Yuji Odagaki, Masakazu Kinoshita, J Javier Meana, Luis F Callado, Jesús A García-Sevilla
{"title":"5-HT<sub>2A</sub> receptor- and M<sub>1</sub> muscarinic acetylcholine receptor-mediated activation of Gα<sub>q/11</sub> in postmortem dorsolateral prefrontal cortex of opiate addicts.","authors":"Yuji Odagaki, Masakazu Kinoshita, J Javier Meana, Luis F Callado, Jesús A García-Sevilla","doi":"10.1007/s43440-021-00248-w","DOIUrl":"https://doi.org/10.1007/s43440-021-00248-w","url":null,"abstract":"<p><strong>Background: </strong>Chronic exposure to opiates causes the development of tolerance and physical dependence as well as persistent brain neuroplasticity. Despite a wealth of postmortem human studies for opiate addicts, little direct information regarding the functional status of serotonergic and cholinergic receptor-mediated signaling pathways in the human brain of opiate addicts is yet available.</p><p><strong>Methods: </strong>Functional activation of Gα<sub>q/11</sub> proteins coupled to 5-HT<sub>2A</sub> and M<sub>1</sub> type muscarinic acetylcholine receptor (mAChR) was assessed by using the method named [<sup>35</sup>S]GTPγS binding/immunoprecipitation in frontal cortical membrane preparations from postmortem human brains obtained from opiate addicts and matched controls.</p><p><strong>Results: </strong>Concentration-response curves for 5-HT and carbachol in individual subjects were analyzed according to a nonlinear regression model, which generated the values of maximum percent increase (%E<sub>max</sub>), negative logarithm of the half-maximal effect (pEC<sub>50</sub>) and slope factor. As for 5-HT<sub>2A</sub> receptor-mediated Gα<sub>q/11</sub> activation, the %E<sub>max</sub> values were reduced significantly and the pEC<sub>50</sub> values were decreased significantly in opiate addicts as compared to the control group. Regarding carbachol-induced Gα<sub>q/11</sub> activation, no significant difference in %E<sub>max</sub> or pEC<sub>50</sub> values was detected between the both groups, whereas the slope factor was increased significantly in opiate addicts as compared to the control group.</p><p><strong>Conclusion: </strong>Our data demonstrate that the signaling pathways mediated by Gα<sub>q/11</sub> proteins coupled with 5-HT<sub>2A</sub> receptors and M<sub>1</sub> mAChRs in prefrontal cortex are functionally altered in opiate addicts in comparison with control subjects. These alterations may underpin some aspects of addictive behavior to opiate as well as neuropsychological consequences or comorbid mental disorders associated with opioid use.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1155-1163"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00248-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25585037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Artur Pałasz, Piotr Żarczyński, Katarzyna Bogus, Kinga Mordecka-Chamera, Alessandra Della Vecchia, Jakub Skałbania, John J Worthington, Marek Krzystanek, Małgorzata Żarczyńska
{"title":"Modulatory effect of olanzapine on SMIM20/phoenixin, NPQ/spexin and NUCB2/nesfatin-1 gene expressions in the rat brainstem.","authors":"Artur Pałasz, Piotr Żarczyński, Katarzyna Bogus, Kinga Mordecka-Chamera, Alessandra Della Vecchia, Jakub Skałbania, John J Worthington, Marek Krzystanek, Małgorzata Żarczyńska","doi":"10.1007/s43440-021-00267-7","DOIUrl":"https://doi.org/10.1007/s43440-021-00267-7","url":null,"abstract":"<p><strong>Background: </strong>Phoenixin, spexin and nesfatin-1 belong to a family of newly discovered multifunctional neuropeptides that play regulatory roles in several brain structures and modulate the activity of important neural networks. However, little is known about their expression and action at the level of brainstem. The present work was, therefore, focused on gene expression of the aforementioned peptides in the brainstem of rats chronically treated with olanzapine, a second generation antipsychotic drug.</p><p><strong>Methods: </strong>Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the brainstem excised. Total mRNA was isolated from homogenized samples of both structures and the RT-PCR method was used for estimation of related SMIM20/phoenixin, NPQ/spexin and NUCB2/nesfatin-1 gene expression.</p><p><strong>Results: </strong>Long-term treatment with olanzapine is reflected in qualitatively different changes in expression of examined neuropeptides mRNA in the rat brainstem. Olanzapine significantly decreased NPQ/spexin mRNA expression, but increased SMIM20/phoenixin mRNA level in the rat brainstem; while NUCB2/nesfatin-1 mRNA expression remained unchanged.</p><p><strong>Conclusions: </strong>Olanzapine can affect novel peptidergic signaling in the rat brainstem. This may cautiously suggest the presence of an alternative mode of its action.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1188-1194"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00267-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38866963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iker Egusquiza, Eva Munarriz-Cuezva, Rafael Segarra, Javier González-Maeso, Luis F Callado, J Javier Meana, Rebeca Diez-Alarcia
{"title":"Characterization of dopamine D<sub>2</sub> receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.","authors":"Iker Egusquiza, Eva Munarriz-Cuezva, Rafael Segarra, Javier González-Maeso, Luis F Callado, J Javier Meana, Rebeca Diez-Alarcia","doi":"10.1007/s43440-021-00305-4","DOIUrl":"https://doi.org/10.1007/s43440-021-00305-4","url":null,"abstract":"<p><strong>Background: </strong>Alterations of dopamine D<sub>1</sub> (D1R) and D<sub>2</sub> receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects.</p><p><strong>Methods: </strong>G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [<sup>35</sup>S]GTPγS-binding stimulation induced by increasing concentrations (10<sup>-10</sup>-10<sup>-3</sup> M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of [<sup>35</sup>S]GTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17).</p><p><strong>Results: </strong>In caudate, [<sup>35</sup>S]GTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [<sup>35</sup>S]GTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC<sub>50H</sub> = 7.94 nM; EC<sub>50L</sub> = 7.08 μM) and control (EC<sub>50H</sub> = 7.24 nM; EC<sub>50L</sub> = 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters.</p><p><strong>Conclusions: </strong>Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [<sup>35</sup>S]GTPγS-binding assays appears to be restricted to signalling through inhibitory G<sub>i/o</sub> proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1136-1146"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00305-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39128591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Special issue \"role of G-proteins and GPCR-mediated signaling in the pathophysiology and treatment of psychiatric disorders\".","authors":"Yuji Odagaki, J Javier Meana","doi":"10.1007/s43440-021-00313-4","DOIUrl":"https://doi.org/10.1007/s43440-021-00313-4","url":null,"abstract":"","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"967-969"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00313-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39300999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jakub Skałbania, Artur Pałasz, Iwona Błaszczyk, Aleksandra Suszka-Świtek, Marek Krzystanek, Karina Paola Tulcanaz, John J Worthington, Kinga Mordecka-Chamera
{"title":"Chlorpromazine affects the numbers of Sox-2, Musashi1 and DCX-expressing cells in the rat brain subventricular zone.","authors":"Jakub Skałbania, Artur Pałasz, Iwona Błaszczyk, Aleksandra Suszka-Świtek, Marek Krzystanek, Karina Paola Tulcanaz, John J Worthington, Kinga Mordecka-Chamera","doi":"10.1007/s43440-021-00259-7","DOIUrl":"https://doi.org/10.1007/s43440-021-00259-7","url":null,"abstract":"<p><strong>Background: </strong>Adult neurogenesis observed both in the subventricular zone (SVZ) and hippocampus may be regulated and modulated by several endogenous factors, xenobiotics and medications. Classical and atypical antipsychotic drugs are able to affect neuronal and glial cell proliferation in the rat brain. The main purpose of this structural study was to determine whether chronic chlorpromazine treatment affects adult neurogenesis in the canonical sites of the rat brain. At present, the clinical application of chlorpromazine is rather limited; however, it may still represent an important model in basic neuropharmacological and toxicological studies.</p><p><strong>Methods: </strong>The number of neural progenitors and immature neurons was enumerated using immunofluorescent detection of Sox2, Musashi1 and doublecortin (DCX) expression within SVZ.</p><p><strong>Results: </strong>Chlorpromazine has a depressive effect on the early phase of adult neurogenesis in the rat subventricular zone (SVZ), as the mean number of Sox-2 immunoexpressing cells decreased following treatment.</p><p><strong>Conclusion: </strong>Collectively, these results may suggest that long-term treatment with chlorpromazine may decrease neurogenic stem/progenitor cell formation in the rat SVZ and may affect rostral migratory stream formation.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1164-1169"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00259-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25598833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebeca Diez-Alarcia, Yuji Odagaki, Patricia Miranda-Azpiazu, Ane M Gabilondo, J Javier Meana, Itziar Muneta-Arrate
{"title":"Correction to: Functional approaches to the study of G-protein-coupled receptors in postmortem brain tissue: [<sup>35</sup>S]GTPγS binding assays combined with immunoprecipitation.","authors":"Rebeca Diez-Alarcia, Yuji Odagaki, Patricia Miranda-Azpiazu, Ane M Gabilondo, J Javier Meana, Itziar Muneta-Arrate","doi":"10.1007/s43440-021-00268-6","DOIUrl":"https://doi.org/10.1007/s43440-021-00268-6","url":null,"abstract":"","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1203"},"PeriodicalIF":4.4,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00268-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38955497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cem Süer, Nurbanu Yıldız, Özlem Barutçu, Burak Tan, Nurcan Dursun
{"title":"Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus.","authors":"Cem Süer, Nurbanu Yıldız, Özlem Barutçu, Burak Tan, Nurcan Dursun","doi":"10.1007/s43440-021-00254-y","DOIUrl":"https://doi.org/10.1007/s43440-021-00254-y","url":null,"abstract":"<p><strong>Background: </strong>The present study examined whether inhibition of guanylate cyclase (GC) is associated with the plasticity-related microtubule-stabilizing protein tau phosphorylation in the dentate gyrus (DG) of hippocampal formation.</p><p><strong>Methods: </strong>To address this issue, methylene blue (MB 50 μM) or saline was infused into the DG starting from the induction of long-term potentiation (LTP) or depression (LTD) for 1 h. Then, protein phosphatase 1 alpha (PP1α), glycogen synthase kinase 3 beta (GSK3β), and tau total and phosphorylated protein levels were measured in these hippocampi using western blotting. LTP and LTD were induced by application of high- and low-frequency stimulation protocols (HFS and LFS), respectively. 5-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike amplitudes at the end of recording were averaged to measure the magnitude of LTP or LTD.</p><p><strong>Results: </strong>Low-frequency stimulation protocols was unable to phosphorylate thr<sup>181</sup> and thr<sup>231</sup>epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser<sup>396</sup> and ser<sup>416</sup> epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser<sup>396</sup> and ser<sup>416</sup> epitopes, without changing tau phosphorylation at thr<sup>181</sup> and thr<sup>231</sup> epitopes. Neither LTP nor LTP-related tau phosphorylation state was changed by MB infusion.</p><p><strong>Conclusion: </strong>Although MB can benefit to stabilize the balance between LTP and LTD, and to fix the increased spike wave discharges, it might trigger deregulation of tau phosphorylation, leading to the development of Alzheimer's disease by a mechanism that goes awry during induction of LTD. Thereby detailed studies to reveal more precise evidence for the use of MB in this disease are needed.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"828-840"},"PeriodicalIF":4.4,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00254-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25541446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The differential functional coupling of phosphodiesterase 4 to human DP and EP2 prostanoid receptors stimulated with PGD<sub>2</sub> or PGE<sub>2</sub>.","authors":"Iori Okura, Nanae Hasuoka, Kanaho Senoo, Akiko Suganami, Keijo Fukushima, John W Regan, Masato Mashimo, Toshihiko Murayama, Yutaka Tamura, Hiromichi Fujino","doi":"10.1007/s43440-021-00247-x","DOIUrl":"https://doi.org/10.1007/s43440-021-00247-x","url":null,"abstract":"<p><strong>Background: </strong>Human DP and EP2 receptors are two of the most homologically related receptors coupling with G<sub>α</sub>s-protein, which stimulate adenylyl cyclase to produce cAMP. Indeed, both receptors are considered to be generated by tandem duplication. It has been reported that other highly homologous and closely related β1- and β2-adrenergic receptors interact distinctly with and differentially regulate cAMP-specific phosphodiesterase (PDE) 4 recruitment.</p><p><strong>Methods: </strong>First, we focused on the cAMP degradation pathways of DP and EP2 receptors stimulated by prostaglandin (PG) D<sub>2</sub> or PGE<sub>2</sub> using HEK cells stably expressing either human DP receptors or EP2 receptors. Then, distances between ligands and amino acids of the receptors were evaluated by molecular dynamics (MD) analysis.</p><p><strong>Results: </strong>We found that PGD<sub>2</sub>/EP2 receptors exerted a greater effect on PDE4 activity than PGE<sub>2</sub>/EP2 receptors. Moreover, by MD analysis, either the PGD<sub>2</sub> or EP2 receptor was moved and the distance was shortened between them. According to the results, DP receptors retain reactivity for PGE<sub>2</sub>, but EP2 receptors may be activated only by PGE<sub>2</sub>, at least in terms of cAMP formation, through the differential functional coupling of PDE4 probably with β-arrestin.</p><p><strong>Conclusion: </strong>Since DP receptors and EP2 receptors are considered to be duplicated genes, DP receptors may still be in a rapid evolutionary stage as a duplicated copy of EP2 receptors and have not yet sufficient selectivity for their cognate ligand, PGD<sub>2</sub>.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"946-953"},"PeriodicalIF":4.4,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00247-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25547582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ginsenoside from ginseng: a promising treatment for inflammatory bowel disease.","authors":"Zengping Kang, Youbao Zhonga, Tiantian Wu, Jiaqi Huang, Haimei Zhao, Duanyong Liu","doi":"10.1007/s43440-020-00213-z","DOIUrl":"https://doi.org/10.1007/s43440-020-00213-z","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is an autoimmune disease mediated by immune disorder and termed as one of the most refractory diseases by the Word Health Organization. Its morbidity has increased steadily over the past half century worldwide. Environmental, genetic, infectious, and immune factors are integral to the pathogenesis of IBD. Commonly known as the king of herbs, ginseng has been consumed in many countries for the past 2000 years. Its active ingredient ginsenosides, as the most prominent saponins of ginseng, have a wide range of pharmacological effects. Recent studies have confirmed that the active components of Panax ginseng have anti-inflammatory and immunomodulatory effects on IBD, including regulating the balance of immune cells, inhibiting the expression of cytokines, as well as activating Toll-like receptor 4, Nuclear factor-kappa B (NF-κB), nucleotide-binding oligomerization domain-like receptor (NLRP), mitogen-activated protein kinase signaling, and so on. Accumulated evidence indicates that ginsenosides may serve as a potential novel therapeutic drug or health product additive in IBD prevention and treatment in the future.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"700-711"},"PeriodicalIF":4.4,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-020-00213-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38832757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibitory effect of intrathecally administered AM404, an endocannabinoid reuptake inhibitor, on neuropathic pain in a rat chronic constriction injury model.","authors":"Yasunori Haranishi, Koji Hara, Tadanori Terada","doi":"10.1007/s43440-021-00250-2","DOIUrl":"https://doi.org/10.1007/s43440-021-00250-2","url":null,"abstract":"<p><strong>Background: </strong>The endocannabinoid system modulates a wide variety of pain conditions. Systemically administered AM404, an endocannabinoid reuptake inhibitor, exerts antinociceptive effects via activation of the endocannabinoid system. However, the mechanism and site of AM404 action are not fully understood. Here, we explored the effect of AM404 on neuropathic pain at the site of the spinal cord.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of intrathecal administration of AM404 on mechanical and cold hyperalgesia were examined using the electronic von Frey test and cold plate test, respectively. Motor coordination was assessed using the rotarod test. To understand the mechanisms underlying the action of AM404, we tested the effects of pretreatment with the cannabinoid type 1 (CB<sub>1</sub>) receptor antagonist AM251, CB<sub>2</sub> receptor antagonist AM630, and transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine.</p><p><strong>Results: </strong>AM404 attenuated mechanical and cold hyperalgesia with minimal effects on motor coordination. AM251 significantly inhibited the antihyperalgesic action of AM404, whereas capsazepine showed a potentiating effect.</p><p><strong>Conclusions: </strong>These results indicate that AM404 exerts antihyperalgesic effects primarily via CB<sub>1</sub>, but not CB<sub>2</sub>, receptor activation at the site of the spinal cord. TRPV1 receptors appear to play a pronociceptive role in CCI rats. The endocannabinoid reuptake inhibitor may be a promising candidate treatment for neuropathic pain.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"820-827"},"PeriodicalIF":4.4,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s43440-021-00250-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25544979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}