Pharmacological blockade of neurokinin1 receptor restricts morphine-induced tolerance and hyperalgesia in the rat

Abstract Objectives The most notable adverse side effects of chronic morphine administration include tolerance and hyperalgesia. This study investigated the involvement of dorsal root ganglion (DRG) protein kinase Cɛ (PKCɛ) expression during chronic morphine administration and also considered the relationship between DRG PKCɛ expression and the substance P- neurokinin1 receptor (SP- NK1R) activity. Methods Thirty-six animals were divided into six groups (n=6) in this study. In the morphine and sham groups, rats received 10 µg intrathecal (i.t.) morphine or saline for eight consecutive days, respectively. Behavioral tests were performed on days 1 and 8 before and after the first injections and then 48 h after the last injection (day 10). In the treatment groups, rats received NK1R antagonist (L-732,138, 25 µg) daily, either alone or 10 min before a morphine injection, Sham groups received DMSO alone or 10 min before a morphine injection. Animals were sacrificed on days 8 and 10, and DRG PKCɛ and SP expression were analyzed by western blot and immunohistochemistry techniques, respectively. Results Behavioral tests indicated that tolerance developed following eight days of chronic morphine injection. Hyperalgesia was induced 48 h after the last morphine injection. Expression of SP and PKCɛ in DRG significantly increased in rats that developed morphine tolerance on day 8 and hyperalgesia on day 10, respectively. NK1R antagonist (L-732,138) not only blocked the development of hyperalgesia and the increase of PKCɛ expression but also alleviated morphine tolerance. Conclusions Our results provide evidence that DRG PKCɛ and SP-NK1R most likely participated in the generation of morphine tolerance and hyperalgesia. Pharmacological inhibition of SP-NK1R activity in the spinal cord suggests a role for NK1R and in restricting some side effects of chronic morphine. All experiments were performed by the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised1996) and were approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.MSP.REC.1396.130).

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Investigating the effect of Ultra-low dose naloxone on spinal BDNF and KCC2 cotransporter in morphine tolerant and hyperalgesia rats

10.21203/rs.2.23771/v1 ◽

2020 ◽

Author(s):

Mozhgan Baratzadeh ◽

Samira Danialy ◽

Jalal Zaringhalam ◽

HOMA MANAHEJI

Keyword(s):

Low Dose ◽

Therapeutic Potential ◽

Morphine Tolerance ◽

Tolerance Test ◽

Morphine Injection ◽

Behavioral Tests ◽

Morphine Group ◽

Chronic Morphine ◽

Before And After ◽

Opioid Induced Hyperalgesia

Abstract Background: Chronic opioids administration could lead to several side effects including morphine tolerance and opioid induced hyperalgesia (OIH). Tolerance and hyperalgesia to opiates reduce their effectiveness in the treatment of severe pain. Although the mechanisms are unclear. Recently, we have shown that repeated morphine treatments induced increases in spinal PKCᵧ and GAT-1 expression. In this study we investigate the BDNF and KCC2 expression through ultra-low dose of naloxone coadministration of morphine.Results: In morphine group, rats received 10 mg i.p. morphine and in treatment group 15ng ultra-low dose of naloxone with morphine for consecutive 8 days. Behavioral tests were performed on day 1 before and after the morphine injection, day 5, 8 (tolerance test) and 10, 48h after last morphine injection (opioid induced hyperalgesia OIH test). A number of rats were sacrificed on day 8 and others on day 10, then expression of BDNF and KCC2 were analyzed by western blot and immunohistochemistry techniques, respectively. Behavioral tests suggested that following 8 days of chronic morphine injection tolerance developed. OIH was shown 48 hours after the last morphine injection. Expression of BDNF significantly was increased and KCC2 downregulated in rats that developed morphine tolerance and OIH respectively. Ultra-low dose of naloxone by decreasing BDNF and increasing KCC2 was able to suppress development of OIH and alleviated morphine tolerance.Conclusions: Our data suggest that BDNF and KCC2 maybe candidate molecules which are involved in tolerance and OIH. Ultra- low dose of naloxone along morphine might be a valuable therapeutic potential for controlling hypersensitivity following chronic morphine administration.

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Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

Neural Plasticity ◽

10.1155/2009/516328 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Michael M. Morgan ◽

Michelle D. Ashley ◽

Susan L. Ingram ◽

MacDonald J. Christie

Keyword(s):

Plasma Membrane ◽

Morphine Tolerance ◽

Receptor Activation ◽

Delta Opioid Receptor ◽

Morphine Injection ◽

Chronic Morphine ◽

Delta Opioid Receptors ◽

Morphine Administration ◽

Consistent Manner ◽

Deltorphin Ii

Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance.

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Exercise Reduces Morphine-Induced Hyperalgesia and Antinociceptive Tolerance

BioMed Research International ◽

10.1155/2021/6667474 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Xingrui Gong ◽

Rongmei Fan ◽

Qinghong Zhu ◽

Xihong Ye ◽

Yongmei Chen ◽

...

Keyword(s):

Spinal Cord ◽

P38 Mapk ◽

Wistar Rats ◽

Chronic Morphine ◽

Tolerance Development ◽

P38 Inhibitor ◽

Morphine Administration ◽

Exercise Preconditioning ◽

Before And After ◽

Male Wistar Rats

Chronic morphine intake for treating various pain is frequently concomitant with morphine-induced hyperalgesia and tolerance. The mechanisms can be explained by the activation of p38-MAPK proteins in microglia in the spinal cord horn. Exercise has been shown to prevent the development of microglia overactivation. Thus, we designed to test whether exercise prevents the morphine-induced hyperalgesia and tolerance as well as suppression of p38 phosphorylation. A p38 inhibitor SB203580, exercise, and exercise preconditioning were used for treating morphine-induced hyperalgesia and tolerance development in the present study. The behavior tests for hyperalgesia and tolerance were performed in male Wistar rats before and after morphine administration. Western blotting and immunostaining for examining phosphorylated-p38 expression were performed after the behavior tests. Our results showed that SB203580 and exercise, but not exercise preconditioning, prevented the occurrence of morphine-induced hyperalgesia and tolerance. Meanwhile, exercise decreased morphine-induced phosphorylated-p38 overexpression. In summary, exercise prevented the development of morphine-induced hyperalgesia and tolerance. The mechanism may be related to inhibition of p38 phosphorylation.

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Melatonin Reduce Morphine-Induced Hyperalgesia and Tolerance of Rats via melatonin-MT1-PKCγ Pathway.

10.21203/rs.3.rs-39356/v1 ◽

2020 ◽

Author(s):

Yuchao Fan ◽

Xiao Liang ◽

Bixin Zheng ◽

Li Song

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Morphine Tolerance ◽

Melatonin Level ◽

Chronic Morphine ◽

Lower Serum ◽

Regulation Of Expression ◽

Spinal Dorsal ◽

Sd Rats ◽

Morphine Administration

Abstract Background: Morphine is commonly used for treating acute and chronic pain. However, its using is complicated with tolerance and hyperalgesia. Endogenous melatoninergic system is involved in development of tolerance and hyperalgesia induced by chronic morphine administration, but the precise mechanism remains unknown. Methods: 18 male SD rats were randomly divided into Saline(Sal), Morphine(Mor) and Morphine+Chelerythrine (Mor+Che) group (n = 6, respectively). Each group were received twice-daily intrathecal injections of saline (10μl), morphine (15μg/10μl) or morphine (15μg/5μl)+ chelerythrine (5μg/5μl) for consecutive 9 days, respectively. MWT and TWL of all animals were recorded on day 1, 3, 5, 7, 9. The morphine tolerance was depicted as MPAE on day 1, 3, 5, 7, 9 and on day 10 which can be used to calculate for ED50 of each group. Then we determined the serum level of melatonin by ELISA and expression of MOR , MT1, MT2 and PKCγ by RT-qPCR and WB in spinal dorsal horn of three group rats.Results: Comparing with Sal group, the Mor group exhibited a significant lower serum melatonin level and up-regulation of expression of the MT1, MT2 and PKCγ in the spinal dorsal horn. Co-administration of chelerythrine with morphine not only attenuates morphine-induced hyperalgesia and tolerance, but also increases the down-regulation of serum melatonin level) and reduces the up-regulation of expression of MT1 and PKCγ in spinal dorsal horn compared with Mor group. Conclusion：Melatonin can reduce morphine-induced hyperalgesia and tolerance of rats via melatonin-MT1-PKCγ pathway.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707887115 ◽

2018 ◽

Vol 115 (9) ◽

pp. E2085-E2094 ◽

Cited By ~ 9

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.

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Perubahan kadar hemoglobin akibat terapi kurkuminoid ekstrak rimpang kunyit dibandingkan natrium diklofenak pada penderita osteoartritis

Jurnal Gizi Klinik Indonesia ◽

10.22146/ijcn.17756 ◽

2011 ◽

Vol 7 (3) ◽

pp. 146

Author(s):

Nyoman Kertia ◽

Ahmad Husain Asdie ◽

Wasilah Rochmah ◽

Marsetyawan Marsetyawan

Keyword(s):

Treatment Group ◽

Side Effects ◽

Group Treatment ◽

Educational Level ◽

Diclofenac Sodium ◽

Hemoglobin Level ◽

Treatment Results ◽

Treatment Groups ◽

Natural Medicine ◽

Before And After

Background: In general, patients with osteoarthritis require long live treatments, especially anti-infammatory drugs. Non steroidal anti infammatory drugs are mostly follow by some side effects such as dyspepsia and gastrointestinal bleeding. The use of natural medicine for rheumatic diseases have commonly been practiced worldwide.Objectives: To learn the changes of hemoglobin level due to treatment with curcuminoid from Curcuma domestica Val. rhizome extract compared to diclofenac sodium as anti-infammatory agent for the treatment of osteoarthritis.Methods: This research is a prospective randomized open end blinded evaluations (PROBE). Patients treated with 30 mg curcuminoid from Curcuma domestica Val. rhizome extract or 25 mg diclofenac sodium three times daily for 4 weeks respectively.The hemoglobin level was checked before and after treatment. Results: A total of 80 patients with knee osteoarthritis participated in this study. There was no signifcant difference in the frequency of sex, educational level, duration of suffering, percentage of co-morbidities in both groups. There was no signifcant different of hemoglobin level before treatment between both treatment group. The hemoglobin level was increase signifcantly in curcuminoid treatment groups while no signifcant change in diclofenac group. Treatment with curcuminoid increasing the hemoglobin level signifcantly compare to diclofenac sodium (p=0.03).Conclusion: Treatment with curcuminoid from Curcuma domestica Val. rhizome increasing the hemoglobin level signifcantly compare to diclofenac sodium treatment for osteoarthritis.

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Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1901182116 ◽

2019 ◽

Vol 116 (27) ◽

pp. 13523-13532 ◽

Cited By ~ 13

Author(s):

Li Zhang ◽

Jingjing Meng ◽

Yuguang Ban ◽

Richa Jalodia ◽

Irina Chupikova ◽

...

Keyword(s):

Bacterial Communities ◽

Prolonged Exposure ◽

Morphine Tolerance ◽

Fecal Microbiota ◽

Chronic Morphine ◽

Analgesic Tolerance ◽

Microbial Dysbiosis ◽

Morphine Administration ◽

Selective Depletion

Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic−treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in Bifidobacteria and Lactobacillaeae. Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine’s efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.

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Biphasic Effect of Curcumin on Morphine Tolerance: A Preliminary Evidence from Cytokine/Chemokine Protein Array Analysis

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/neq018 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Jui-An Lin ◽

Jenn-Han Chen ◽

Yuan-Wen Lee ◽

Chao-Shun Lin ◽

Ming-Hui Hsieh ◽

...

Keyword(s):

Low Dose ◽

Morphine Tolerance ◽

Preliminary Evidence ◽

Protein Array ◽

High Dose ◽

Morphine Injection ◽

Response Curves ◽

Biphasic Effect ◽

Induced Tolerance ◽

Protein Array Analysis

The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously.

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Aktivitas Antischistosomiasis Sediaan Nanopartikel Ekstrak Biji Pinang pada Tikus Putih Jantan Terinfeksi Schistosoma japonicum

KOVALEN ◽

10.22487/kovalen.2021.v7.i1.15438 ◽

2021 ◽

Vol 7 (1) ◽

pp. 89-97

Author(s):

Marzela Dewi ◽

David Pakaya ◽

Joni Tandi

Keyword(s):

Side Effects ◽

Schistosoma Japonicum ◽

Ethanol Extract ◽

Positive Control ◽

Treatment Groups ◽

Significant Difference ◽

Before And After ◽

Treatment Data ◽

The Mean ◽

Nonparametric Statistical

Schistosomiasis is a disease caused by Schistosoma japonicum worms and Oncomelania hupensis lindoensis as the intermediate snails. Praziquantel is a drug used to reduce the prevalence of schistosomiasis. However, its use has several side effects such as headaches, dizziness, nausea, vomiting as well as abdominal, joint, and muscle pain. The development of alternative drugs is a solution to reduce side effects. Betel (A. catechu) seeds are known to the public to have an anthelmintic effect because they contain alkaloids, tannins, flavan, phenolic compounds, as well as arecoline. To increase the bioavailability and efficacy of the extract, the seeds were prepared in the formulation of nanoparticles. This study aims to determine the antischistosomiasis activity of the ethanol extract nanoparticles of betel nut as an antischistosomiasis. The rats were divided into 9 treatment groups consisting of normal, negative and positive control groups, extract treatment and treatment of nanoparticle preparations with dose variations of 30, 60, and 120 mg/kgBW. The parameter observed was the number of S. japonicum eggs in rat feces before and after treatment. Data obtained from the mean number of S. japonicum eggs was tested for normality with Saphiro-Wilk test, and showed that the data were not normally distributed. Furthermore, nonparametric statistical analysis was carried out with Kruskal-Wallis which showed there was no significant difference in the mean number of S. japonicum eggs in all treatment groups. The results showed that the ethanol extract nanoparticles of A. catechu had antischistosomiasis activity.

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Local Treatment of Recent Arterial Thromboembolic Occlusions with Brinase

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651408 ◽

1975 ◽

Vol 34 (02) ◽

pp. 498-503 ◽

Cited By ~ 1

Author(s):

D Nyman ◽

M. A da Silva ◽

L. K Widmer ◽

F Duckert

Keyword(s):

Side Effects ◽

Local Treatment ◽

Before And After ◽

Local Side

SummaryBrinase was administered intra-arterially in 16 patients with thrombotic or embolic arterial occlusions. Angiography could be performed before and after treatment in 13 patients. Thrombolysis was obtained in 3 of 9 patients with thrombotic and in 3 of 4 patients with embolic occlusions. In 3 patients severe local side effects occurred.

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