Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

Burke, Nikita N.; Kerr, Daniel M.; Moriarty, Orla; Finn, David P.; Roche, Michelle

doi:10.1016/j.bbi.2014.06.015

Cited by 146 publications

(124 citation statements)

References 73 publications

(100 reference statements)

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“…However, Bravo et al (2014) found that there was no difference in mechanical allodynia between rats experiencing CMS combined with sciatic nerve chronic constriction injury (CCI) and non-CMS rats with CCI. Burke et al (2013, 2014) reported normal mechanical allodynia and thermal hyperalgesia in OB-SNL rats. These conflicting results may be related to differences among neuropathic pain models, experimental paradigms or animal handling methods before the behavior tests.…”

Section: Discussionmentioning

confidence: 98%

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

Xiao

Sun

Luo

2017

Front. Cell. Neurosci.

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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.

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Section: Discussionmentioning

confidence: 98%

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

Xiao

Sun

Luo

2017

Front. Cell. Neurosci.

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“…Accumulating evidence has suggested the key role of neuroinflammation mediated by microglia in linking neuropathic pain and depression (Burke et al, 2014; Fiore and Austin, 2016). It is reported that pro-inflammatory cytokines led to hyperalgesia (Schiavuzzo et al, 2015); meanwhile, pro-inflammatory cytokines also induced depressive-like behaviors in animals (Norman et al, 2010); In human studies, pro-inflammatory cytokines such as TNF-α and IL-1β are increased in the cerebrospinal fluid and blood in patients with chronic neuropathic pain (Alexander et al, 2005), suggesting a critical role of M1-mediated neuroinflammation in this disorder.…”

Section: Discussionmentioning

confidence: 99%

Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors

et al. 2017

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Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1β, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.

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“…In the present study, we used a 64-channel multi-electrode array recording system to examine the potential role of microglia in LTP induction in the ACC. We found that bath application of minocycline, a potent microglia inhibitor [11,12], failed to affect either post-LTP or pre-LTP in the ACC of normal adult mice. The spatial properties of post-LTP or pre-LTP distribution were also unaltered by minocycline, suggesting a rather minor role of microglial cells in cingulate synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…To address this question, we used a 64-channel multi-electrode dish (MED64) recording system to test the effects of minocycline, a potent microglial inhibitor [11,12], on the induction of two forms of LTP in the adult mouse ACC: presynaptic LTP (pre-LTP) [27] and postsynaptic LTP (post-LTP) [28]. Our recent work demonstrates the co-existence of these two forms of LTP in the ACC synapses, which have different mechanisms of induction and behavioral implications [29].…”

Section: Introductionmentioning

confidence: 99%

Minocycline does Not Affect Long-Term Potentiation in the Anterior Cingulate Cortex of Normal Adult Mice

2015

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It has been reported that activated microglia plays important roles in chronic pain-related sensory signaling at the spinal cord dorsal horn. Less is known about the possible contribution of microglia to cortical plasticity that has been found to be important for chronic pain. In the present study, we used a 64-channel multi-electrode array recording system to investigate the role of microglia in cortical plasticity of the anterior cingulate cortex (ACC) in normal adult mice. We found that bath application of minocycline, an inhibitor of microglial activation, had no effect on postsynaptic LTP (post-LTP) induced by theta burst stimulation in the ACC. Furthermore, presynaptic LTP (pre-LTP) induced by the combination of low-frequency stimulation with a GluK1-containing kainate receptor agonist was also not affected. The spatial distribution of post-LTP or pre-LTP among the cingulate network is also unaltered by minocycline. Our results suggest that minocycline does not affect cingulate plasticity and neurons are the major player in pain-related cortical plasticity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12990-015-0025-2) contains supplementary material, which is available to authorized users.

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Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

Cited by 146 publications

References 73 publications

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

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

Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors

Minocycline does Not Affect Long-Term Potentiation in the Anterior Cingulate Cortex of Normal Adult Mice

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