PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease

Author:

Sulaiman Maha I.1,Alabsi Wafaa23,Szabo Lajos2,Hay Meredith456,Polt Robin23ORCID,Largent-Milnes Tally M.17ORCID,Vanderah Todd W.17

Affiliation:

1. Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85721, USA

2. Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA

3. Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, 1703 E. Mabel St, Tucson, AZ 85721, USA

4. The BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA

5. Department of Physiology, The University of Arizona, Tucson, AZ 85721, USA

6. Evelyn F. McKnight Brain Institute, The University of Arizona, Tucson, AZ 85721, USA

7. Comprehensive Pain and Addiction Center, University of Arizona, Tucson, AZ 85721, USA

Abstract

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.

Funder

Comprehensive Pain and Addiction Center, University of Arizona Health Sciences

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference57 articles.

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