Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA.

Lie Zhang,Wen-Jun Zhao,Wei Hu,Yan Sun,Ming-Jie He,Qing-Rong Fan,Jun-Bin Yin,Alan D Kaye,Tan Ding,En-Ren Wang,Zhi-Chun Qiu

doi:10.3389/fphar.2018.00317

Abstract

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.

Highlights

The formalin test includes two well-identified phases of spontaneous pain behaviors, which is considered as a model of acute inflammatory pain (Wheeler-Aceto and Cowan, 1991; Rocha-Gonzalez et al, 2005; Sun et al, 2013)
We directed attention to the brain limbic system and tried to figure out the anatomic sites and underlying mechanisms involved in the transition from spontaneous pain to hyperalgesia induced by hindpaw formalin injection
Local infusion 5-HT (100 nmol) into the central nucleus of amygdala (CeA) significantly produced analgesic effects on the mechanical (Figure 8F, P < 0.01) and thermal (Figure 8H, P < 0.01) hyperalgesia. These results indicate that DUL exerted obvious analgesic effects through enhancing the serotonin levels in the CeA after formalin injection

Summary

Introduction

The formalin test includes two well-identified phases of spontaneous pain behaviors, which is considered as a model of acute inflammatory pain (Wheeler-Aceto and Cowan, 1991; Rocha-Gonzalez et al, 2005; Sun et al, 2013). It is well accepted that the spontaneous pain response occurred immediately after formalin injection into the hindpaw or tail of rodent animals. Formalin injection induced-secondary mechanical hyperalgesia was observed after the acute phase (Wiertelak et al, 1994; Fu et al, 2000, 2001; Lin et al, 2007; Vierck et al, 2008; Yin et al, 2016). The formalin test is a suitable model to investigate the transition from acute to chronic pain. We directed attention to the brain limbic system and tried to figure out the anatomic sites and underlying mechanisms involved in the transition from spontaneous pain to hyperalgesia induced by hindpaw formalin injection

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Conclusion