Impaired Spinal Glucocorticoid Receptor Signaling Contributes to the Attenuating Effect of Depression on Mechanical Allodynia and Thermal Hyperalgesia in Rats with Neuropathic Pain.

Xiao Wei,Yuqi Sun,Fei Luo

doi:10.3389/fncel.2017.00145

Abstract

Although depression-induced altered pain perception has been described in several laboratory and clinical studies, its neurobiological mechanism in the central nervous system (CNS), particularly in the spinal dorsal horn, remains unclear. Therefore, in this study, we aimed to clarify whether nociceptive sensitivity of neuropathic pain is altered in the olfactory bulbectomy (OB) model of depression and whether glucocorticoid receptor (GR), which is involved in the etio-pathologic mechanisms of both major depression and neuropathic pain, contributes to these processes in the spinal dorsal horn of male Sprague-Dawley rats. The results showed that mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation (SNL) were attenuated in OB-SNL rats with decreased spinal GR expression and nuclear translocation, whereas non-olfactory bulbectomy (NOB)-SNL rats showed increased spinal GR nuclear translocation. In addition, decreased GR nuclear translocation with normal mechanical nociception and hypoalgesia of thermal nociception were observed in OB-Sham rats. Intrathecal injection (i.t.) of GR agonist dexamethasone (Dex; 4 μg/rat/day for 1 week) eliminated the attenuating effect of depression on nociceptive hypersensitivity in OB-SNL rats and aggravated neuropathic pain in NOB-SNL rats, which was associated with the up-regulation of brain-derived neurotrophic factor (BDNF), TrkB and NR2B expression in the spinal dorsal horn. The present study shows that depression attenuates the mechanical allodynia and thermal hyperalgesia of neuropathic pain and suggests that altered spinal GR-BDNF-TrkB signaling may be one of the reasons for depression-induced hypoalgesia.

Highlights

Major depression and chronic pain are difficult to completely heal, have high comorbidity (Bair et al, 2003; Doan et al, 2015) and show clinical interactions with each other
The mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) of non-olfactory bulbectomy (NOB)-Sham rats (p = 0.481, p = 0.632, respectively) and olfactory bulbectomy (OB)-Sham rats (p = 0.059, p = 0.132, respectively) were not affected following Dex administration. These results revealed that spinal glucocorticoid receptor (GR) activation was involved in the development of mechanical allodynia and thermal hyperalgesia of NOB-spinal nerve ligation (SNL) rats and that decreased GR nuclear translocation, at least in part, contributed to the OB-induced attenuation of neuropathic pain in OB-SNL rats
We demonstrated that the OB-induced reduction in GR nuclear translocation in the spinal dorsal horn contributed to the attenuation of mechanical allodynia and thermal hyperalgesia in OB-SNL rats

Summary

Introduction

Major depression and chronic pain are difficult to completely heal, have high comorbidity (Bair et al, 2003; Doan et al, 2015) and show clinical interactions with each other. More than half of depression patients suffer from chronic pain (Bair et al, 2003). Depression Attenuates Neuropathic Pain Nociception on chronic pain perception is a controversial topic. Other clinical and laboratory studies found that depression patients showed reduced sensitivity to noxious stimuli applied to the skin (Lautenbacher et al, 1994; Bär et al, 2006). Depressive-like rats combining with chronic pain exhibited hypoalgesia to nociceptive mechanical and thermal stimuli compared to chronic pain rats without depression (Shi et al, 2010a,b; Wang et al, 2010). Studies on the mechanism of hypoalgesia induced by depression are currently focused on the physiopsychology of pain perception and the neural activity of supraspinal nuclei, such as the reduction of pain-avoidance motivation (Wang et al, 2016) and altered neural activity in the thalamo-cortical circuits of the medial/lateral pain pathway (Wang N. et al, 2013). Whether nociceptive transmission and related neuropathological mechanisms are altered in the spinal dorsal horn under this circumstance is still unclear

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