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Plasticity of opioid receptors in the female periaqueductal Gray: multiparity-induced increase in the activity of genes encoding for mu and kappa receptors and a post-translational decrease in delta receptor expression

TEODOROV, Elizabeth; BERNARDI, Maria Martha; FERRARI, Merari de Fatima Ramires; FIOR-CHADI, Débora Rejane; FELÍCIO, Luciano Freitas
Fonte: Totowa Publicador: Totowa
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
36.96%
The periaqueductal gray (PAG) has been reported as a potential site for opioid regulation of behavioral selection. Opioid-mediated behavioral and physiological responses differ between nulliparous and multiparous females. This study addresses the effects of multiple reproductive experiences on μ-, κ- and δ-opioid receptor (Oprm1, Oprk1, and Oprd1 respectively) gene activity and μ, κ and δ protein expression (MOR, KOR and DOR respectively) in the PAG of the female rats. This was done by evaluating the opioid gene expression using real-time (RT-PCR) and quantification of each protein receptor by Western blot analysis. The RT-PCR results show that multiple reproductive experiences increase Oprm1 and Oprk1 gene expression. Western blot analysis revealed increased MOR and KOR while DOR protein was decreased in multiparous animals. Taken together, these data suggest that multiple reproductive experiences influence both gene activity and opioid receptor expression in the PAG. Post-translational mechanisms seem particularly relevant for DOR expression. Thus, opioid transmission in the PAG might be modulated by different mechanisms of multiparity-induced plasticity according to the opioid receptor type

Antinociception induced by acute oral administration of sweet substance in young and adult rodents: The role of endogenous opioid peptides chemical mediators and mu(1)-opioid receptors

de Freitas, Renato Leonardo; Lopes Kuebler, Joao Marcus; Elias-Filho, Daoud Hibraim; Coimbra, Norberto Cysne
Fonte: PERGAMON-ELSEVIER SCIENCE LTD; OXFORD Publicador: PERGAMON-ELSEVIER SCIENCE LTD; OXFORD
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
37%
The present work aimed to investigate the effects of acute sucrose treatment on the perception of painful stimuli. Specifically, we sought to determine the involvement of the endogenous opioid peptide-mediated system as well as the role of the mu(1)-opioid receptor in antinociception organisation induced by acute sucrose intake. Nociception was assessed with the tail-flick test in rats (75, 150 and 250 g) of different ages acutely pre-treated with 500 mu L. of a sucrose solution (25, 50, 150 and 250 g/L) or tap water. Young and Adult rats (250 g) showed antinociception after treatment with 50 g/L (during 5 min) and 150 g/L and 250 g/L (during 20 min) sucrose solutions. Surprisingly, this antinociception was more consistent in mature adult rodents than in pups. To evaluate the role of opioid systems, mature adult rodents were pre-treated with different doses (0.25, 1 or 4mg/kg) of the non-selective opioid receptor antagonist naloxone, the selective pi-opioid receptor antagonist naloxonazine or vehicle followed by 250 g/L sucrose solution treatment. Sucrose-induced antinociception was reduced by pre-treatment with both naloxone and naloxonazine. The present findings suggest that sweet substance-induced hypo-analgesia is augmented by increasing sucrose concentrations in young and adult rodents. Acute oral sucrose treatment inhibits pain in laboratory animal by mediating endogenous opioid peptide and mu(1)-opioid receptor actions. (C) 2011 Elsevier Inc. All rights reserved.; FAPESP; FAPESP [proc. 03/03118-0...

Activation of μ opioid receptors in the LPBN facilitates sodium intake in rats

Pavan, Carolina G.; Roncari, Camila F.; Barbosa, Silas P.; Paula, Patricia Maria de; Colombari, Débora S. A.; Luca Júnior, Laurival A. de; Colombari, Eduardo; Menani, José V.
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 20-25
ENG
Relevância na Pesquisa
36.98%
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Important inhibitory mechanisms for the control of water and sodium intake are present in the lateral parabrachial nucleus (LPBN). Opioid receptors are expressed by LPBN neurons and injections of endorphin (nonspecific opioid receptor agonist) in this area induce 0.3 M NaCl and water intake in satiated rats. In the present study, we investigated the effects of the injections of endomorphin-1 (opioid receptor agonist) alone or combined with the blockade of , or opioid receptors into the LPBN on 0.3 M NaCl and water intake induced by subcutaneous injections of the diuretic furosemide (FURO) combined with low dose of the angiotensin converting enzyme inhibitor captopril (CAP). Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of endomorphin-1 (0.1, 0.25, 0.5, 1.0, 2.0 and 4.0 nmol/0.2 l) into the LPBN increased 0.3 M NaCl and water intake induced by FURO + CAP. The previous blockade of opioid receptor with CTAP (1.0 nmol/0.2 l) into the LPBN reduced the effect of endomorphin-1 on FURO + CAP-induced 0.3 M NaCl. GNTI ( opioid receptor antagonist; 2.0 nmol/0.2 l) and naltrindole ( opioid receptor antagonist; 2.0 nmol/0.2 l) injected into the LPBN did not change the effects of endomorphin-1 on FURO + CAP-induced 0.3 M NaCl. The results suggest that opioid receptors in the LPBN are involved in the control of sodium intake.

Mecanismos opióides centrais envolvidos no efeito protetor da testosterona no desenvolvimento da dor da ATM em ratos; Central mu- kappa opioid receptor cooperativity mediates the protective effect of testosterone on temporomandibular joint nociception development in rats

Cristina Gomes de Macedo
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/02/2012 PT
Relevância na Pesquisa
37%
Disfunções temporomandibulares são condições dolorosas que envolvem a articulação temporomandibular e os músculos mastigatórios com maior prevalência, severidade e duração no sexo feminino. Recentemente foi demonstrado que a testosterona apresenta um efeito protetor ao diminuir o risco de ratos desenvolverem dor na Articulação Temporomandibular (ATM), o que explica pelo menos em parte, a menor prevalência de dor no sexo masculino. No entanto, o mecanismo através do qual a testosterona induz o efeito protetor em machos não é conhecido. Assim, o objetivo deste trabalho foi investigar se o efeito protetor da testosterona é mediado pela ativação do sistema opióide endógeno no sistema nervoso central e quais os subtipos de receptores opióides estão envolvidos nesse efeito protetor sobre o desenvolvimento de dor na ATM em ratos. Para o procedimento experimental foram usados ratos machos Wistar (230-300 g), intactos, gonadectomizados (Gx) e sham gonadectomizados (sham Gx) e a injeção de formalina 0,5% na ATM foi usada como estímulo nociceptivo. Para testar o envolvimento de um mecanismo neural central dependente da ativação do sistema opióide, os animais receberam injeção de naloxona, antagonista não seletivo de receptores opióides...

It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

Chartoff, Elena H.; Connery, Hilary S.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
36.98%
Opioids selective for the G protein-coupled mu opioid receptor (MOR) produce potent analgesia and euphoria. Heroin, a synthetic opioid, is considered one of the most addictive substances, and the recent exponential rise in opioid addiction and overdose deaths has made treatment development a national public health priority. Existing medications (methadone, buprenorphine, and naltrexone), when combined with psychosocial therapies, have proven efficacy in reducing aspects of opioid addiction. Unfortunately, these medications have critical limitations including those associated with opioid agonist therapies (e.g., sustained physiological dependence and opioid withdrawal leading to high relapse rates upon discontinuation), non-adherence to daily dosing, and non-renewal of monthly injection with extended-release naltrexone. Furthermore, current medications fail to ameliorate key aspects of addiction such as powerful conditioned associations that trigger relapse (e.g., cues, stress, the drug itself). Thus, there is a need for developing novel treatments that target neural processes corrupted with chronic opioid use. This requires a basic understanding of molecular and cellular mechanisms underlying effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. The focus of this review is to discuss how crosstalk between MOR-associated G protein signaling and glutamatergic neurotransmission leads to immediate and long-term effects on emotional states (e.g....

Tissue distribution of opioid receptor gene expression in the rat

Wittert, G.; Hope, P.; Pyle, D.
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Artigo de Revista Científica
Publicado em //1996 EN
Relevância na Pesquisa
37%
The endogenous opioid peptides have multiple physiological actions at both a central and peripheral level which are mediated by 3 main classes of opioid receptors, mu, delta and kappa. The rat mu, delta and kappa opioid receptors have recently been cloned and their distribution of expression in the central nervous system has been mapped. In these studies we have used the reverse transcriptase polymerase chain reaction and Southern blotting to determine the distribution of expression of the mu, delta and kappa opioid receptors in the peripheral tissues of the rat. All 3 opioid receptors were found to be widely expressed in several peripheral tissues including the small intestine, large intestine, adrenal, kidney, lung, spleen, testis, ovary and uterus. In the stomach, delta and kappa but not mu opioid receptor transcripts were detected. Predominantly delta transcripts were detected in the heart, with no mu and only a weak signal for the kappa receptor. In the liver mu and delta but not kappa transcripts were present. Opioid receptor expression was not detected in endothelium or synovium. There is therefore a broad, but tissue specific distribution of opioid receptor expression in the periphery of the rat, suggesting that the endogenous opioid peptides play an endocrine...

Food intake and food choice: the role of the endogenous opioid peptides in the marsupial Sminthopsis crassicaudata.

Hope, P.; Chapman, I.; Morley, J.; Horowitz, M.; Wittert, G.
Fonte: ELSEVIER SCIENCE BV Publicador: ELSEVIER SCIENCE BV
Tipo: Artigo de Revista Científica
Publicado em //1997 EN
Relevância na Pesquisa
37.03%
Endogenous opioid peptides activate food seeking behaviour and influence macronutrient choice in a number of animal species and previous studies have suggested that the palatability of food is strongly modulated by the opioid feeding system. The effect of opioid peptides on appetite and food choice in marsupials has not been evaluated. The aim of these studies was to determine the effect of mu, delta and K opioid receptors on food intake and food choice in the marsupial Sminthopsis crassicaudata. When offered a choice of mealworms or laboratory diet after 24 h food deprivation, S. crassicaudata ate predominantly mealworms. After a 24 h fast, adult male S. crassicaudata were injected peripherally with opioid receptor antagonists or saline. Animals were re-fed with either their laboratory diet alone, or a choice of laboratory diet and mealworms. In animals re-fed with laboratory diet alone, naloxone at doses of 15 and 10 mg/kg produced a 31% (P < 0.05) and 38% (P < 0.05) respectively reduction in food intake in the first 30 min after laboratory diet was re-introduced, but lower doses had no effect. The selective delta antagonist naltrindole at 20 mg/kg resulted in a 65% (P < 0.01) reduction in food intake compared to controls between 30 and 60 min. The selective kappa opioid antagonist nor-binaltorphimine had no effect on the intake of laboratory diet. In animals offered a choice of laboratory diet and mealworms...

Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward

Hutchinson, M.; Johnson, K.; Rice, K.; Maier, S.; Watkins, L.
Fonte: The ScientificWorld Ltd. Publicador: The ScientificWorld Ltd.
Tipo: Artigo de Revista Científica Formato: 719046 bytes; application/pdf
Publicado em //2007 EN
Relevância na Pesquisa
37%
This review will introduce the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (-)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover...

Injection of medications used in opioid substitution treatment in Australia after the introduction of a mixed partial agonist-antagonist formulation

Degenhardt, L.; Larance, B.; Bell, J.; Winstock, A.; Lintzeris, N.; Ali, R.; Scheuer, N.; Mattick, R.
Fonte: Australasian Med Publ Co Ltd Publicador: Australasian Med Publ Co Ltd
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
37%
Objectives: To examine the levels and predictors of injection of buprenorphine–naloxone (BNX) — a combination of a partial opioid agonist and an opioid antagonist for treating opioid dependence — which was specifically developed to limit injecting. Comparison was made with injecting of two other opioid substitution treatment medications, methadone and buprenorphine (BPN); severe harms have been documented after injection of the latter. Design and participants: Injecting was studied in regular injecting drug users (“IDUs”) and current opioid substitution treatment clients (“clients”). Regular IDUs are interviewed annually in each Australian capital city (about 900 per year) and data for 2003–2007 were used; 399 clients were interviewed in 2007. Data on injection of opioid substitution treatment medications between 2003 and 2007 were adjusted for availability of medications (from national sales data for methadone, BPN and BNX). Predictors of injecting were analysed by multiple regression analyses. Setting: Capital cities of all Australian states and territories. Main outcome measure: Injection of opioid substitution treatment medications among individuals both in and out of treatment. Results: In the year after its introduction in Australia...

Lack of association between the A118G polymorphism of the mu opioid receptor gene (OPRMI) and opioid defendence: A meta-analysis

Coller, J.; Beardsley, J.; Bignold, J.; Li, Y.; Merg, F.; Sullivan, T.; Cox, T.; Somogyi, A.
Fonte: Dove Medical Press Ltd Publicador: Dove Medical Press Ltd
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
37%
Mu opioid receptor (OPRM1) gene variants, particularly the common A118G single nucleotide polymorphism (SNP), are among the most frequently studied candidate genes associated with opioid dependence. However, despite numerous case-control studies and meta-analyses, no definitive conclusion has been reached regarding the association of the A118G SNP and risk of developing opioid dependence. This study aimed to resolve this discrepancy by reinvestigating the association between A118G SNP allelic, and for the first time, genotype frequencies and opioid dependence. A meta-analysis of sixteen case-control studies of opioid dependence was performed with a total of 5169 subjects. No association between the A118G allele (P = 0.23) and genotype (P = 0.34) frequencies and opioid dependence was found. However, significant heterogeneity between studies precluded highly definitive conclusions. In addition, the possibility that other OPRM1 SNPs albeit rarer may influence the risk of opioid dependence remains to be investigated at this level. Nonetheless, despite no evidence of a direct association with risk of dependence, A118G may still influence the pharmacological response to opioids impacting on an individual’s dosage requirements.; Janet K Coller...

Pharmacogenomics of ABCB1 in maintenance pharmacotherapies for opioid dependence.

Barratt, Daniel Thomas
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2010
Relevância na Pesquisa
37.08%
Opioid dependence is a significant public health problem. Whilst long-term opioid maintenance is the most cost-effective approach for treating opioid dependence, the safe and effective use of substitution opioids like methadone and buprenorphine is complicated by their narrow therapeutic indices and a considerable, as yet unexplained, interindividual variability in their dose-effect relationships. Since there is evidence that the P-glycoprotein efflux transporter may influence the plasma pharmacokinetics and CNS distribution of opioids, it was hypothesised that genetic variability in the ABCB1 gene (encoding P-glycoprotein) could play a major role in the interindividual variability in opioid maintenance treatment response. Therefore, the primary aim of this thesis was to investigate ABCB1 genetic variability as a determinant of opioid requirements during maintenance therapy, as well as treatment outcome. This thesis also set out to identify the relationship between ABCB1 genetic variability and the risk of illicit opioid use and dependence, as well as develop new methods for investigating the dynamic interactions between ABCB1 genetic variability, P-glycoprotein expression/function and opioid exposure. For the first major study of this thesis...

Exploring the neuroimmunopharmacology of opioids: An integrative review of mechanisms of central immune signaling and their implications for opioid analgesia

Hutchinson, M.; Shavit, Y.; Grace, P.; Rice, K.; Maier, S.; Watkins, L.
Fonte: Amer Soc Pharmacology Experimental Therapeutics Publicador: Amer Soc Pharmacology Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
36.98%
Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology...

Opioid activation of toll-like receptor 4 contributes to drug reinforcement

Hutchinson, M.; Northcutt, A.; Hiranita, T.; Wang, X.; Lewis, S.; Thomas, J.; van Steeg, K.; Kopajtic, T.; Loram, L.; Sfregola, C.; Galer, E.; Miles, N.; Bland, S.; Amat, J.; Rozeske, R.; Maslanik, T.; Chapman, T.; Strand, K.; Fleshner, M.; Bachtell, R.;
Fonte: Soc Neuroscience Publicador: Soc Neuroscience
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
37.03%
Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively...

Comparison of pain models to detect opioid-induced hyperalgesia

Krishnan, S.; Salter, A.; Sullivan, T.; Gentgall, M.; White, J.; Rolan, P.
Fonte: Dove Medical Press Ltd Publicador: Dove Medical Press Ltd
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
36.98%
OBJECTIVE: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it. METHODS: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse. RESULTS: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3) in the buprenorphine group and 4.5 (95% CI 1.7–15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance...

Neuro-endocrine function in older men with chronic pain : effects of chronic opioid usage.

Haylock, Clare Louise
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2013
Relevância na Pesquisa
37.07%
Background: There is increasing concern regarding adverse effects of long-term opioid medication use in non-cancer pain. Chronic opioid use has been shown to affect both the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Hormonal deficiency due to chronic opioid use might contribute to altered pain sensitivity and functional decline. This may be more pronounced in the geriatric population who has poor functional reserve. Methods: A cross sectional study was performed looking at men over the age of 65 years, who have chronic non-malignant pain. Active arm subjects were taking continuous opioid treatment (≥ 4 weeks; dose equivalence ≥ 10mg oral morphine/day); control subjects were not receiving opioid treatment. Assessments included androgen studies (dehdroepiandrosterone sulphate (DHEA-S), testosterone, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH)), waking salivary cortisol, low dose Synacthen test, neuropsychology testing, experimental cold pressor testing, cortisol testing during cold pressor testing, functional assessments (Instrumental Activities of Daily Living (IADL) Questionnaire, grip strength, and Timed Up and Go), Geriatric Depression Scale (GDS)...

Glial TLR4 signaling does not contribute to opioid-induced depression of respiration

Zwicker, J.D.; Zhang, Y.; Ren, J.; Hutchinson, M.R.; Rice, K.C.; Watkins, L.R.; Greer, J.J.; Funk, G.D.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
36.98%
Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1-10 μM, a TLR4-antagonist). Bath application of (-)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally...

Evaluation and treatment of opioid-induced hyperalgesia

Hay, Justin Luke
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2007
Relevância na Pesquisa
37.05%
Methadone is effective as an opioid substitution therapy, yet its use results in adverse effects such as tolerance and increased pain sensitivity to certain modalities of pain. Recent research has indicated that opioids have the potential to increase pain sensitivity following both acute and chronic dosing. While the pain sensitivity profile of methadone maintained patients is well established, no studies have compared the similarities and differences of chronic opioid users with different aetiologies, namely, chronic pain patients with moderate to severe pain and patients with a substance use disorder on a methadone maintenance treatment program. Furthermore, limited guidelines exist for the treatment of acute pain in opioid-tolerant patients. Recent animal research and human studies in opioid-naïve patients have shown that the addition of ultra-low doses of an opioid antagonist can enhance the antinociceptive effectiveness and reduce adverse effects of opioid agonists. Moreover, recently developed, high potency opioid agonists such as remifentanil have shown to be antinociceptive in both experimental pain models and for acute pain following surgery. The antinociceptive effectiveness and safety of these novel and emerging pharmacotherapies have not been previously determined in methadone maintained patients. Additionally...

Opioid antagonists with minimal sedation for opioid withdrawal

Gowing, L.; Ali, R.; White, J.
Fonte: Update Software Ltd Publicador: Update Software Ltd
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
37.03%
Background Managed withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. Objectives To assess the effectiveness of opioid antagonists in combination with minimal sedation to manage opioid withdrawal. Search strategy We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. Selection criteria Controlled studies of interventions involving the use of opioid antagonists in combination with minimal sedation to manage withdrawal in opioid-dependent participants compared with other approaches or different opioid antagonist regimes. Data collection and analysis One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. Main results Nine studies (6 randomised controlled trials), involving 837 participants, met the inclusion criteria for the review. The quality of the evidence is low, but suggests that withdrawal induced by opioid antagonists in combination with an adrenergic agonist is more intense than withdrawal managed with clonidine or lofexidine alone...

OPIOIDS AND GLIA: INVESTIGATING THE MECHANISMS THROUGH WHICH ULTRA-LOW DOSE OPIOID ANTAGONISTS MODULATE OPIOID TOLERANCE AND HYPERALGESIA.

Mattioli, THERESA ALEXANDRA
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
EN; EN
Relevância na Pesquisa
37.1%
Ultra-low doses (ULD) of the opioid receptor antagonists, naloxone and naltrexone, augment the analgesic actions of morphine, block the induction of tolerance, and reverse established tolerance by an unknown mechanism. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Thus, this thesis investigated the inhibition of spinal gliosis as a mechanism by which ULD antagonists attenuate analgesic tolerance and opioid-induced hyperalgesia. Immune cell activation is implicated in the etiology of morphine tolerance and intrathecal catheterization, a technique commonly used to study the spinal effects of drugs, causes profound gliosis. Thus, the first study investigated the effects of catheter-induced gliosis on acute and chronic morphine analgesic tolerance. Catheterization-induced gliosis did not alter antinociceptive responses to acute intrathecal morphine; however, tolerance to chronic morphine was exacerbated in catheterized rats compared to sham and surgery-naïve controls. The potentiation of analgesic tolerance to chronic morphine by spinal gliosis provided evidence that glia modulate opioid analgesia; therefore...

Endomorphin peptides: pharmacological and functional implications of these opioid peptides in the brain of mammals. Part two

Leff Gelman,Philippe; González Herrera,Norma Estela; Matus Ortega,Maura Epifanía; Beceril Villanueva,Enrique; Téllez Santillán,Carlos; Salazar Juárez,Alberto; Antón Palma,Benito
Fonte: Instituto Mexicano de Psiquiatría Ramón de la Fuente Publicador: Instituto Mexicano de Psiquiatría Ramón de la Fuente
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2010 EN
Relevância na Pesquisa
37.02%
Endomorphin-1 (EM1) and Endomorphin-2 (EM2) represent the two endogenous C-terminal amide tetrapeptides shown to display a high binding affinity and selectivity for the µ-opioid receptor as reported previously (see previous paper, Part I). Endomorphins injected into the VTA were shown to enhance the development of behavioral sensitization responses to amphetamine (AMPH), besides of inducing an increase of locomotion (horizontal) activity in animals. These studies showed that EM2 was significantly more potent than EM1 in modulating the increased opioid-mediated ambulatory responses by altering the dopamine (DA) projecting system in the globus pallidus in tested animals. Several transmission systems (e.g., GABA) have been shown to participate in the endormorphin-induced locomotor responses. EM1 injected into the VTA produced potent rewarding effects in rodents, similar to the rewarding responses produced by distinct opiate compounds. The opioid rewarding responses induced by EM1-2 were shown to be mediated via the activation of both GABAergic and the dopamine (VTA-NAc-PFCx) transmission systems in the brain. Moreover, EM1-2 peptides injected into the VTA, but not in the NAc, produced similar related-rewarding responses induced by low doses of morphine. However...