PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease
Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/15007 |
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| author | Maha I. Sulaiman Wafaa Alabsi Lajos Szabo Meredith Hay Robin Polt Tally M. Largent-Milnes Todd W. Vanderah |
| author_facet | Maha I. Sulaiman Wafaa Alabsi Lajos Szabo Meredith Hay Robin Polt Tally M. Largent-Milnes Todd W. Vanderah |
| author_sort | Maha I. Sulaiman |
| collection | DOAJ |
| description | Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:43:05Z |
| publishDate | 2023-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c4d8185fc5ce499e9097d6c375a5250a2023-11-19T14:33:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191500710.3390/ijms241915007PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone DiseaseMaha I. Sulaiman0Wafaa Alabsi1Lajos Szabo2Meredith Hay3Robin Polt4Tally M. Largent-Milnes5Todd W. Vanderah6Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85721, USADepartment of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USADepartment of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USAThe BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USADepartment of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85721, USAPain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.https://www.mdpi.com/1422-0067/24/19/15007PNA6Angiotensin-(1-7)mas receptorbreastcancerpain |
| spellingShingle | Maha I. Sulaiman Wafaa Alabsi Lajos Szabo Meredith Hay Robin Polt Tally M. Largent-Milnes Todd W. Vanderah PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease International Journal of Molecular Sciences PNA6 Angiotensin-(1-7) mas receptor breast cancer pain |
| title | PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease |
| title_full | PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease |
| title_fullStr | PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease |
| title_full_unstemmed | PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease |
| title_short | PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease |
| title_sort | pna6 a lactosyl analogue of angiotensin 1 7 reverses pain induced in murine models of inflammation chemotherapy induced peripheral neuropathy and metastatic bone disease |
| topic | PNA6 Angiotensin-(1-7) mas receptor breast cancer pain |
| url | https://www.mdpi.com/1422-0067/24/19/15007 |
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