Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons
Kaurenoic acid (KA) is a diterpene extracted from <i>Sphagneticola trilobata</i> (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the pre...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/3/343 |
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| author | Tiago H. Zaninelli Sandra S. Mizokami Mariana M. Bertozzi Telma Saraiva-Santos Felipe A. Pinho-Ribeiro Gabriele Inácio de Oliveira Renata Streck Eduardo J. A. Araújo Nilton S. Arakawa Sergio M. Borghi Rubia Casagrande Waldiceu A. Verri |
| author_facet | Tiago H. Zaninelli Sandra S. Mizokami Mariana M. Bertozzi Telma Saraiva-Santos Felipe A. Pinho-Ribeiro Gabriele Inácio de Oliveira Renata Streck Eduardo J. A. Araújo Nilton S. Arakawa Sergio M. Borghi Rubia Casagrande Waldiceu A. Verri |
| author_sort | Tiago H. Zaninelli |
| collection | DOAJ |
| description | Kaurenoic acid (KA) is a diterpene extracted from <i>Sphagneticola trilobata</i> (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7–14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia. |
| first_indexed | 2024-03-11T06:02:56Z |
| format | Article |
| id | doaj.art-1b65d1b86344463d8c4cc642199b5b10 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T06:02:56Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-1b65d1b86344463d8c4cc642199b5b102023-11-17T13:11:28ZengMDPI AGPharmaceuticals1424-82472023-02-0116334310.3390/ph16030343Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia NeuronsTiago H. Zaninelli0Sandra S. Mizokami1Mariana M. Bertozzi2Telma Saraiva-Santos3Felipe A. Pinho-Ribeiro4Gabriele Inácio de Oliveira5Renata Streck6Eduardo J. A. Araújo7Nilton S. Arakawa8Sergio M. Borghi9Rubia Casagrande10Waldiceu A. Verri11Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilDepartment of Pharmaceutical Sciences, Center of Health Sciences, Londrina State University, Londrina 86039-440, Paraná, BrazilDepartment of Histology, Londrina State University, Londrina 86057-970, Paraná, BrazilDepartment of Histology, Londrina State University, Londrina 86057-970, Paraná, BrazilDepartment of Pharmaceutical Sciences, Center of Health Sciences, Londrina State University, Londrina 86039-440, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilDepartment of Pharmaceutical Sciences, Center of Health Sciences, Londrina State University, Londrina 86039-440, Paraná, BrazilLaboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, BrazilKaurenoic acid (KA) is a diterpene extracted from <i>Sphagneticola trilobata</i> (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7–14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia.https://www.mdpi.com/1424-8247/16/3/343neuropathic painchronic constriction injuryCCInitric oxideanalgesia<i>Sphagneticola trilobata</i> |
| spellingShingle | Tiago H. Zaninelli Sandra S. Mizokami Mariana M. Bertozzi Telma Saraiva-Santos Felipe A. Pinho-Ribeiro Gabriele Inácio de Oliveira Renata Streck Eduardo J. A. Araújo Nilton S. Arakawa Sergio M. Borghi Rubia Casagrande Waldiceu A. Verri Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons Pharmaceuticals neuropathic pain chronic constriction injury CCI nitric oxide analgesia <i>Sphagneticola trilobata</i> |
| title | Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons |
| title_full | Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons |
| title_fullStr | Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons |
| title_full_unstemmed | Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons |
| title_short | Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons |
| title_sort | kaurenoic acid reduces ongoing chronic constriction injury induced neuropathic pain nitric oxide silencing of dorsal root ganglia neurons |
| topic | neuropathic pain chronic constriction injury CCI nitric oxide analgesia <i>Sphagneticola trilobata</i> |
| url | https://www.mdpi.com/1424-8247/16/3/343 |
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