Paroxetine effects on morphine analgesic tolerance in rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Navideh Sahebi Vaighan ◽  
Soha Parhiz ◽  
Masoumeh Sabetkasaei ◽  
Taraneh Moini Zanjani ◽  
Malek Zarei
Keyword(s):  
Intraperitoneal Injection ◽  
Tolerance Induction ◽  
Morphine Tolerance ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Analgesic Tolerance ◽  
Progressive Decline ◽  
Morphine Administration ◽  
Male Wistar Rats ◽  
Daily Intraperitoneal Injection

Abstract Objectives To alleviate different pain intensities, morphine administration has been extensively used. However, prolonged administration of morphine leads to a progressive decline of its analgesic effect which limits their overall utility. Morphine tolerance is considered as a challenging issue for the treatment of both acute and chronic pain. We conducted this study in rats to investigate the effect of paroxetine on morphine tolerance when used preemptively or after morphine tolerance had developed. Methods Male Wistar rats (weight 250–300 g, n=10) were used to evaluate the effects of paroxetine on tolerance to morphine. In order to induce tolerance, daily intraperitoneal injection of morphine (7 mg/kg) was done. After tolerance induction, a group of animals received intraperitoneal injection of 10 mg/kg paroxetine 30 min prior to each morphine dose. In another trial, to investigate the potential of paroxetine to prevent tolerance to morphine, animals were pretreated with 10 mg/kg paroxetine 30 min before morphine administration. In the control groups, 10 mL/kg of saline was injected. The behavioral test (tail-flick test) was done for all groups. Results Our data showed that paroxetine significantly reversed tolerance to morphine when used after tolerance induction (p<0.001). However, administration of paroxetine before occurrence of tolerance had no effect. Conclusions We conclude that paroxetine could decrease tolerance to morphine when used after the occurrence of morphine tolerance, while it was not able to prevent morphine tolerance when administered preemptively. Ethical committee number IRIB.SBMU.MSP.REC.1394.098.

Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats

Drug Research ◽  
2017 ◽  
Vol 68 (01) ◽  
pp. 33-37 ◽  
Author(s):  
Hamed Ghavimi ◽  
Sara Darvishi ◽  
Saeed Ghanbarzadeh
Keyword(s):  
Male Rats ◽  
Control Group ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Attenuation Effect ◽  
Morphine Administration ◽  
Male Wistar Rats ◽  
Potent Growth ◽  
Induced Tolerance ◽  
Withdrawal Signs

Abstract Background Dependence and tolerance to morphine are major problems which limit its chronic clinical application. Purpose This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. Methods Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5–25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. Results Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). Conclusion In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence.

Suppressing HMGB1-TLR4-Mediated Neuroinflammation Alleviates Morphine Tolerance via Inhibiting AMPK-HO-1 Pathway in The Spinal Cord of Mice

2020 ◽  
Author(s):  
Tong-Tong Lin ◽  
Lei Sheng ◽  
Li Wan ◽  
Lu-Lu Ji ◽  
Jin-Can Li ◽  
...  
Keyword(s):  
Western Blot ◽  
Cell Line ◽  
High Mobility ◽  
Morphine Tolerance ◽  
Nuclear Factor Κb ◽  
Immunofluorescence Staining ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Analgesic Tolerance ◽  
Microglial Cell Line

Abstract Background and objectives: A major unresolved issue in treating pain is the analgesic tolerance produced by opioids. Neuroinflammation was thought to be important in the development of morphine tolerance. The role of High mobility group box-1 (HMGB1) in morphine tolerance is elusive. Methods: ICR mice were used for tail-flick test to evaluate morphine tolerance. SD rats were used to collect the CSF to investigate whether morphine could induce the efflux of HMGB1 into extracellular environment. The neural cell line SH-SY5Y and the microglial cell line BV-2 were used to investigate the pharmacological effects and the mechanism of morphine-induced neuroinflammation. The activation of microglia was assessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HMGB1 and related signaling pathway were evaluated by western blot and immunofluorescence staining.Results: Morphine induces the release of HMGB1 from neurons. The released HMGB1 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of nuclear factor-κB (NF-κB) p65 and the upregulation of IL-1β. The secretion of HMGB1 was under the control of AMPK-HO-1 pathway. AMPK inhibitor and HO-1 inhibitor inhibited the release of HMGB1 and suppressed HMGB1-TLR4 mediated neuroinflammation.Conclusion: Our study indicated that morphine-induced extracellular HMGB1 was critical for morphine tolerance. The release of HMGB1 was regulated by AMPK-HO-1 pathway. Our findings may represent a bright prospect for the improvement of morphine tolerance with HMGB1 inhibitor and/or the inhibitors for AMPK-HO-1 axis.

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 Investigation of Origanum compactum essential oil for analgesic and anti-inflammatory activities

2021 ◽  
Vol 319 ◽  
pp. 01104
Author(s):  
Jamila Hamamouchi ◽  
Mohammed El Mahi ◽  
Moulay El Abbes Faouzi
Keyword(s):  
Essential Oil ◽  
Opiate Receptors ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Aerial Parts ◽  
Male Wistar Rats ◽  
Origanum Compactum ◽  
Specific Antagonist ◽  
Anti Inflammatory ◽  
Dose Dependent

Origanum compactum Benth. has been widely used in moroccan traditional medicine for various therapeutic treatments. Belonging to the same genus, O. onites was found to have marked analgesic and anti-inflammatory activities. The aim of this work is to evaluate theses pharmacological properties of the essential oil of O. compactum in order to provide a basis for the folkloric use of the plant. Aerial parts of plant were subjected to steam distillation, according to the French Pharmacopoeia. Male OF1 mice and male Wistar rats were used for these studies. The analgesic effect was done using Writhing test in mice and Tail-Flick test in rats. The mechanism investigation was evaluated employing an antagonism assay using naloxone, a specific antagonist of opiate receptors. Anti- inflammatory property has been studied using carrageenin and experimental trauma induced edema in rats. The essential oil of the aerial parts of Origanum compactum was found to exert central analgesic properties. Such a dose-dependent action was obtained against chemical and thermic stimuli, respectively, from the doses of 6.25 and 12.5 mg/kg and it was inhibited by a naloxone pretreatment, a specific morphinic antagonist compound. Significant and dose-dependent anti-inflammatory effects were observed on an acute inflammatory process from the dose of 100 mg/kg.

scholarly journals Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway

2018 ◽  
Vol 115 (9) ◽  
pp. E2085-E2094 ◽  
Author(s):  
Sevasti Gaspari ◽  
Immanuel Purushothaman ◽  
Valeria Cogliani ◽  
Farhana Sakloth ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Protein Signaling ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Biochemical Assays ◽  
Morphine Administration ◽  
Promising Target

Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/β-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2–Gαz complexes near the membrane and promotes β-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gαz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction.

scholarly journals Modulation of Morphine-induced Antinociception in Acute and Chronic Opioid Treatment by Ibudilast

2009 ◽  
Vol 111 (6) ◽  
pp. 1356-1364 ◽  
Author(s):  
Tuomas O. Lilius ◽  
Pekka V. Rauhala ◽  
Oleg Kambur ◽  
Eija A. Kalso
Keyword(s):  
Cell Activation ◽  
Antinociceptive Effect ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Test ◽  
Glial Cell Activation ◽  
Sprague Dawley Rats ◽  
Antinociceptive Effects

Background Opioid analgesics are effective in relieving chronic pain, but they have serious adverse effects, including development of tolerance and dependence. Ibudilast, an inhibitor of glial activation and cyclic nucleotide phosphodiesterases, has shown potential in the treatment of neuropathic pain and opioid withdrawal. Because glial cell activation could also be involved in the development of opioid tolerance in rats, the authors studied the antinociceptive effects of ibudilast and morphine in different models of coadministration. Methods Antinociception was assessed using male Sprague- Dawley rats in hot plate and tail-flick tests. The effects of ibudilast on acute morphine-induced antinociception, induction of morphine tolerance, and established morphine tolerance were studied. Results Systemic ibudilast produced modest dose-related antinociception and decreased locomotor activity at the studied doses of 2.5-22.5 mg/kg. The highest tested dose of 22.5 mg/kg produced 52% of the maximum possible effect in the tail-flick test. It had an additive antinociceptive effect when combined with systemic morphine. Coadministration of ibudilast with morphine did not attenuate the development of morphine tolerance. However, in morphine-tolerant rats, ibudilast partly restored morphine-induced antinociception. Conclusions Ibudilast produces modest antinociception, and it is effective in restoring but not in preventing morphine tolerance. The mechanisms of the effects of ibudilast should be better understood before it is considered for clinical use.

scholarly journals Possible Involvement of Serotonergic Mechanism(s) in the Antinociceptive Effects of kaempferol

2020 ◽  
pp. 64-70
Keyword(s):  
Locomotor Activity ◽  
Receptor Antagonist ◽  
Serotonin Receptors ◽  
Metabolic Diseases ◽  
Male Rats ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Way 100635 ◽  
Antinociceptive Effects ◽  
Male Wistar Rats

Background and Objectives: A flavonoid kaempferol (KM) exerts an anti-inflammatory effect and is reportedly capable of preventing metabolic diseases. Nonetheless, a limited number of studies have been carried out on the antinociceptive effects of kaempferol. Objectives: The present study aimed to investigate the involvement of serotonin receptors in the antinociceptive-like activity of KM in male Wistar rats using the tail-flick test. Materials and Methods: The compounds (i.e., KM, morphine, and diclofenac) were intracerebroventricularly administered to rats for the examination of central effects on the thermal pain using the tail-flick test. For the evaluation of the involvement of serotonin receptors in the possible antinociceptive effects of kaempferol, several antagonists (i.e., tropisetron, ketanserin, GR113808, WAY 100635, and penbutolol) were used. Additionally, locomotor activity and motor responses were investigated by the rotarod test after KM treatment. Results: The intracerebroventricular microinjections of KM showed antinociceptive effects using the tail-flick test. The pretreatment with tropisetron as a 5-HT3 receptor antagonist at 1 and 10 mg completely reversed the KM-related antinociception. Furthermore, ketanserin (5-HT2A receptor antagonist) and GR113808 (5-HT4 receptor antagonist) both at 10 mg reduced KM-related antinociception; however, 5-HT1A receptor antagonist WAY 100635 and 5-HT1B antagonist penbutolol did not decrease KM-related antinociception. All KM doses were not observed with a significant effect on locomotor activity or motor reactions. Conclusion: The results of the current study suggested that serotonergic receptors (i.e., 5-HT2A, 5-HT3, and 5-HT4) are effective in the KM antinociceptive activity in male rats.

scholarly journals The Effects of Ketamine and Its Enantiomers on the Morphine- or Dexmedetomidine-induced Antinociception after Intrathecal Administration in Rats

2000 ◽  
Vol 93 (1) ◽  
pp. 231-241 ◽  
Author(s):  
Gabriella Joó ◽  
Gyöngyi Horvath ◽  
Walter Klimscha ◽  
Gabriella Kekesi ◽  
Ildiko Dobos ◽  
...  
Keyword(s):  
Time Course ◽  
Antinociceptive Effect ◽  
Motor Impairment ◽  
Intrathecal Administration ◽  
Fixed Dose ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Male Wistar Rats ◽  
Racemic Ketamine ◽  
Alpha2 Adrenoceptor

Background The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and alpha2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexmedetomidine. Methods Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 microg), morphine (0.1-3.0 microg), dexmedetomidine (0.3-10.0 microg), and mixtures of two doses of ketamines (30 or 100 microg) with different doses of morphine or dexmedetomidine for fixed-dose analysis. Results Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 microg (95% confidence interval: 1.04-2.32) and 4. 85 microg (3.96-5.79), respectively. A low dose (30 microg) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 microg racemic ketamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. Conclusions These data indicate that racemic ketamine and S(+)-ketamine, but not R(-)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.

scholarly journals Profiling the Effects of Repetitive Morphine Administration on Motor Behavior in Rats

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4355
Author(s):  
Alok K. Paul ◽  
Nuri Gueven ◽  
Nikolas Dietis
Keyword(s):  
Motor Behavior ◽  
Tail Flick ◽  
High Dose ◽  
Behavioral Tolerance ◽  
Sprague Dawley ◽  
Analgesic Tolerance ◽  
Morphine Dose ◽  
Analgesic Effects ◽  
Sprague Dawley Rats ◽  
Morphine Administration

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague–Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.

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.

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