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Ferulic acid dimer as a non-opioid therapeutic for acute pain

Authors Priebe A, Hunke M, Tonello R, Sonawane Y, Berta T, Natarajan A, Bhuvanesh N, Pattabiraman M, Chandra S

Received 30 December 2017

Accepted for publication 3 April 2018

Published 6 June 2018 Volume 2018:11 Pages 1075—1085

DOI https://doi.org/10.2147/JPR.S161161

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Minal Joshi

Peer reviewer comments 3

Editor who approved publication: Dr Katherine Hanlon

Alaini Priebe,1,* Megan Hunke,1,* Raquel Tonello,2 Yogesh Sonawane,3 Temugin Berta,2 Amarnath Natarajan,3 Nattamai Bhuvanesh,4 Mahesh Pattabiraman,5 Surabhi Chandra1

1Department of Biology, University of Nebraska-Kearney, Kearney, NE, USA; 2Department of Anesthesiology, University of Cincinnati, Cincinnati, OH, USA; 3Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Chemistry, Texas A&M University, TX, USA; 5Department of Chemistry, University of Nebraska-Kearney, Kearney, NE, USA

*These authors contributed equally to this work

Purpose: Search for alternate pain medications has gained more importance in the past few years due to adverse effects associated with currently prescribed drugs including nervous system dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has been explored for the treatment of pain, as these have been used for generations in regional communities and tend to lack major side effects in general. One such phytomedicine, incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis has its primary antinociceptive action through the adenosine receptor, a novel pain target. We hypothesized that derivatives of cinnamic acid dimers, which are structurally similar to INCA, would show potent antinociceptive action and that their effect would be mediated through adenosine receptor action.
Materials and methods: Dimers of cinnamic acid (INCA analogs) were synthesized using cavitand-mediated photodimerization (CMP) method, which utilizes a macromolecule (γ-cyclodextrin) to control excited state reactivity of photoactive compounds. Acute pain response was assessed by using formalin-induced licking behavior in hind paw of mice, and neurologic function was monitored through locomotor activity, mechanical hyperalgesia, and thermal sensitivity upon administration of test compound. For mechanistic studies, binding to adenosine receptor was determined by using computer modeling.
Results: Ferulic acid dimer (FAD), which has the same chemical functionalities on the aromatic ring as INCA, showed significant suppression of formalin-induced acute pain. Antinociceptive effect was observed primarily in the inflammatory phase, and no apparent behavioral changes related to the nervous system were noticeable. Inhibition of opioid receptor did not reverse antinociceptive response, and modeling data suggest adenosine 3 receptor binding.
Conclusion: FAD (INCA analog) shows potent nonopioid antinociceptive action mediated predominantly through A3AR – adenosine 3 receptor action. Further characterization and selection of such INCA analogs will help us generate a new class of antinociceptives with precise chemical modifications by using CMP methodology.

Keywords: adenosine, incarvillateine, cinnamic acid, formalin, antinociceptive

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