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Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis

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Journal of Pharmaceutical Analysis 2023年第10期13卷 1135-1152页

作者： Jia-Jia Zhang Chang-Geng Song Miao Wang Gai-Qin Zhang Bin Wang Xi Chen Peng Lin Yu-Meng Zhu Zhi-Chuan Sun Ya-Zhou Wang Jian-Li Jiang Ling Li Xiang-Min Yang Zhi-Nan Chen National Translational Science Center for Molecular Medicine&Department of Cell Biology Fourth Military Medical UniversityXi'an710032China Department of Neurology Xijing HospitalFourth Military Medical UniversityXi'an710032China Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials ScienceNorthwest UniversityXi'an710032China Department of Neurosurgery Xi'an Daxing HospitalXi'an710032China Department of Neurobiology and Institute of Neurosciences Collaborative Innovation Center for Brain ScienceSchool of Basic MedicineFourth Military Medical UniversityXi'an710032China

morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy

关键词： morphine tolerance Mu-opioid receptor Endocytosis Monoclonal antibody Physical dependence

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Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway

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Neural Regeneration Research 2023年第9期18卷 2067-2074页

作者： Tong-Tong Lin Chun-Yi Jiang Lei Sheng Li Wan Wen Fan Jin-Can Li Xiao-Di Sun Chen-Jie Xu Liang Hu Xue-Feng Wu Yuan Han Wen-Tao Liu Yin-Bing Pan Jiangsu Key Laboratory of Neurodegeneration Department of PharmacologyNanjing Medical UniversityNanjingJiangsu ProvinceChina Department of Anesthesiology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina Department of Anesthesiology and Pain Nanjing First HospitalNanjing Medical UniversityNanjingJiangsu ProvinceChina State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjingJiangsu ProvinceChina Department of Anesthesiology Eye&ENT HospitalFudan UniversityShanghaiChina Institute of Translational Medicine Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.

关键词： adenosine 5’-monophosphate-activated protein kinase heme oxygenase-1 high mobility group box-1 interleukin-1β microglia morphine tolerance neuroinflammation neuron nuclear factor-κB p65 Toll-like receptor 4

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Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

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Neuroscience Bulletin 2014年第6期30卷 936-948页

作者： Liying Bai Caihong Zhai Kun Han Zhisong Li Junliang Qian Ying Jing Wei Zhang Ji-Tian Xu Department of Anesthesiology The First Affiliated HospitalZhengzhou University Department of Physiology Medical School of Zhengzhou University

Nuclear factor kappa B（NF-κB） in the spinal cord is involved in pro-infl ammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65（p-p65） was increased in the dorsal horn of the lumbar 4–6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate（PDTC） or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphae-roides, an antagonist of toll-like receptor 4（TLR4）, blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawalinduced pain hypersensitivity.

关键词： nuclear factor-κB pro-inflammatory cytokines Toll-like receptor 4 morphine tolerance hyperalgesia

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Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

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Neuroscience Bulletin 2012年第2期28卷 182-192页

作者： Hai-Jing Chen Wei-Yan Xie Fang Hu Ying Zhang Jun Wang Yun Wang Neuroscience Research Institute Peking University Department of Neurobiology School of Basic Medical SciencesPeking University Beij＇ing 100191 China Beijing Neurosurgical Institute Beijing Tiantan Hospital Affiliated to Capital Medical University Beijing 100050 China Department of Anatomy and Histology School of Basic Medical Sciences Peking University Beo＇ing 100191 China

Objective Our previous study identified Threonine 161 （Thr-161）, located in the second intracellular loop of the 6-opioid receptor （DOR）, as the only consensus phosphorylation Cdte for cyclin-dqpendent kinase 5 （CdkS）. The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund＇s adjuvant （CFA）-induced inflammatory pain and morphine tolerance. Methods Dorsal root ganglion （DRG） neurons of rats with CFA-induced in- flammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 （pThr-161-DOR）, and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Results Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. lntrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR （Tat-DOR-2L） increased inflammatory hypersensitivity, and inhibited DOR- but not μ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Conclusion Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr- 161 attenuates morphine tolerance.

关键词： inflammatory hypersensitivity cyclin-dependent kinase 5 6-opioid receptor morphine tolerance

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morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance

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Journal of Molecular Cell Biology 2019年第12期11卷 1056-1068页

作者： Hong Kong Chun-Yi Jiang Liang Hu Peng Teng Yan Zhang Xiu-Xiu Pan Xiao-Di Sun Wen-Tao Liu Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University Department of PharmacologyNanjing Medical UniversityNanjingChina Research Division of Pharmacology China Pharmaceutical UniversityNanjingChina Department of Anesthesiology The First Affiliated Hospital of Nanjing Medical UniversityNanjingChina Department of Pharmacy Sir Run Run Shaw Hospital Affiliated to Nanjing Medical UniversityNanjingChina

The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.

关键词： mitophagy PINK1 Parkin ROS SQSTM1/p62 morphine tolerance

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Intrathecal co-administration of ketamine and morphine preventing activation of astrocytes and decreasing releases of IL-1β and IL-6 from spinal cord in rats of morphine tolerance

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Journal of Nanjing Medical University 2005年第5期19卷 227-231页

作者： Daolin Jian Yuke Tian Department of Anesthesiology TongjiHospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective： To investigate the effects of intrathecal administration of ketamine, a non-competitive N-methy-D-aspartate receptor antagonist, combined with morphine on the activation of astrocytes and releases of IL-1β and IL-6 from spinal cord in the rats of morphine tolerance. Methods： Twenty-seven Sprague-Dawley male rats were randomly divided into sham-operated, morphine tolerance, and morphine plus ketamine group. The subarachnoid catheterication of all the rats was prepared by the method of Jianping Yang. morphine 20μg in 10μl was adminstrated intrathecally to induce spinal morphine tolerance once daily for 5 consecutive days. morphine and ketamine 250μg in 10μl total volume was given in morphine plus ketamine group. Three groups all received intrathecal morphine 5μg in 10μl for morphine challenge test at 24h after last administration of the morphine. After morphine challenge test, lumbar spinal tissues were taken for measurement of glial fibrillary acidic protein （GFAP） of astrocyte in lumbar spinal horn cord by immunohistochemistry and IL-1β and IL-6 of spinal cord by ELISA. Results： The decrease of %MPE induced by chronic intrathecal morphine was inhibibed by ketamine and hyperalgesia and allodynia induced by morphine-withdrawl were alleviated. The average areas, the average absorbency （A^-）, the integral absorbency （A） of GFAP immuno-reactive cells in the dorsal horn, and IL-1β and IL-6 of spinal cord were significantly larger in morphine tolerance group than in morphine plus ketamine group. Conclusion：Co-administration of ketamine and morphine enhance antinociceptive effect of morphine and prevent the development of morphine tolerance. Ketamine might attenuate the activation of astrocytes and inhibit the release of IL-1β and IL-6 from spinal cord in repeated intrathecal morphine rats.

关键词： morphine tolerance ketamine N-methy-D-aspartate receptor astrocyte proinflammatory cytoldne

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The changes of TTX-resistant currents in DRG neurons from rats with morphine tolerance and visceral hyperalgesia

The changes of TTX-resistant currents in DRG neurons from ra...

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2002全国青年药理学英文学术会议

作者： CHEN Jing-hong, LIU Yin, DONG Hua-jin, GONG Ze-hui, QIN Bo-yi(Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China)

AIM The recent discovery of a tetrodotoxin-resistant voltage-gated Na channel (TTX-R Na channel), which has a specific distribution and role in sensory processing and nociception, has provided a promise target for pharmaceutical intervention. Blockade of the channel expression or function may produce analgesia without side effects. Utilizing the experiment of colorectal distension in awake rats, we found that morphine tolerance result in the phenomenon of visceral hyperalgesia. And visceral hyperalgesia also could be induced by the persistent inflammation in our previously studies. DRG neurons are the starting-point of the somatic and visceral pain pathway, and following some injuries, these

关键词： morphine tolerance visceral hyperalgesia DRG TTX-resistant Na+ channel

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Multiple glial-neuronal dialogues in morphine tolerance:role of P2X7 receptor downstream cascades in the spinal cord

Multiple glial-neuronal dialogues in morphine tolerance:role...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Meng-Ling CHEN~#,Hong CAO~#,Long-Zhen CHENG,Yu-Xia CHU,Yu-Qiu ZHANG,Zhi-Qi ZHAO~* Institute of Neurobiology,Institutes of Brain Science & State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200032,China

Objective morphine is a potent analgesic.However,its clinical application is restricted due to morphine tolerance.The underlying mechanism is not fully understood.Glia are thought to be involved in morphine tolerance, and P2X purinergic receptor(P2XR) has been implicated in neuron- glia communication and chronic pain. This study investigated microglia-expressed P2X receptor(P2XR) and its downstream mechanisms underlying the induction of tolerance to morphine analgesia in rats.Methods Behavioral tests,SiRNA,Western Blotting, immunohistochemistry,ELISA and electrophysiology methods were used in this study.Results Chronic morphine treatment induced morphine tolerance and an increase in the expression of P2XR and IL-18 by microglia,IL-18 receptor(IL-18R) by astrocytes and PKCy by neurons in the spinal cord,respectively,which was blocked by a P2XR antagonist or targeting siRNA.Meanwhile,the release of astroglial D-serine,a ligand for NMDA receptor,was increased by chronic morphine,which was attenuated by the D-serine degradation.The D-serine-mediated presynaptic mechanism may contribute to the potentiation of spinal pain-sensitive neurons by chronic morphine treatment. Conclusion The present study revealed multiple dialogues between glial and neuronal cells via cascades involving P2XRs,IL-18,D-serine,NMDARs and PKCy in morphine tolerance,which may provide novel targets for preventing morphine tolerance.

关键词： morphine tolerance P2X7 receptor IL-18 D-serine PKCy glial-neuronal dialogue

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The spinal CCL2/CCR2 signaling mediates morphine antinociceptive tolerance in rats

The spinal CCL2/CCR2 signaling mediates morphine antinocicep...

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中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： Chun-Mei ZHAO~1,Yu CHEN~2,Fen HU~1,Jian-Qiang FENG~1,Yu CUI~(1,*) 1 Department of Physiology,Zhongshan Medical College,Sun Yat-sen University,Guangzhou 510080,China 2 Department of Anesthesiology,First Facilitated Hospital,Sun Yat-Sen University,Guangzhou 510080,China

＜正＞Background:The chemokine CCL2 and its receptor CCR2 have been suggested to contribute to peripheral and central sensitization in neuropathic pain.However,whether CCL2/CCR2 signaling pathway mediates the development of morphine antinociceptive tolerance is poorly characterized.Results:Our findings showed that intrathecal chronic morphine for 7 days resulted in continuous and significant decrease in morphine analgesia, indicating the development of morphine tolerance.Compared with the behavioral data,western blotting result showed that chronic morphine exposure unregulated the CCL2 expression in neurons of spinal cord.In addition, double immunofluorescence result revealed that CCL2 expression was localized in neurons,but not in astrocyte or microglia.To uncover the role of CCL2 in morphine tolerance,CCL2 neutralizing antibody or antagonist of CCL2 receptor（CCR2）,RS 102895 was injected intrathecally before each morphine administration.We found that CCL2 neutralizing antibody or RS102895 significantly blocked the development of morphine antinociceptive tolerance. Furthermore,RS 102895 also attenuated the expression of the phosphorylated p38（p-p38） MAPK in the microglia of spinal cord.However,blocking the activity of CCL2 or CCR2 with neutralizing antibody or RS 102895 respectively has no effect on morphine analgesia following the development of tolerance.Conclusions:The present study provided new evidence that the spinal neuronal CCL2/CCR2 played an important role in mediating the development but not maintenance of morphine tolerance.CCL2/CCR2 might be a new target for preventing the development of morphine antinociceptive tolerance.

关键词： morphine tolerance CCL2 CCR2 p38 MAPK

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NLRP3 is involved in the development of morphine analgesic tolerance

NLRP3 is involved in the development of morphine analgesic t...

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中国神经科学学会第十二届全国学术会议

作者： Yuanhang Zhu Hua Jin Da-lin Chen Xin-nan Li Yu-jin Li Gao-peng Xiao Guang-qiong Guo Department of Anesthesiology the First People's Hospital of Yunnan Province Medical Faculty Kunming University of Science and Technology

Objective: Microglia-mediated inflammation plays an important role in morphine tolerance. However, the underlying mechanism remains largely unknown. Nucleotidebinding domain-like protein 3（NLRP3） is an important member of nucleotide-binding oligomerization domain-like receptor family, which could recognize a variety of pathogen-and host-derived "danger" signals. NLPR3 can form inflammasome with adaptor protein ASC and pro-caspase-1, which is a multiprotein complexe that can activate caspase-1 and ultimately lead to the processing and secretion of interleukin（IL）-1β and IL-18. The present study is to explore the role of NLRP3 in morphine tolerance in vivo and in vitro. Methods: The antinociceptive responses were determined by mechanical（Von Frey filaments） and thermal（tail-flick） test paradigms. The levels of protein and m RNA are examined by Western Blot and RT-PCR methods. Results:（1） morphine induced the activation of NLRP3 inflammasome.（2） The inhibition of NLRP3 inflammasome suppresses the development of morphine analgesic tolerance.（3） morphine activates NLRP3 inflammasome by activating the P2 X7 receptor signaling pathway, thereby promoting the maturation and release of IL-1β and IL-18. Conclusion: These results confirm that NLRP3 inflammasome is involved in the development of morphine analgesic tolerance and elucidates the signaling pathway of morphine-activated NLRP3 inflammasome. This study provides a new target for the effective prevention and treatment of morphine analgesic tolerance.

关键词： morphine tolerance NLRP3 inflammasome inflammation

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