interfering RNA (siRNA) attenuates the formation of morphine tolerance, partially reverses the development of morphine tolerance and alleviates morphine-induced hyperalgesia. MRAK159688 is located in the nucleus and cytoplasm of neurons, and it colocalizes with repressor element-1 silencing transcription factor (REST) in the nucleus. MRAK159688 potentiates the expression and function of REST, thereby inhibiting the expression of mu opioid receptor (MOR) and subsequently inducing morphine tolerance. Moreover, REST overexpression blocks the effects of MRAK159688 siRNA on relieving morphine tolerance. In general, chronic morphine administration-mediated upregulation of MRAK159688 in the spinal cord contributes to morphine tolerance and hyperalgesia by promoting REST-mediated inhibition of MOR. MRAK159688 downregulation may represent a novel RNA-based therapy for morphine tolerance.


Assuntos
Tolerância a Medicamentos , Regulação da Expressão Gênica , Hiperalgesia , Morfina/farmacologia , Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides , RNA Longo não Codificante , Receptores Opioides mu , Proteínas Repressoras/metabolismo , Medula Espinal , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , RNA Longo não Codificante/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Ratos , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Transtornos Relacionados ao Uso de Substâncias
4.
Brain Res Bull ; 178: 1-8, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34774992

RESUMO

Kratom, derived from the plant Mitragyna speciosa (M. speciosa) Korth is a traditional psychoactive preparation widely used in Southeast Asia and increasingly in the rest of the world. Use and abuse of Kratom preparations can be attributed to mitragynine (MIT), the main psychoactive compound isolated from its leaves. While MIT may have beneficial effects as a recreational drug, for pain management, and for opiate withdrawal, it may have an addiction potential at higher doses. However, its action in the reward system of the brain is currently unknown. This study investigated how mitragynine (10 mg/kg, i.p.) affects extracellular activity of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of the brain, compared to morphine (MOR; 10 mg/kg, i.p.) and methamphetamine (METH; 10 mg/kg, i.p.). Using in-vivo microdialysis in freely moving rats, we found a significant increase of extracellular DA after MOR and METH, but not after MIT in all three brain regions. MIT led to a significant increase of DOPAC and/or HVA in these brain regions while MOR and METH had only moderate effects. These findings suggest a strong and prolonged effect of MIT on DA synthesis/metabolism, but not on extracellular DA activity, which may limit the addiction risk of MIT, in contrast to MOR and METH.


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Metanfetamina/farmacologia , Morfina/farmacologia , Entorpecentes/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/farmacologia , Animais , Corpo Estriado/metabolismo , Dopaminérgicos/administração & dosagem , Metanfetamina/administração & dosagem , Mitragyna , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Córtex Pré-Frontal/metabolismo , Ratos , Alcaloides de Triptamina e Secologanina/administração & dosagem
5.
Hum Brain Mapp ; 43(4): 1419-1430, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34873784

RESUMO

Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain-wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = -0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = -0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL- and MRP-DA release patterns (ΔR2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL- and MRP-induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern-based characterization of drug-induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.


Assuntos
Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Adulto , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos
7.
Brain Res Bull ; 176: 130-141, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34480979

RESUMO

For processing the development of psychological dependency, opioid reinforcement, and opiate-related associative reward, learning, and memory in the brain, the ventral tegmental area (VTA) is considered the key zone. As the responsible region for the morphine role in conditioned place preference (CPP), this area has an important role. So, the present research was conducted to investigate the effects of different intensities of electrical stimulation on VTA utilizing CPP, with two morphine doses. Reversible inactivation of VTA was performed via bilateral microinjection of Lidocaine into this area with two implanted separate cannulas. Our findings indicated that 5 mg/kg morphine-induced CPP was suppressed by 150 µA VTA electrical stimulation. The results also showed that bilateral Intra-VTA administration of Lidocaine significantly decreased the 5 mg/kg morphine-induced CPP acquisition phase in comparison with their respective sham group, which reversed in the reinstatement test. It should be concluded that these findings are important for the detection of mesolimbic nervous system ties and could help to find new ways to attenuate the rewarding action of morphine.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Lidocaína/farmacologia , Masculino , Ratos , Ratos Wistar , Recompensa
8.
Neurosci Lett ; 765: 136272, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34582973

RESUMO

It has been shown that carbamazepine, an anticonvulsant drug, has antidepressant effects. Moreover, the involvement of opioid system has been shown in the pathophysiology of depression. Here, we sought to determine the possible role of the opioid system in the antidepressant-like effect of carbamazepine after acute and repeated administration. The antidepressant-like activity was assessed in the mice forced swimming test (FST). Carbamazepine (20, 30, and 40 mg/kg, i.p.) or morphine were administrated 30 min before the OFT or FST. Data showed that carbamazepine has an antidepressant effect in a dose-dependent manner which was attenuated by naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). ED50 values against despair behaviors were 34.75 (29.37-50.81) mg/kg and 0.34 (0.09-0.78) mg/kg for carbamazepine and morphine, respectively. Additionally, low dose of dose of carbamazepine (30 mg/kg) induced a synergistic effect in the FST with low dose of morphine (0.1 mg/kg) that was antagonized by naloxone. Furthermore, in contrast to morphine, carbamazepine after repeated administration induced neither tolerance to the antidepressant-like effect nor withdrawal syndrome. The results demonstrated that carbamazepine exerted an antidepressant-like effect possibly through the opioidergic pathway, without inducing tolerance and withdrawal signs.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Carbamazepina/farmacologia , Animais , Tolerância a Medicamentos , Masculino , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Síndrome de Abstinência a Substâncias
9.
Behav Brain Res ; 415: 113506, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34352292

RESUMO

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0-10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6-56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.


Assuntos
Acatisia Induzida por Medicamentos/tratamento farmacológico , Benzamidas/farmacologia , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Piridinas/administração & dosagem
10.
J Clin Pharmacol ; 61 Suppl 2: S70-S88, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34396552

RESUMO

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl-laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH-7921 and MT-45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid-mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half-life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.


Assuntos
Transtornos Relacionados com Narcóticos/fisiopatologia , Entorpecentes/farmacologia , Analgésicos Opioides/farmacologia , Analgésicos Opioides/toxicidade , Relação Dose-Resposta a Droga , Overdose de Drogas/epidemiologia , Meia-Vida , Humanos , Drogas Ilícitas/farmacologia , Drogas Ilícitas/toxicidade , Entorpecentes/farmacocinética , Entorpecentes/toxicidade , Uso Indevido de Medicamentos sob Prescrição/efeitos adversos , Receptores Opioides/agonistas
11.
Pharmacol Biochem Behav ; 209: 173244, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363828

RESUMO

The development of sensitization is one of the hallmarks of addictive drugs such as morphine. We administered morphine (10 mg/kg; MOR) to induce locomotor sensitization and ERK activation in the VTA and NAc. In the first experiment, four groups of rats received five daily 30 min sessions in an open-field, and locomotion was measured. For the first four sessions, one group received MOR pre-test (MOR-P); a second group received vehicle pre-test (MOR-UP) and MOR 30 min post-test; the remaining 2 groups received vehicle (VEH) pre-test. On the fifth session, the MOR-P, MOR-UP, and one VEH group received MOR pre-test and the remaining VEH group received VEH. Sensitization emerged in the first 5 min and progressed over to the second and third 5 min blocks only in the MOR-P group. For the second experiment, 4 groups received MOR and 4 groups VEH, and were then returned to their home cage and after 5, 15, 30 or 60 min post-injection, were euthanized for ERK measurements in VTA and NAc. ERK activation increased and peaked at 5 min post injection in the MOR group and then declined to VEH levels by 30 min. Another two groups received either MOR or VEH immediately before a 5 min arena test and ERK was measured immediately post-test. MOR had no effect on locomotion but increased ERK in the VTA and NAc. The peak ERK activation in VTA reflected activation of reward systems by morphine that reinforced locomotor behavior and with repeated treatments, induced a sensitization effect.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Recompensa , Animais , Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Reforço Psicológico , Área Tegmentar Ventral/efeitos dos fármacos
12.
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
13.
Behav Brain Res ; 413: 113451, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256079

RESUMO

Many animal studies and early clinical trials suggested that N-acetylcysteine (NAC) may benefit addiction treatment. The present study tried to evaluate whether chronic administration of systemic NAC during the extinction period and acute administration of systemic NAC on the reinstatement day could reduce the maintenance of the morphine rewarding properties in the conditioned place preference (CPP) paradigm in the rats. Ninety-six adult male Wistar rats (190-220 g) were examined with morphine (7 mg/kg; sc) and saline (1 mL/kg; sc) during the 3-day conditioning phase in the CPP paradigm. After the acquisition of morphine CPP, different doses of NAC were daily administered during the extinction period (5, 10, 25, and 50 mg/kg; ip), or 30 min before the CPP test on the reinstatement day (2, 5, 10, 25, and 50 mg/kg; ip). Conditioning score and locomotor activity were recorded by the video tracking system and Ethovision software after acquisition on the post-conditioning day, the extinction period, and reinstatement day. Daily NAC administration in high doses (25 and 50 mg/kg; ip) reduced extinction-responding compared with the vehicle-control group during the extinction period. Although a single injection of NAC in doses 10, 25, 50 mg/kg decreased the reinstatement of morphine-induced CPP, two lower doses (2 and 5 mg/kg) could not significantly reduce the CPP scores. These are the first data suggesting that NAC's application during the extinction period could attenuate the morphine reward-associated behaviors in the rats. Moreover, NAC could inhibit the reinstatement of morphine CPP, which adds to the growing appreciation that the NAC may have potential therapeutic use in combating morphine dependence. It can be consistent with the hypothesis of the involvement of the glutamatergic system in the pathophysiology of addiction.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Dependência de Morfina/tratamento farmacológico , Morfina/farmacologia , Entorpecentes/farmacologia , Reforço Psicológico , Acetilcisteína/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Condicionamento Clássico , Modelos Animais de Doenças , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Wistar , Recompensa
14.
Pharmacol Biochem Behav ; 208: 173242, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34302853

RESUMO

Synthetic opioids have been implicated as the single greatest contributor to rising drug-related fatalities in recent years. This study evaluated mu-opioid receptor (MOR) mediated effects of seven fentanyl-related substances that have emerged in the recreational drug marketplace, and for which there are no existing or only limited in vivo data. Adult male Swiss Webster mice were administered fentanyl-related substances and their effects on nociception and locomotion as compared to MOR agonist standards were observed. In locomotor activity tests, morphine (100, 180 mg/kg), fentanyl (1, 10 mg/kg), beta-methylfentanyl (10 mg/kg), para-methoxyfentanyl (10 mg/kg), fentanyl carbamate (100 mg/kg), and 3-furanylfentanyl (10 mg/kg), elicited significant (p ≤ 0.05) dose-dependent increases in locomotion. However, para-methylfentanyl and beta'-phenylfentanyl did not produce significant effects on locomotion at doses up to 100 mg/kg and phenylfentanyl (100 mg/kg) significantly decreased locomotion. In warm-water tail-withdrawal tests, all substances produced significant dose-dependent increases in antinociception with increasing ED50 values (95% CI) of fentanyl [0.08 mg/kg (0.04-0.16)] > para-methoxyfentanyl [0.43 mg/kg (0.23-0.77)] > 3-furanylfentanyl [0.51 mg/kg (0.36-0.74)] > beta-methylfentanyl [0.74 mg/kg (0.64-0.85)] > para-methylfentanyl [1.92 mg/kg (1.48-2.45)] > fentanyl carbamate [5.59 mg/kg (4.11-7.54)] > morphine [7.82 mg/kg (5.42-11.0)] > beta'-phenylfentanyl [19.4 mg/kg (11.0-34.4)] > phenylfentanyl [55.2 mg/kg (33.5-93.0)]. Naltrexone (1 mg/kg) increased ED50 values several fold with decreasing magnitudes of para-methylfentanyl (63.1×) > para-methoxyfentanyl (22.5×) > beta'-phenylfentanyl (21.0×) > 3-furanylfentanyl (20.6×) > beta-methylfentanyl (19.2×) > phenylfentanyl (5.23×) > fentanyl (3.95×) > fentanyl carbamate (2.21×) > morphine (1.48×). These findings expand upon in vivo results from previous studies and establish that the effects of these fentanyl related-related substances are at least in part mediated by the MOR.


Assuntos
Fentanila/farmacologia , Locomoção/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacologia , Animais , Fentanila/análogos & derivados , Furanos/farmacologia , Masculino , Camundongos , Morfina/farmacologia , Naltrexona/farmacologia , Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Receptores Opioides mu/agonistas
15.
Behav Brain Res ; 414: 113477, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34302880

RESUMO

Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.


Assuntos
Comportamento Animal , Condicionamento Clássico , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Histonas/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens , Córtex Pré-Frontal , Proteínas Proto-Oncogênicas c-fos , Teofilina/farmacologia , Acetilação , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Inibidores de Histona Desacetilases/administração & dosagem , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Teofilina/administração & dosagem , Vorinostat/farmacologia
16.
Neurosci Lett ; 759: 135996, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34062194

RESUMO

The lateral habenula (LHb) plays a principal role in response to aversive stimuli and negative emotional states. In this study, we have evaluated the effects of unilateral electrical stimulation (e-stim) of the LHb on morphine-conditioned place preference (CPP), before or after bilateral injections of Gamma-aminobutyric acid-B receptor (GABABR) antagonist, phaclofen, in male rats. Morphine (5 mg/kg; s.c.) induced a significant CPP, using a 5-day CPP paradigm. Intra-LHb microinjection of phaclofen or the LHb e-stim decreased only the acquisition of CPP. The 150 µA stimulation plus phaclofen significantly suppressed the expression phase but induced aversion in the acquisition of CPP, and an e-stim of 25 µA in combination with the antagonist, significantly prevented only the acquisition phase. The findings of this study confirm the possible role of GABABRs in the LHb on the acquisition and the expression of CPP. These results show that e-stim of LHb alone or plus phaclofen may change the GABA transmission, involving into CPP. Therefore, the GABAergic system, especially through GABABRs, may play a prominent role in the behavioral responses to morphine-induced CPP by LHb stimulation.


Assuntos
Condicionamento Clássico/fisiologia , Estimulação Elétrica/métodos , Antagonistas de Receptores de GABA-B/farmacologia , Habenula/fisiologia , Dependência de Morfina/fisiopatologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Wistar
17.
Neurosci Lett ; 756: 135984, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34029649

RESUMO

Levo-tetrahydropalmatine (L-THP) is the main active ingredient of Corydalis and Stephania and is widely used for its sedative, analgesic, and neuroleptic effects. Though L-THP is an antagonist of dopamine receptors and has been proven to be effective in treating drug addiction, its effect on fentanyl-induced reward learning still remains unclear. This experiment was designed to investigate the effects of L-THP on fentanyl-induced rewarding behavior through conditioned place preference (CPP) in mice. Western blot assays were used to dissect the accompanying changes in the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in related brain regions, including the hippocampus (Hip), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc), which may mediate the effects of L-THP on fentanyl-induced CPP. The results revealed that fentanyl could induce CPP in mice at doses of 0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, and 0.2 mg/kg, and L-THP could attenuate the acquisition of fentany-induced CPP at a dose of 10.0 mg/kg. The levels of p-ERK and p-CREB of the saline+fentanyl group (0.05 mg/kg) increased significantly in the Hip, NAc, and PFC compared to the saline+saline group. Furthermore, L-THP (10.0 mg/kg) co-administered with fentanyl during conditioning prevented the enhanced phosphorylation of ERK and CREB in the Hip, NAc, and PFC. Our research revealed that L-THP could suppress the rewarding properties of fentanyl-induced CPP, the inhibitory effect may be related to the suppression of ERK and CREB phosphorylation in the Hip, NAc, and PFC of mice. Thus, L-THP may have therapeutic potential for fentanyl addiction.


Assuntos
Alcaloides de Berberina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Fentanila/farmacologia , Entorpecentes/farmacologia , Animais , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Recompensa
18.
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
19.
Neurosci Lett ; 756: 135946, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33974952

RESUMO

Relapse to drugs such as opioids is a major challenge in addiction therapy. It has been known that the orexinergic system has a significant role in mediating reward processing and addiction, as shown by the conditioned place preference (CPP). The dentate gyrus (DG) of the hippocampus receives orexinergic projections from the lateral hypothalamus that has been approved as a critical area arbitrating the maintenance of drug-seeking behavior following the extinction. The present study aimed to investigate the effects of intra-DG administration of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) antagonists on the extinction of morphine-induced CPP in male rats. Animals received different doses of SB334867 (as OX1R antagonist) or TCS OX2 29 (as OX2R antagonist) (0.5, 2.5, and 12.5 nM/0.5 µl DMSO 12 %) bilaterally into the DG during the extinction phase, after CPP had been induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. The conditioning scores were recorded during the test. The results demonstrated that intra-DG administration of the highest dose of OX1R antagonist (12.5 nM/0.5 µl DMSO 12 %) shortened the extinction latency of morphine-CPP compared to the DMSO group, while the OX2R antagonist did not significantly alter the latency. Findings imply that the blockade of OX1R, but not OX2R, within the DG facilitates the extinction of morphine-induced reward. In conclusion, the OX1R antagonist might be kept in mind as a convenient therapeutic factor in repressing drug-seeking behaviors in an optimum amount of treatment considering the low dose-treatments applied.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Animais , Benzoxazóis/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Isoquinolinas/farmacologia , Masculino , Naftiridinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Ureia/análogos & derivados , Ureia/farmacologia
20.
J Neurophysiol ; 125(6): 2228-2236, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978485

RESUMO

The infants experience withdrawal from opiates, and time-dependent adaptations in neuronal activity of nucleus accumbens (NAc) may be crucial for this process. A key adaptation is an increased release of acetylcholine. The present study investigates muscarinic acetylcholine receptors (mAChRs) functions in the NAc at short-term (SWT) and long-term (LWT) withdrawal time following chronic morphine exposure in neonatal rats. The inhibitory role of presynaptic mAChRs activation in spontaneous excitatory postsynaptic currents (sEPSCs) in medium spiny neurons was decreased at LWT but not at SWT. Whereas, the excitatory role of post/extrasynaptic mAChRs activation in membrane currents was reduced at LWT but enhanced at SWT. Furthermore, the inhibitory effect of acute morphine on post/extrasynaptic mAChRs-mediated inward currents was enhanced at SWT but not at LWT. These results suggest that withdrawal from morphine leads to downregulation of presynaptic and post/extrasynaptic mAChRs functions in the NAc, which may coregulate the development of withdrawal in neonates.NEW & NOTEWORTHY We investigated for the first time how the duration of withdrawal affects mAChRs functions in the nucleus accumbens in neonatal rats. Compared with short-term withdrawal time, rats showed downregulation of presynaptic and post/extrasynaptic mAChRs functions during long-term withdrawal time. Our finding introduces a new possible correlation between the mAChRs dysfunction in the nucleus accumbens and the development of withdrawal in neonates.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Morfina/farmacologia , Entorpecentes/farmacologia , Síndrome de Abstinência Neonatal/metabolismo , Núcleo Accumbens/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fatores de Tempo
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