Spinal activation of alpha7-nicotinic acetylcholine receptor attenuates posttraumatic stress disorder-related chronic pain via suppression of glial activation

Sun, Renhua; Zhang, Wei; Jiang, Bo; Zhang, Zuoxia; Lei, Yishan; Huo, Wenwen; Liu, Yue; Ma, Zhengliang; Gu, Xiaoping

doi:10.1016/j.neuroscience.2016.12.029

Cited by 29 publications

(14 citation statements)

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“…Finally, acetylcholine (ACh), which signals through a variety of receptor subtypes to regulate both excitatory and inhibitory neurotransmission centrally and in the parasympathetic nervous system, may contribute to SPS phenotypes. Initial evidence, though scant, indicates that SPS increases muscarinic ACh receptor binding in HC and mPFC ( 132 ) and also that activation of spinal α7 nicotinic ACh receptors can reverse SPS-induced hyperalgesia ( 288 ). Especially in light of clinical findings that PTSD symptoms are associated with parasympathetic dysregulation ( 289 ) this suggests that the ACh system may be a promising target for treating both the central and peripheral pathophysiology of PTSD.…”

Section: Neural and Molecular Mechanisms In Spsmentioning

confidence: 99%

“…There is also evidence that glial processes may contribute to post-SPS dysfunction and poor behavioral recovery. For example, microglial activation caused by glucocorticoid signaling in the spinal cord ( 288 , 347 ) and HC ( 348 ) appears to contribute to post-SPS hyperalgesia. Immunohistochemical data indicate that glial cell number is decreased in the HC in a time-dependent manner following SPS, and magnetic resonance spectroscopy findings of decreased choline in the HC ( 312 ) and creatine in the HC ( 312 ) and mPFC ( 154 ) are consistent with a glial-related mechanism ( 312 ).…”

Section: Neural and Molecular Mechanisms In Spsmentioning

confidence: 99%

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Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

et al. 2018

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Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD.

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Section: Neural and Molecular Mechanisms In Spsmentioning

confidence: 99%

Section: Neural and Molecular Mechanisms In Spsmentioning

confidence: 99%

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

et al. 2018

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“… 10 , 24 Furthermore, numerous studies have demonstrated that α7nAChR activation significantly suppresses glial activation. 25 – 27 An in vitro trial showed that the activation of α7nAChR promoted the conversion of M1 microglia to the M2 phenotype. 28 These results suggest that activated α7nAChR may contribute to the inhibition of glial activation and further to the regulation of CM conditions.…”

Section: Introductionmentioning

confidence: 99%

α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

Liu¹,

Liu²,

Jiang³

et al. 2018

JPR

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BackgroundEvidence suggests that the activation of α7 nicotinic acetylcholine receptor (α7nAChR) can greatly decrease the neuroinflammation response. Neuroinflammation plays a pivotal role in the pathogenesis of chronic migraine (CM). Clinical observations also show that nicotine gum induces analgesic effects in migraine patients. However, whether α7nAChR is involved in CM is unclear.ObjectiveTo investigate the role of α7nAChR in CM and provide a new therapeutic target for CM.Materials and methodsThirty-six male Sprague–Dawley rats were distributed randomly into control, CM, PNU-282987, and α-bungarotoxin groups (n=9 rats in each group). The CM model was established by the recurrent daily administration of inflammatory soup on the dura over the course of 1 week. The hind paw threshold and facial allodynia were assessed by the von Frey test. The expression levels of α7nAChR, tumor necrosis factor-alpha, and interleukin-1 beta were analyzed by Western blot and real-time fluorescence quantitative polymerase chain reaction. The location of α7nAChR in the hippocampus was quantified by immunofluorescence, as well as the microglial and astrocyte alterations. Changes in the calcitonin gene-related peptide and the phosphorylated JNK protein among different groups were measured by Western blot.ResultsWe found that the expression of α7nAChR was reduced after repeated inflammatory soup administration. The increased expression of tumor necrosis factor-alpha, interleukin-1 beta, and calcitonin gene-related peptide in CM group were significantly decreased by PNU-282987 and aggravated by α-bungarotoxin. Moreover, PNU-282987 decreased the numbers of astrocytes and microglia compared with the numbers in the CM group in both hippocampal CA1 and CA3 regions. In contrast, α-bungarotoxin activated the astrocytes and microglia, but the differences with respect to the CM group were not significant. Activated c-Jun N-terminal kinase signaling was observed in CM rats and was also blocked by PNU-282987.ConclusionThe activation of α7nAChR increased the mechanical threshold and alleviated pain in the CM rat model. α7nAChR activation also decreased the upregulation of astrocytes and microglia through the p-c-Jun N-terminal kinase–mitogen-activated protein kinase signaling pathway.

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“…[48][49][50][51] According to our recent studies, spinal microglia were active in RIH rats, 52 and a7-nAChRs activation induced by PNU-120596 has an anti-hyperalgesia effect in RIH. 28 What's more, the activation of a7-nAChRs attenuated posttraumatic stress disorder-related mechanical allodynia via the suppression of spinal microglia.…”

Section: Discussionmentioning

confidence: 94%

Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats

Zhang

Lei

et al. 2017

Mol Pain

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Background Accumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K-Cl cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K-Cl cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic. Results We demonstrated that the brain-derived neurotrophic factor/tyrosine receptor kinase B-K-Cl cotransporter-2 signal played a critical role in the development of remifentanil-induced postoperative hyperalgesia. Intrathecal administration of PNU-120596 (8 µg/kg, 15 min before surgery) was associated with earlier signs of recovery from remifentanil-induced postoperative hyperalgesia. Simultaneously, remifentanil-induced postoperative hyperalgesia-induced K-Cl cotransporter-2 downregulation was partly reversed and coincided with a decreased expression of brain-derived neurotrophic factor/tyrosine receptor kinase B in the spinal dorsal horn, approximately correlating with the time course of the nociceptive behavior. Moreover, intrathecal administration of the K-Cl cotransporter-2 inhibitor VU0240551 significantly reduced the analgesic effect of PNU-120596 on remifentanil-induced postoperative hyperalgesia. Conclusions The activation of alpha-7 nicotinic acetylcholine receptors induced a shorter duration of remifentanil-induced postoperative hyperalgesia by restoring the brain-derived neurotrophic factor/tyrosine receptor kinase B-K-Cl cotransporter-2 signal in the spinal dorsal horn of rats, which provides new insight into treatment in clinical postoperative pain management.

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Spinal activation of alpha7-nicotinic acetylcholine receptor attenuates posttraumatic stress disorder-related chronic pain via suppression of glial activation

Cited by 29 publications

References 61 publications

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats

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Spinal activation of alpha7-nicotinic acetylcholine receptor attenuates posttraumatic stress disorder-related chronic pain via suppression of glial activation

Cited by 29 publications

References 61 publications

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

&alpha;7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats

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α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation