The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition
Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/6/1546 |
| _version_ | 1797595998303813632 |
|---|---|
| author | Vittoria Borgonetti Claudia Mugnaini Federico Corelli Nicoletta Galeotti |
| author_facet | Vittoria Borgonetti Claudia Mugnaini Federico Corelli Nicoletta Galeotti |
| author_sort | Vittoria Borgonetti |
| collection | DOAJ |
| description | Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions. |
| first_indexed | 2024-03-11T02:45:18Z |
| format | Article |
| id | doaj.art-f59ee93fa91a490695af397952da4507 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T02:45:18Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-f59ee93fa91a490695af397952da45072023-11-18T09:24:53ZengMDPI AGBiomedicines2227-90592023-05-01116154610.3390/biomedicines11061546The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 InhibitionVittoria Borgonetti0Claudia Mugnaini1Federico Corelli2Nicoletta Galeotti3Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, ItalyNeuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions.https://www.mdpi.com/2227-9059/11/6/1546CB2 receptor agonistcannabinoid systemneuropathic painmicrogliaHDAC1 |
| spellingShingle | Vittoria Borgonetti Claudia Mugnaini Federico Corelli Nicoletta Galeotti The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition Biomedicines CB2 receptor agonist cannabinoid system neuropathic pain microglia HDAC1 |
| title | The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition |
| title_full | The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition |
| title_fullStr | The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition |
| title_full_unstemmed | The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition |
| title_short | The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition |
| title_sort | selective cb2 agonist cor167 reduced symptoms in a mice model of trauma induced peripheral neuropathy through hdac 1 inhibition |
| topic | CB2 receptor agonist cannabinoid system neuropathic pain microglia HDAC1 |
| url | https://www.mdpi.com/2227-9059/11/6/1546 |
| work_keys_str_mv | AT vittoriaborgonetti theselectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT claudiamugnaini theselectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT federicocorelli theselectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT nicolettagaleotti theselectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT vittoriaborgonetti selectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT claudiamugnaini selectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT federicocorelli selectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition AT nicolettagaleotti selectivecb2agonistcor167reducedsymptomsinamicemodeloftraumainducedperipheralneuropathythroughhdac1inhibition |