Neuropharmacology最新文献_第5页

Long-term folic acid treatment relieves chronic inflammatory pain and pain-induced anxiety by reducing MMP2 expression in rats

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-10 DOI: 10.1016/j.neuropharm.2025.110352

Wen-Hui Ni , Ke Wang , Yun Wang , Jia Lu , Chun-Ting Lu , Wen Rong , Yi-Feng Gu , Wen-Juan Qian , Hai-Long Zhang

Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.

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引用次数: 0

Synergistic insights into positive allosteric modulator and agonist using Gaussian accelerated and tau random acceleration simulations in the metabotropic glutamate receptor 2

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-08 DOI: 10.1016/j.neuropharm.2025.110351

Baoyu He , Longfei Mao , Lili Xi , Jingjing Guo

Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. Related research shows activating metabotropic glutamate receptors holds therapeutic potential. Agonist-positive allosteric modulations (ago-PAMs) not only activate metabotropic glutamate receptors but also enhance glutamate-induced responses, offering a promising treatment strategy. However, the molecular mechanisms by which ago-PAM enhances glutamate-induced responses remain unclear, as does the potential influence of glutamate on ago-PAM. In this study, Gaussian accelerated molecular dynamics and tau random acceleration molecular dynamics simulations were employed to investigate the molecular mechanism between ago-PAM and glutamate in full-length mGlu₂. Results suggest that the ago-PAM JNJ-46281222 enhances the binding affinity and residence time of glutamates in the Venus flytrap (VFT) domains by initiating a variant reverse communication from the heptahelical transmembrane (7TM) domains to VFTs via the cysteine-rich domains. Meanwhile, glutamate facilitates the interaction between Trp676 and Glu701 to further induce the relaxation of TM5, promoting the opening of the PAM-binding pocket. Glutamate can also promote the upward rotation of the cyclopropylmethyl group of the JNJ-46281222 to bring the TM6-TM6 distance closer. Nevertheless, it remains uncertain how the binding between mGlu₂ and G protein differs when induced by small molecules binding in allosteric sites, orthosteric sites, or both. In conclusion, this study shed new light on the positive coordination relationship between ago-PAM and glutamate in the full-length mGlu₂ receptor, which could help develop novel and more effective ago-PAM to treat schizophrenia.

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引用次数: 0

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-08 DOI: 10.1016/j.neuropharm.2025.110345

Alev Ecevitoglu , Renee A. Rotolo , Gayle A. Edelstein , Alexandra Goldhamer , Matthew Mitola , Rose E. Presby , Abigail Yu , Deanna Pietrorazio , Emma Zorda , Merce Correa , John D. Salamone

Dopamine (DA) regulates behavioral activation and effort-related aspects of motivation. Blockade of DA storage by tetrabenazine (TBZ) induces depressive symptoms in humans, including fatigue and apathy. TBZ shifts choice behavior in rodents from high-effort to low-effort options, which can be used to model motivational symptoms observed in psychiatric disorders. The catecholamine transport inhibitor methylphenidate (MPH) reverses the effort-related effects of TBZ in male rats, but this effect needs to be investigated in females. The current study examined the effects of MPH on effort-based choice in male and female rats. Animals were tested on the fixed ratio 5 (FR5)/chow feeding choice task. Because of sex differences in the effects of TBZ, 1.0 mg/kg was used in males, while 2.0 mg/kg was used in females. In both sexes, TBZ shifted choice from lever pressing to chow intake. Co-administration of MPH reversed the effort-related effects of TBZ in males at all doses tested (0.5–4.0 mg/kg IP), whereas only 1.0 and 2.0 mg/kg MPH reversed the effects of TBZ in females. Rats also were tested on a progressive ratio (PROG) schedule and a PROG/chow feeding choice task to assess the effects of MPH administered alone (0.5–4.0 mg/kg IP). MPH increased high-effort PROG responding on both tasks in males, whereas females showed no significant increase in lever pressing across the dose range tested. Investigating sex differences in the pharmacology and neurochemistry of effort-based choice enhances our understanding of sex as a factor in motivational dysfunctions, and may foster the development of treatments for effort-related psychiatric symptoms.

{"title":"Effort-related motivational effects of methylphenidate: Reversal of the low-effort bias induced by tetrabenazine and enhancement of progressive ratio responding in male and female rats","authors":"Alev Ecevitoglu , Renee A. Rotolo , Gayle A. Edelstein , Alexandra Goldhamer , Matthew Mitola , Rose E. Presby , Abigail Yu , Deanna Pietrorazio , Emma Zorda , Merce Correa , John D. Salamone","doi":"10.1016/j.neuropharm.2025.110345","DOIUrl":"10.1016/j.neuropharm.2025.110345","url":null,"abstract":"<div><div>Dopamine (DA) regulates behavioral activation and effort-related aspects of motivation. Blockade of DA storage by tetrabenazine (TBZ) induces depressive symptoms in humans, including fatigue and apathy. TBZ shifts choice behavior in rodents from high-effort to low-effort options, which can be used to model motivational symptoms observed in psychiatric disorders. The catecholamine transport inhibitor methylphenidate (MPH) reverses the effort-related effects of TBZ in male rats, but this effect needs to be investigated in females. The current study examined the effects of MPH on effort-based choice in male and female rats. Animals were tested on the fixed ratio 5 (FR5)/chow feeding choice task. Because of sex differences in the effects of TBZ, 1.0 mg/kg was used in males, while 2.0 mg/kg was used in females. In both sexes, TBZ shifted choice from lever pressing to chow intake. Co-administration of MPH reversed the effort-related effects of TBZ in males at all doses tested (0.5–4.0 mg/kg IP), whereas only 1.0 and 2.0 mg/kg MPH reversed the effects of TBZ in females. Rats also were tested on a progressive ratio (PROG) schedule and a PROG/chow feeding choice task to assess the effects of MPH administered alone (0.5–4.0 mg/kg IP). MPH increased high-effort PROG responding on both tasks in males, whereas females showed no significant increase in lever pressing across the dose range tested. Investigating sex differences in the pharmacology and neurochemistry of effort-based choice enhances our understanding of sex as a factor in motivational dysfunctions, and may foster the development of treatments for effort-related psychiatric symptoms.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110345"},"PeriodicalIF":4.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Memory enhancement by unconditioned and conditioned heroin withdrawal: Role of corticotropin-releasing factor in the central amygdala

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-07 DOI: 10.1016/j.neuropharm.2025.110341

Nana Baidoo , Aiden Shaver , Brooke Ginson , Julia Castellani , Thomas Lapointe , Michael Wolter , Francesco Leri

To test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through shared neurobiological mechanisms, the current study focused on the central amygdala (CeA) and local corticotropin-releasing factor (CRF) neurotransmission. In the unconditioned withdrawal experiments, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin (or sham surgery) and injected with 3 mg/kg naloxone (NLX) to precipitate withdrawal. In the conditioned withdrawal experiments, rats injected with heroin (2 mg/kg x 2 injections) received 3 mg/kg NLX immediately prior to confinement to one compartment (CS+) of a place conditioning apparatus, or vehicle prior to confinement in the alternative compartment (CS-). Using immunohistochemistry, it was established that both precipitated withdrawal and confinement to the withdrawal-paired CS + compartment elevated c-Fos expression within the CeA. More importantly, using the post-training approach to target consolidation of object memory, it was found that intra-CeA infusions of the CRF1 receptor antagonist ANT (0.2–2 μg/inf) blocked the memory-enhancing effects of both precipitated withdrawal and exposure to the withdrawal-paired CS + compartment. These findings indicate that pharmacological and conditioned opioid withdrawal influence memory consolidation through a common CRF-mediated mechanism within the CeA.

{"title":"Memory enhancement by unconditioned and conditioned heroin withdrawal: Role of corticotropin-releasing factor in the central amygdala","authors":"Nana Baidoo , Aiden Shaver , Brooke Ginson , Julia Castellani , Thomas Lapointe , Michael Wolter , Francesco Leri","doi":"10.1016/j.neuropharm.2025.110341","DOIUrl":"10.1016/j.neuropharm.2025.110341","url":null,"abstract":"<div><div>To test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through shared neurobiological mechanisms, the current study focused on the central amygdala (CeA) and local corticotropin-releasing factor (CRF) neurotransmission. In the unconditioned withdrawal experiments, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin (or sham surgery) and injected with 3 mg/kg naloxone (NLX) to precipitate withdrawal. In the conditioned withdrawal experiments, rats injected with heroin (2 mg/kg x 2 injections) received 3 mg/kg NLX immediately prior to confinement to one compartment (CS+) of a place conditioning apparatus, or vehicle prior to confinement in the alternative compartment (CS-). Using immunohistochemistry, it was established that both precipitated withdrawal and confinement to the withdrawal-paired CS + compartment elevated c-Fos expression within the CeA. More importantly, using the post-training approach to target consolidation of object memory, it was found that intra-CeA infusions of the CRF1 receptor antagonist ANT (0.2–2 μg/inf) blocked the memory-enhancing effects of both precipitated withdrawal and exposure to the withdrawal-paired CS + compartment. These findings indicate that pharmacological and conditioned opioid withdrawal influence memory consolidation through a common CRF-mediated mechanism within the CeA.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110341"},"PeriodicalIF":4.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Behavioral manifestations and neural mechanisms of empathic pain

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-06 DOI: 10.1016/j.neuropharm.2025.110344

Siqi Yang , Jiahui Zhang , Qi Zhang , Suwan Hu , Yawei Ji , Xiaokai Zhou , Yinbing Pan , Yuanyuan Wang

Empathy is an important trait that allows individuals to comprehend and share the emotions and sentiments of others. It not only facilitates effective interpersonal communication, but also helps in establishing meaningful connections and fostering trust and understanding. Impaired empathy development can manifest as excessive self-centeredness, extreme egoism, and antisocial behaviors. Many psychiatric disorders, such as autism, narcissistic personality disorder, and schizophrenia, are often accompanied by empathy disorders. Pain empathy, which is a common behavioral paradigm of empathic behavior, is not only observed in humans but also in animals. By delving into the study of pain empathy, we can gain a deeper understanding of empathy itself. This understanding not only contributes to the advancement of scientific, clinical, and social fields, but also promotes the cultivation of emotional resonance and social harmony among humans, with profound significance and impact. This article provides a brief overview of the current understanding and mechanistic studies of pain empathy, as well as suggests future research directions.

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引用次数: 0

Sex-specific signatures of GLP-1 and amylin on resting state brain activity and functional connectivity in awake rats

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.neuropharm.2025.110348

Tanzil M. Arefin , Stina Börchers , Doris Olekanma , Samuel R. Cramer , Morgan R. Sotzen , Nanyin Zhang , Karolina P. Skibicka

Gut-produced glucagon-like peptide-1 (GLP-1) and pancreas-made amylin robustly reduce food intake by directly or indirectly affecting brain activity. While for both peptides a direct action in the hindbrain and the hypothalamus is likely, few studies examined their impact on whole brain activity in rodents and did so evaluating male rodents under anesthesia. However, both sex and anesthesia may significantly alter the influence of feeding controlling molecules on brain activity. Therefore, we investigated the effect of GLP-1 and amylin on brain activity and functional connectivity (FC) in awake adult male and female rats using resting-state functional magnetic resonance imaging (rsfMRI). We further examined the relationship between the altered brain activity or connectivity and subsequent food intake in response to amylin or GLP-1. We observed sex divergent effects of amylin and GLP-1 on the brain activity and FC patterns. Most importantly correlation analysis between FC and feeding behavior revealed that different brain areas potentially drive reduced food intake in male and female rats. Our findings underscore the distributed and distinctly sex divergent neural network engaged by each of these anorexic peptides and suggest that different brain areas may be the primary drivers of the feeding outcome in male and female rats. Moreover, prominent activity and connectivity alterations observed in brain areas not typically associated with feeding behavior in both sexes may either indicate novel feeding centers or alternatively suggest the involvement of these substances in behaviors beyond feeding and metabolism. The latter question is of potential translational significance as analogues of both amylin and GLP-1 are clinically utilized.

{"title":"Sex-specific signatures of GLP-1 and amylin on resting state brain activity and functional connectivity in awake rats","authors":"Tanzil M. Arefin , Stina Börchers , Doris Olekanma , Samuel R. Cramer , Morgan R. Sotzen , Nanyin Zhang , Karolina P. Skibicka","doi":"10.1016/j.neuropharm.2025.110348","DOIUrl":"10.1016/j.neuropharm.2025.110348","url":null,"abstract":"<div><div>Gut-produced glucagon-like peptide-1 (GLP-1) and pancreas-made amylin robustly reduce food intake by directly or indirectly affecting brain activity. While for both peptides a direct action in the hindbrain and the hypothalamus is likely, few studies examined their impact on whole brain activity in rodents and did so evaluating male rodents under anesthesia. However, both sex and anesthesia may significantly alter the influence of feeding controlling molecules on brain activity. Therefore, we investigated the effect of GLP-1 and amylin on brain activity and functional connectivity (FC) in awake adult male and female rats using resting-state functional magnetic resonance imaging (rsfMRI). We further examined the relationship between the altered brain activity or connectivity and subsequent food intake in response to amylin or GLP-1. We observed sex divergent effects of amylin and GLP-1 on the brain activity and FC patterns. Most importantly correlation analysis between FC and feeding behavior revealed that different brain areas potentially drive reduced food intake in male and female rats. Our findings underscore the distributed and distinctly sex divergent neural network engaged by each of these anorexic peptides and suggest that different brain areas may be the primary drivers of the feeding outcome in male and female rats. Moreover, prominent activity and connectivity alterations observed in brain areas not typically associated with feeding behavior in both sexes may either indicate novel feeding centers or alternatively suggest the involvement of these substances in behaviors beyond feeding and metabolism. The latter question is of potential translational significance as analogues of both amylin and GLP-1 are clinically utilized.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110348"},"PeriodicalIF":4.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neural mechanisms, influencing factors and interventions in empathic pain

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.neuropharm.2025.110349

Furui Liu, Ziwan He, Yongjie Wang

Empathic pain, defined as the emotional resonance with the suffering of others, is akin to the observer's own experience of pain and is vital for building and sustaining positive interpersonal relationships. Despite its importance, the neural mechanism of empathic pain remains poorly understood. In this review, we integrated and summarized the currently knowledge on the neural networks associated with empathic pain, focusing on key brain regions such as the insula, anterior cingulate cortex (ACC), ventral tegmental area (VTA), nucleus accumbens (NAc), and locus coeruleus (LC)/norepinephrine (NE)-sympatho-adrenomedullar (LC/NE-SAM) system. We also reviewed the factors that affect empathic pain, including gender, personal beliefs, the intimacy of relationships, and the nature of interpersonal relationships, and highlighted the central role of the insula and ACC in the neural circuitry of empathy, the importance of the IC-BLA and ACC-NAc/VTA connections in modulating empathic pain, and the involvement of the LC/NE-SAM system in mediating pain empathy. We further discussed how gender significantly influences empathic pain, with women showing more intense emotional reactions to social distress than men. It also summarized the roles of personal pain history and empathy levels in modulating empathic responses. Furthermore, the review emphasized the impact of social factors such as the nature of interpersonal relationships and experiences of social exclusion on empathic pain. By providing a detailed exploration of the neural mechanisms and influencing factors of empathic pain, this review aims to establish a robust foundation for developing targeted therapeutic strategies and improving pain management in clinical settings.

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引用次数: 0

Antiplatelet therapy as a novel approach in Parkinson's disease: Repositioning Ticagrelor to alleviate rotenone-induced parkinsonism via modulation of ER stress, apoptosis, and autophagy

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.neuropharm.2025.110346

Muhammad Muneeb , Dalaal M. Abdallah , Hanan S. El-Abhar , Walaa Wadie , Kawkab A. Ahmed , Yasmine S. Abul Fadl

Cardiovascular diseases, such as myocardial infarction, ischemic stroke, and coronary heart ailments have been closely associated with Parkinson's disease (PD). Despite this established link, the potential neuroprotective impact of the potent antiplatelet agent ticagrelor (Tica) remains unexplored against PD. Thus, we hypothesized that Tica could be repurposed as a therapeutic agent against PD. Rotenone experimental model was adopted in Wistar male rats by administering rotenone subcutaneously on alternate days during a 21-day experimental period and treating a subset of rats with Tica orally for the last 11 consecutive days. The administration of Tica improved motor function (open field test, hanging wire test) and restored striatal histological features. Additionally, Tica opposed the rotenone effect and markedly obliterated the striatal α-synuclein content but enhanced the protein expression of tyrosine hydroxylase and dopamine content. On the molecular level, Tica inhibited striatal endoplasmic reticulum stress (ERS) as evidenced by the downregulation of the ER-resident transmembrane sensor inositol-requiring enzyme 1 alpha and its downstream molecular targets, TNF receptor-associated factor 2 and c-Jun N-terminal kinase, along with a reduction in caspase-3 activity. On the other hand, Tica augmented the autophagy machinery by upregulating the autophagosome markers Beclin-1 and light chain 3-II, while inhibiting the content of cathepsin D. Therefore, the current study is the first to accentuate the neuroprotective potential of Tica in a rat model of PD via modulating the crosstalk between ERS, apoptosis, and autophagy to represent a potential novel therapeutic candidate for managing PD, particularly in patients with or prone to cardiovascular diseases.

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引用次数: 0

The neural basis of affective empathy: What is known from rodents

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.neuropharm.2025.110347

Siqi Peng , Moyi Li , Xiuqi Yang, Wei Xie

Empathy is the cornerstone of social interactions between conspecies for human beings and other social animals. Human beings with empathy defects might either suffer unpleasant or failed social interactions as ASD patients, or even display antisocial behaviors. To find efficient cure for empathy defects, first of all, the neural mechanisms underpinning various empathy behaviors should be well studied and understood. And the research in the field of affective empathy thrives fast in recent years. It is necessary to review the important contributions in this field, especially for understanding the delicate neural mechanisms of diverse forms of affective empathy. Here, we have summarized the characteristics of various types of affective empathy. We also discuss the distinctions between empathy for pain and fear, as well as instinctive and experienced empathy. Our analysis further highlights the findings in the complex neural mechanisms and potential brain regions underlying different affective empathy behaviors. Above all, this work is expected to help enhance our comprehension of behavioral dynamics and neural basis of affective empathy along with its role in emotional regulation and social behavior.

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引用次数: 0

Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.neuropharm.2025.110343

Liu-Ying Wu , Meng-Nan Zhai , Xue-Qiang Bai , Cheng He , Yun-Ying Guo , Yu-Qi Zhang , Juan Wang , Yong-Tao Gao , Qi-Feng Tu , Mei Liu , Jun-Jie Chen , Zhi-Jun Zhang

Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.

{"title":"Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane","authors":"Liu-Ying Wu , Meng-Nan Zhai , Xue-Qiang Bai , Cheng He , Yun-Ying Guo , Yu-Qi Zhang , Juan Wang , Yong-Tao Gao , Qi-Feng Tu , Mei Liu , Jun-Jie Chen , Zhi-Jun Zhang","doi":"10.1016/j.neuropharm.2025.110343","DOIUrl":"10.1016/j.neuropharm.2025.110343","url":null,"abstract":"<div><div>Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110343"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0