Treatment With the Delta Opioid Agonist UFP-512 Alleviates Chronic Inflammatory and Neuropathic Pain: Mechanisms Implicated.

Sara Polo,Andrés Felipe Díaz,Sergi Leánez,Gianfranco Balboni,Núria Gallardo,Olga Pol

doi:10.3389/fphar.2019.00283

Abstract

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 or neuropathic pain caused by the chronic constriction of sciatic nerve: (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, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), inducible nitric oxide synthase, 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.

Highlights

Chronic pain is a complex experience that is composed of sensory and affective components
Recent works demonstrated that the administration of nuclear factor erythroid 2-related factor 2 (Nrf2) inducers reduced inflammatory (Redondo et al, 2017) and neuropathic pain (Negi et al, 2011; McDonnell et al, 2017a; Wang and Wang, 2017) via activation of the Nrf2/HO–1/NAD(P)H quinone oxidoreductase 1 (NQO1) signaling pathway and/or inhibition of the synthesis of pro-inflammatory mediators and mitogen-activated protein kinases (MAPK) activation (Negi et al, 2011; McDonnell et al, 2017b; Redondo et al, 2017; Wang and Wang, 2017). Based on these findings and that UFP-512 exerts its cytoprotective effects in cell cultures via activation of the Nrf2/HO–1/NQO1 pathway (Cao S. et al, 2015), we evaluated whether the inhibitory effects of this DOR agonist during chronic inflammatory or neuropathic pain were produced via activation of this antioxidant pathway and/or reduction of the inflammatory and nociceptive responses implicated in the maintenance of chronic pain
To study the antinociceptive actions of UPF-512 during inflammatory pain, we evaluated the effects of acute intraperitoneal administration of 1, 3, 10, 20, and 30 mg/kg UPF-512 on complete Freund’s adjuvant (CFA)-induced mechanical allodynia and thermal hyperalgesia 14 days after injection

Summary

Introduction

Chronic pain is a complex experience that is composed of sensory and affective components. It is curious that while the administration of MOR agonists is highly effective for the treatment of inflammatory pain, these agents exhibit limited efficacy in neuropathic pain and produce several adverse side effects, such as sedation, constipation, and respiratory depression. The administration of several DOR agonists produce limited analgesic effects in acute pain, these agonists reduced chronic inflammatory and neuropathic pain with similar efficacy (Pradhan et al, 2011). To the present study we evaluated the antinociceptive effects produced by another specific DOR agonist, H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), in animals with chronic inflammatory (14 days after induction) or neuropathic (28 days after surgery) pain. We used UFP-512 because this agonist did not produce convulsions or alter locomotor activity, and it exhibits anxiolytic and antidepressant properties without signs of tolerance after chronic administration in contrast to other DOR agonists, for example, UFP-502 (Vergura et al, 2006, 2008; Aguila et al, 2007)

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