Impact Factor 3.831
2017 JCR, Clarivate Analytics 2018

Frontiers journals are at the top of citation and impact metrics

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00283


 Sara Polo1, 2, Andrés F. Díaz1, 2, Núria Gallardo1, 2, Sergi Leánez1, 2,  Gianfranco Balboni3 and  Olga Pol1, 2*
  • 1Sant Pau Institute for Biomedical Research, Spain
  • 2Institute of Neurosciences, Autonomous University of Barcelona, Spain
  • 3Università degli studi di Cagliari, Italy


We investigated whether administration of the δ-opioid receptor (DOR) agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), which also activates nuclear factor erythroid 2-related factor 2 (Nrf2), alleviated chronic inflammatory and/or neuropathic pain and inhibited the depressive-like behaviors associated with persistent neuropathic pain. The possible mechanisms implicated were also assessed. We evaluated the following effects in male C57BL/6J mice with inflammatory pain induced by complete Freund’s adjuvant (CFA) or neuropathic pain caused by the chronic constriction of sciatic nerve (CCI): 1) the antinociceptive effects of UFP-512; 2) the effects of UFP-512 on the expression of Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), inducible nitric oxide synthase (NOS2), DOR and mitogen-activated protein kinases (MAPK) in the spinal cord of animals with inflammatory or neuropathic pain; 3) the antinociceptive effects of the coadministration of UFP-512 with the Nrf2 activator sulforaphane (SFN); and 4) the antidepressant effects of UFP-512 in animals with depressive like-behaviors associated with neuropathic pain. Our results demonstrated that the intraperitoneal administration of UFP-512 inhibited chronic inflammatory and neuropathic pain and reduced the depressive-like behaviors associated with persistent neuropathic pain. The antiallodynic effects of UFP-512 were significantly augmented when it was coadministered with SFN in both types of chronic pain. The administration of UFP-512 increased/reestablished the spinal cord protein levels of Nrf2 and HO-1 in mice with inflammatory or neuropathic pain. However, while during inflammatory pain UFP-512 inhibited spinal c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation induced by peripheral inflammation. This DOR agonist blocked the spinal activated PI3K/Akt signaling pathway under chronic neuropathic pain conditions, but it did not alter the enhanced protein levels of p-JNK or p-ERK1/2 induced by sciatic nerve injury. These results revealed the antinociceptive and antidepressant effects of UFP-512 in animals with chronic pain and the different mechanism of action of this DOR agonist in the presence of inflammatory or neuropathic pain. Our data also suggest the administration of UFP-512 as an alternative for the treatment of chronic pain and the depressive-like behaviors associated with neuropathic pain.

Keywords: Analgesia, Depression, Nrf2 (nuclear factor erythroid 2-related factor 2), delta opioid receptor, Oxidative Stress, Chronic Pain, UFP-512

Received: 10 Dec 2018; Accepted: 07 Mar 2019.

Edited by:

Francisco Ciruela, University of Barcelona, Spain

Reviewed by:

Mariana Spetea, University of Innsbruck, Austria
Temugin Berta, University of Cincinnati, United States  

Copyright: © 2019 Polo, Díaz, Gallardo, Leánez, Balboni and Pol. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Olga Pol, Sant Pau Institute for Biomedical Research, Barcelona, 08025, Catalonia, Spain,