scholarly journals Disulfiram Abrogates Morphine Tolerance—A Possible Role of µ-Opioid Receptor-Related G-Protein Activation in the Striatum

2021 ◽  
Vol 22 (8) ◽  
pp. 4057
Author(s):  
Anna de Corde-Skurska ◽  
Pawel Krzascik ◽  
Anna Lesniak ◽  
Mariusz Sacharczuk ◽  
Lukasz Nagraba ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Dorsal Striatum ◽  
Morphine Tolerance ◽  
Brain Structures ◽  
Receptor Activation ◽  
Tail Flick ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Analgesic Tolerance ◽  
Protein Activation

One of the key strategies for effective pain management involves delaying analgesic tolerance. Early clinical reports indicate an extraordinary effectiveness of off-label disulfiram—an agent designed for alcohol use disorder—in potentiating opioid analgesia and abrogation of tolerance. Our study aimed to determine whether sustained µ-opioid signaling upon disulfiram exposure contributes to these phenomena. Wistar rats were exposed to acute and chronic disulfiram and morphine cotreatment. Nociceptive thresholds were assessed with the mechanical Randal-Selitto and thermal tail-flick tests. µ-opioid receptor activation in brain structures important for pain processing was carried out with the [35S]GTPγS assay. The results suggest that disulfiram (12.5–50 mg/kg i.g.) augmented morphine antinociception and diminished morphine (25 mg/kg, i.g.) tolerance in a supraspinal, opioid-dependent manner. Disulfiram (25 mg/kg, i.g.) induced a transient enhancement of µ-opioid receptor activation in the periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM), hypothalamus, prefrontal cortex and the dorsal striatum at day 1 of morphine treatment. Disulfiram rescued µ-opioid receptor signaling in the nucleus accumbens and caudate-putamen 14 days following morphine and disulfiram cotreatment. The results of this study suggest that striatal µ-opioid receptors may contribute to the abolition of morphine tolerance following concomitant treatment with disulfiram.

The K+-evoked release of [3H]acetylcholine from slices of rat globus pallidus: modulation by δ-opioid receptors

1991 ◽  
Vol 69 (3) ◽  
pp. 414-418 ◽  
Author(s):  
Bianca B. Ruzicka ◽  
Khem Jhamandas
Keyword(s):  
Globus Pallidus ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Cholinergic Neurons ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Release Of Acetylcholine ◽  
Δ Opioid Receptor ◽  
Tritium Release

Previous investigations have shown that the activation of δ-opioid receptors depresses the release of acetylcholine (ACh) in the rat caudate putamen. This finding raised the possibility that the release of ACh is similarly modulated in the globus pallidus, a region containing a distinct population of cholinergic neurons and enriched in enkephalinergic nerve terminals. In the present study the pallidal release of ACh was characterized and the effects of δ-opioid receptor activation on this release were examined. The results show that this release is stimulated by high K+ in a concentration- and Ca2+-dependent manner. D-Pen2,L-Pen5-enkephalin (0.1 – 10 μM), a selective δ-opioid receptor agonist, produced a dose-related inhibition of the 25 mM K+-evoked tritium release. The maximal inhibitory effect, representing a 34% decrease in the K+-induced tritium release, was observed at a concentration of 1 μM. This opioid effect was attenuated by the selective δ-opioid receptor antagonist, ICI 174864 (1 μM). These findings support the role of a δ-opioid receptor in the modulation of ACh release in the rat globus pallidus.Key words: globus pallidus, acetylcholine, enkephalin, release.

Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats

2020 ◽  
Author(s):  
Tayfun Baser ◽  
Ercan Ozdemir ◽  
Ahmet Kemal Filiz ◽  
Ahmet Sevki Taskiran ◽  
Sinan Gursoy
Keyword(s):  
Analgesic Activity ◽  
Receptor Agonist ◽  
Morphine Tolerance ◽  
Peptide Hormone ◽  
Tail Flick ◽  
Analgesic Tolerance ◽  
Ghrelin Receptor ◽  
Analgesic Effects ◽  
Ghrelin Receptor Agonist ◽  
Ghrelin Receptor Antagonist

Ghrelin is a peptide hormone released from the gastric endocrine glands and shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not been elucidated yet. The purpose of the study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [D-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adults rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance a 3-day cumulative dose regimen was used in rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg/kg), [D-Lys3]-GHRP-6 (10 mg/kg), and morphine (5 mg/kg) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [D-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Besides, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.

scholarly journals A Continuous, Fluorescence-based Assay of µ-Opioid Receptor Activation in AtT-20 Cells

2012 ◽  
Vol 18 (3) ◽  
pp. 269-276 ◽  
Author(s):  
Alisa Knapman ◽  
Marina Santiago ◽  
Yan Ping Du ◽  
Philip R. Bennallack ◽  
Macdonald J. Christie ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Opioid Receptor ◽  
High Throughput ◽  
High Throughput Screening ◽  
Receptor Activation ◽  
Maximum Effect ◽  
Individual Response ◽  
Dependent Manner ◽  
Membrane Hyperpolarization ◽  
Opioid Ligands

Opioids are widely prescribed analgesics, but their use is limited due to development of tolerance and addiction, as well as high variability in individual response. The development of improved opioid analgesics requires high-throughput functional assays to assess large numbers of potential opioid ligands. In this study, we assessed the ability of a proprietary “no-wash” fluorescent membrane potential dye to act as a reporter of µ–opioid receptor (MOR) activation and desensitization via activation of G-protein-coupled inwardly rectifying potassium channels. AtT-20 cells stably expressing mouse MOR were assayed in 96-well plates using the Molecular Devices FLIPR membrane potential dye. Dye emission intensity decreased upon membrane hyperpolarization. Fluorescence decreased in a concentration-dependent manner upon application of a range of opioid ligands to the cells, with high-efficacy agonists producing a decrease of 35% to 40% in total fluorescence. The maximum effect of morphine faded in the continued presence of agonist, reflecting receptor desensitization. The effects of opioids were prevented by prior treatment with pertussis toxin and blocked by naloxone. We have demonstrated this assay to be an effective method for assessing ligand signaling at MOR, which may potentially be scaled up as an additional high-throughput screening technique for characterizing novel opioid ligands.

scholarly journals Honey potentially mitigates morphine analgesic tolerance and physical dependence in rats

2018 ◽  
Vol 17 (1) ◽  
pp. 138-143
Author(s):  
Siti Norhajah Hashim ◽  
Nasir Mohamad ◽  
Zulkifli Mustapha ◽  
Nor Hidayah Abu Bakar ◽  
Rohayah Husain ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Physical Dependence ◽  
Medical Science ◽  
Morphine Tolerance ◽  
Morphine Dependence ◽  
P Value ◽  
Concomitant Treatment ◽  
Sprague Dawley ◽  
Chronic Morphine ◽  
Analgesic Tolerance

Introduction:Honey has been used traditionally in medicine as well as food supplements. Honeybees are said to be able to cure many diseases. However, its influences on opioid tolerance and dependence have not yet been clarified.Materials and Methods:Adult male Sprague- Dawley rats were rendered tolerant to the analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 14 days. To develop morphine dependence rats given escalating doses of chronic morphine. To determine the effect of stingless bee honey on the development of morphine tolerance and dependence. The hotplate and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.The results: Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Methadone+morphine (MetM), methadone+morphine+ honey (MetMH) and morphine+Honey (MH) significantlylower the development of morphine tolerance with p-value p<0.05. In addition, concomitant treatment of morphine with MH and MetMH attenuated almost all of the naloxone-induced withdrawal signs which include abdominal contraction, diarrhea, pertussis, teeth chattering, and jumping.Conclusion: The data indicate that honey has a potential to reduce tolerant and dependence property.Bangladesh Journal of Medical Science Vol.17(1) 2018 p.138-143

TGF-β1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation

2006 ◽  
Vol 290 (5) ◽  
pp. F1202-F1212 ◽  
Author(s):  
Neil G. Docherty ◽  
Orfhlaith E. O'Sullivan ◽  
Declan A. Healy ◽  
Madeline Murphy ◽  
Amanda J. O'Neill ◽  
...  
Keyword(s):  
Growth Factor ◽  
Western Blotting ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Receptor Activation ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Akt Phosphorylation

Apoptosis and epithelial-mesenchymal transdifferentiation (EMT) occur in stressed tubular epithelial cells and contribute to renal fibrosis. Transforming growth factor (TGF)-β1 promotes these responses and we examined whether the processes were interdependent in vitro. Direct (caspase inhibition) and indirect [epidermal growth factor (EGF) receptor stimulation] strategies were used to block apoptosis during TGF-β1 stimulation, and the subsequent effect on EMT was assessed. HK-2 cells were exposed to TGF-β1 with or without preincubation with ZVAD-FMK (pan-caspase inhibitor) or concomitant treatment with EGF plus or minus preincubation with LY-294002 (PI3-kinase inhibitor). Cells were then assessed for apoptosis and proliferation by flow cytometry, crystal violet assay, and Western blotting. Markers of EMT were assessed by microscopy, immunofluorescence, real-time RT-PCR, Western blotting, PAI-1 reporter assay, and collagen gel contraction assay. TGF-β1 caused apoptosis and priming for staurosporine-induced apoptosis. This was blocked by ZVAD-FMK. However, ZVAD-FMK did not prevent EMT following TGF-β1 treatment. EGF inhibited apoptosis and facilitated TGF-β1 induction of EMT by increasing proliferation and accentuating E-cadherin loss. Additionally, EGF significantly enhanced TGF-β1-induced collagen I gel contraction. EGF increased Akt phosphorylation during EMT, and the prosurvival effect of this was confirmed using LY-294002, which reduced EGF-induced Akt phosphorylation and reversed its antiapoptotic and proproliferatory effects. TGF-β1 induces EMT independently of its proapoptotic effects. TGF-β1 and EGF together lead to EMT. EGF increases proliferation and resistance to apoptosis during EMT in a PI3-K Akt-dependent manner. In vivo, EGF receptor activation may assist in the selective survival of a transdifferentiated, profibrotic cell type.

scholarly journals The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

2021 ◽  
Author(s):  
Richard A. Slivicki ◽  
Jiwon Yi ◽  
Victoria E. Brings ◽  
Phuong Nhu Huynh ◽  
Robert W. Gereau
Keyword(s):  
Side Effects ◽  
Cannabinoid Receptor ◽  
Thermal Hyperalgesia ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Drg Neurons ◽  
Cellular Mechanisms ◽  
Analgesic Tolerance ◽  
Repeated Dosing

AbstractActivation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1 receptors is accompanied by unwanted side effects, such as tolerance and dependence. Efforts to develop novel analgesics have focused on targeting peripheral CB1 receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-related phenotypes in an inflammatory model of pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion (DRG) neurons. CB-13 reduced inflammation-induced mechanical allodynia in a peripheral CB1 receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse DRG neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E2, providing potential mechanistic explanations for the analgesic actions of peripheral CB1 receptor activation. With acute dosing, phenotypes associated with central CB1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1 receptor dependence, even at a dose that did not produce central CB1 receptor-mediated phenotypes on acute dosing. This suggests repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.

Selective Modulation of Excitatory Transmission by μ-Opioid Receptor Activation in Rat Supraoptic Neurons

1999 ◽  
Vol 82 (6) ◽  
pp. 3000-3005 ◽  
Author(s):  
Qing-Song Liu ◽  
Sheng Han ◽  
You-Sheng Jia ◽  
Gong Ju
Keyword(s):  
Opioid Receptor ◽  
Amplitude Distribution ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Membrane Hyperpolarization ◽  
Postsynaptic Currents ◽  
Cell Recording ◽  
Μ Opioid Receptor ◽  
Neuroendocrine Neurons ◽  
Supraoptic Neurons

Opioid peptides have profound inhibitory effects on the production of oxytocin and vasopressin, but their direct effects on magnocellular neuroendocrine neurons appear to be relatively weak. We tested whether a presynaptic mechanism is involved in this inhibition. The effects of μ-opioid receptor agonist d-Ala2, N-CH3-Phe4, Gly5-ol-enkephalin (DAGO) on excitatory and inhibitory transmission were studied in supraoptic nucleus (SON) neurons from rat hypothalamic slices using whole cell recording. DAGO reduced the amplitude of evoked glutamatergic excitatory postsynaptic currents (EPSCs) in a dose-dependent manner. In the presence of tetrodotoxin (TTX) to block spike activity, DAGO also reduced the frequency of spontaneous miniature EPSCs without altering their amplitude distribution, rising time, or decaying time constant. The above effects of DAGO were reversed by wash out, or by addition of opioid receptor antagonist naloxone or selective μ-antagonist Cys2-Tyr3-Orn5-Pen7-NH2(CTOP). In contrast, DAGO had no significant effect on the evoked and spontaneous miniature GABAergic inhibitory postsynaptic currents (IPSCs) in most SON neurons. A direct membrane hyperpolarization of SON neurons was not detected in the presence of DAGO. These results indicate that μ-opioid receptor activation selectively inhibits excitatory activity in SON neurons via a presynaptic mechanism.

Antinociception by Spinal and Systemic Oxycodone: Why Does the Route Make a Difference?

2006 ◽  
Vol 105 (4) ◽  
pp. 801-812 ◽  
Author(s):  
Kim K. Lemberg ◽  
Vesa K. Kontinen ◽  
Antti O. Siiskonen ◽  
Kaarin M. Viljakka ◽  
Jari T. Yli-Kauhaluoma ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Opioid Receptor ◽  
Subcutaneous Administration ◽  
Receptor Activation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Tail Flick ◽  
Hot Plate ◽  
Mu Opioid ◽  
Pressure Tests

Background The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats. Methods Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. Mu-opioid receptor agonist-stimulated GTPgamma[S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective kappa-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs. Results Oxycodone showed lower efficacy and potency to stimulate GTPgamma[S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests. Conclusions The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate mu-opioid receptor activation in the spinal cord.

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