Enhancement of Morphine Analgesic Effect with Induction of μ-Opioid Receptor Endocytosis in Rats

2006 ◽  
Vol 105 (3) ◽  
pp. 574-580 ◽  
Author(s):  
Tatsuya Hashimoto ◽  
Yoji Saito ◽  
Kazuo Yamada ◽  
Nobumasa Hara ◽  
Yumiko Kirihara ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Relative Activity ◽  
Receptor Internalization ◽  
Hot Plate Test ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Opiate Drug ◽  
Satisfactory Analgesia

Background Morphine can desensitize mu-opioid receptor (MOR), but it does not cause internalization of the receptor after binding. Acute desensitization of MOR impairs the efficiency of signaling, whereas the receptor internalization restores the cell responsiveness to the agonists. Thereby, the property of morphine may limit the analgesic effects of this opiate drug. It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. The authors examined whether the acute analgesic effect of morphine can be potentiated by low relative activity versus endocytosis agonists DAMGO and fentanyl. Methods Rats injected intrathecally with opioids were subjected to a hot plate test for antinociceptive effect. Immunostained spinal dorsal horn was analyzed by confocal microscopy. Results Fentanyl induced MOR internalization to a lesser extent than DAMGO at equianalgesic doses. Coadministration of fentanyl promoted morphine-induced MOR internalization. The analgesic effect of morphine was greatly potentiated together with decrease in the relative activity versus endocytosis value when MOR internalization was induced by coadministration of a subanalgesic dose of DAMGO or fentanyl. In contrast, the combination of DAMGO and fentanyl increased neither the analgesic effect nor the internalization of MOR. Conclusions The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.

scholarly journals N-acetylcysteine dose-dependently improves the analgesic effect of acetaminophen on the rat hot plate test

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samaneh Nakhaee ◽  
Mohammad Dastjerdi ◽  
Hesam Roumi ◽  
Omid Mehrpour ◽  
Khadijeh Farrokhfall
Keyword(s):  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Latency Period ◽  
Drug Formulation ◽  
Male Rats ◽  
Sprague Dawley ◽  
Concurrent Administration ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Analgesic Effects

Abstract Background Acetaminophen (APAP) induced hepatotoxicity is a clinically important problem. Up to now, interventive therapy with n-acetylcysteine (NAC) has been considered as a gold-standard treatment for APAP overdose. However, no study has focused on the efficacy of these drugs’ concurrent administration on probable enhancing therapeutic outcomes. Thus, this study was aimed to investigate the analgesic effect of co-administration of NAC and acetaminophen in male rats. The NAC-APAP drug formulation may demonstrate the stranger antinociceptive effect. Methods Forty-eight male Sprague-Dawley rats (12–14 weeks) randomly divided into six equal groups; control, APAP (received 300 mg/kg APAP), NAC (received 600 mg/kg NAC) and APAP+ NAC groups that received simultaneously 300 mg/kg APAP with 200–600 mg/kg NAC (AN200, AN400, AN600). All administrations were done orally for once. The antinociceptive effect was recorded by measurement of latency period on a hot plate in 30, 60, and 90 min after administrations. Results The results showed that NAC’s concurrent administration with APAP, dose-dependently increased APAP analgesic effects (p< 0.0001). Moreover, NAC treatment exhibited an antinociceptive effect in 60 and 90 min, per se. The treatments had no adverse effect on liver enzymes and oxidative stress. Conclusion Co-administration of NAC with APAP can improve the antinociceptive effect of APAP. It is suggested that this compound can enhance analgesic effects of APAP and eventually lead to a reduction in acetaminophen dose. Further studies are needed to evaluate the molecular mechanism of this hyper analgesic effect.

scholarly journals Analgesic Activity of the Kappa Opioid Receptor Agonist RU-1205 in Rats

2018 ◽  
Vol 3 (2) ◽  
pp. 13 ◽  
Author(s):  
AA Spasov ◽  
OY Grechko ◽  
DM Shtareva ◽  
AI Raschenko ◽  
Natalia Eliseeva ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Analgesic Activity ◽  
Analgesic Effect ◽  
Physical Dependence ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test

Introduction: Opioid analgesics are the most efficient and widely used drugs for the management of moderate to severe pain. However, side effects associated with mu receptor activation, such as respiratory depression, tolerance and physical dependence severely limit their clinical application. Currently, the kappa-opioid system is the most attractive in terms of the clinical problem of pain, because kappa-agonists do not cause euphoria and physical dependence. The purpose of this study was to evaluate the antinociceptive effect of the novel compound - RU-1205. Methods: The analgesic activity of RU-1205 was studied on nociceptive models that characterize the central and peripheral pathways of pain sensitivity (hot plate test, electrically induced vocalisation, formalin test, writhing test). Results: RU-1205 exhibited highly potent antinociceptive effects in rodent models of acute pain with ED50 values of 0.002 - 0.49 mg /kg. Pretreatment with the κ-opioid receptor antagonist norBinaltorphimine significantly attenuated the analgesic activity of investigated substance in a hot plate test. Conclusions: It was established that the compound shows a significant dose-dependent central and peripheral analgesic effect. It was assumed kappa-opioidergic mechanism of analgesic effect of RU-1205.

scholarly journals Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Pain ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 2277-2284 ◽  
Author(s):  
Antonio Rodriguez-Gaztelumendi ◽  
Viola Spahn ◽  
Dominika Labuz ◽  
Halina Machelska ◽  
Christoph Stein
Keyword(s):  
Abdominal Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Analgesic Effects ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor ◽  
Ph Dependent

Antinociceptive Effect of Clomipramine Through Interaction with Serotonin 5-Нт2 And 5-Нт3 Receptor Subtypes

Folia Medica ◽  
2012 ◽  
Vol 54 (4) ◽  
pp. 69-77 ◽  
Author(s):  
Ilia D. Kostadinov ◽  
Delian P. Delev ◽  
Ivanka I. Kostadinova
Keyword(s):  
Acetic Acid ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Positive Control ◽  
Control Group ◽  
Receptor Subtypes ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test ◽  
Acid Test

Abstract INTRODUCTION: Tricyclic antidepressants are used in the treatment of various pain syndromes. The antidepressant clomipramine inhibits predominantly the reuptake of serotonin in the central nervous system. The mechanism of its analgesic effect is not fully understood. The AIM of the present study was to find experimentally any dose-effect dependence in the analgesic effect of clomipramine and the involvement of the 5-НТ2 and 5-НТ3 receptors in the mechanism of this effect. Material and methods: Fifty male Wistar rats were used in the study allocated to five groups (10 animals each): a saline treated control group, one positive control group treated with metamizole and three experimental groups treated with intraperitoneally administered clomipramine in doses of 5, 10 and 20 mg/kg bw, respectively. To study the role of 5-НТ2 and 5-НТ3 receptors in this effect we used another five groups (10 animals each): control, positive control and three experimental groups treated with clomipramine only, clomipramine and granisetrone and clomipramine and cyproheptadine, respectively. Three nociceptive tests were used: the hot plate test, analgesimeter and the acetic acid-induced writhing test. To gauge the antinociceptive action we used the increased latency in the hot plate test expressed as maximum possible effect % (%MPE), the increase in paw pressure to withdraw the hind paw in analgesimeter and decrease in the number of spinal cord writhes in the acetic acid test. RESULTS: Clomipramine in a dose of 20 mg/kg bw significantly increased the %MPE in hot plate test and the pressure to withdraw the hind paw in the analgesimeter when compared with the control. In the acetic acid test clomipramine decreased non-significantly the number of writhes compared with the controls. Granisetrone reduced non-significantly the antinociceptive effect of clomipramine in all tests. Cyproheptadine potentiated the analgesic effect of clomipramine in acetic acid test and decreased it significantly in the hot plate test. In analgesimeter cyproheptadine decreased significantly the paw pressure to withdraw the tested hind paw at 1 hour and non-significantly at 2 hours. CONCLUSION: Clomipramine in the dose of 20 mg/kg bw has a pronounced antinociceptive affect towards thermal and mechanical pain stimulation. The 5-HT2 and 5-HT3 receptor subtypes are very likely involved in the mechanism of this effect.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients

2010 ◽  
Vol 1 (1) ◽  
pp. 24-33 ◽  
Author(s):  
K.K. Lemberg ◽  
T.E. Heiskanen ◽  
M. Neuvonen ◽  
V.K. Kontinen ◽  
P.J. Neuvonen ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Adverse Effects ◽  
Opioid Receptor ◽  
Placebo Administration ◽  
Rescue Analgesia ◽  
Analgesic Effects ◽  
Patient Reported ◽  
Chronic Pain Patients ◽  
Μ Opioid Receptor ◽  
Pain Patients

AbstractOxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients.The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1.Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P = 0.003), and that of noroxycodone by 100% (5–280%; P < 0.0001) but decreased the AUC0–12 h of oxymorphone by 67% (−100 to −22%; P < 0.0001) and that of noroxymorphone by 68% (−100 to −16%; P < 0.0001).Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine.No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied.The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

scholarly journals Dissecting the roles of GRK2 and GRK3 in μ-opioid receptor internalization and β-arrestin2 recruitment using CRISPR/Cas9-edited HEK293 cells

2020 ◽  
Author(s):  
Thor C. Møller ◽  
Mie F. Pedersen ◽  
Jeffrey R. van Senten ◽  
Sofie D. Seiersen ◽  
Jesper M. Mathiesen ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Hek293 Cells ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Individual Contributions ◽  
Μ Opioid Receptor ◽  
G Protein Coupled ◽  
Target Effects

AbstractMost G protein-coupled receptors (GPCRs) recruit β-arrestins and internalize upon agonist stimulation. For the μ-opioid receptor (μ-OR), this process has been linked to development of opioid tolerance. GPCR kinases (GRKs), particularly GRK2 and GRK3, have been shown to be important for μ-OR recruitment of β-arrestin and internalization. However, the contribution of GRK2 and GRK3 to β-arrestin recruitment and receptor internalization, remain to be determined in their complete absence. Using CRISPR/Cas9-mediated genome editing we established HEK293 cells with knockout of GRK2, GRK3 or both to dissect their individual contributions in β-arrestin2 recruitment and μ-OR internalization upon stimulation with four different agonists. We showed that GRK2/3 removal reduced agonist-induced μ-OR internalization and β-arrestin2 recruitment substantially and we found GRK2 to be more important for these processes than GRK3. Furthermore, we observed a sustained and GRK2/3 independent component of β-arrestin2 recruitment to the plasma membrane upon μ-OR activation. Rescue expression experiments restored GRK2/3 functions. Inhibition of GRK2/3 using the small molecule inhibitor CMPD101 showed a high similarity between the genetic and pharmacological approaches, cross-validating the specificity of both. However, off-target effects were observed at high CMPD101 concentrations. These GRK2/3 KO cell lines should prove useful for a wide range of studies on GPCR function.

scholarly journals Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

2020 ◽  
Vol 21 (13) ◽  
pp. 4699 ◽  
Author(s):  
Zhennan Zhao ◽  
Tingting Huang ◽  
Jiazhong Li
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Opioid Analgesics ◽  
Dynamics Simulation ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

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