Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior

Coyle, Dennis E.

doi:10.1002/(sici)1098-1136(199805)23:1<75::aid-glia7>3.0.co;2-3

Cited by 266 publications

(115 citation statements)

References 53 publications

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“…More importantly, the genetic deletion of AMPK resulted in thermal hyperalgesia and the activation of astrocytes (one major type of glial cells) and over production of IL-1β. Ample studies have demonstrated that the activation of glial cells and subsequent production of proinflammatory mediators, including IL-1β, play an important role in the enhanced neuronal activation at the spinal cord under different pathological pain conditions, including chronic pain induced by nerve injury, 52,53 inflammation induced by complete Freund’s adjuvant, 54,55 carrageenan, 56 and bone cancer. 57 TNF-α and IL-1β can increase excitatory glutamatergic synaptic activities in the SDH.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

et al. 2015

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Background Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn (SDH) are implicated in the genesis of neuropathic pain. We determined if adenosine monophosphate-activated protein kinase (AMPK) in the SDH regulates these processes in rodents with neuropathic pain. Methods Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs. Results AMPK activities were reduced in the SDH of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1beta and activities of glycogen synthase kinase 3β, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10), and induced by inhibiting spinal AMPK in naïve rats (n = 7 to 8). Spinal AMPKα knockdown (n = 6) and AMPKα1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1β (n = 4). Conclusion These findings suggest enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

et al. 2015

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“…Both activated microglia and astrocytes release pro-inflammatory cytokines, which can cause spinal nociceptive sensitization in neuropathic pain [12,54,55]. Several studies using immunohistochemistry have also demonstrated that the activation of astrocytes and microglia parallels nociceptive behaviors following peripheral nerve injury [55,56]. Many studies suggest that microglia are involved in the initiation of neuropathic pain, whereas astrocytes function to maintain neuropathic pain [20,21,57,58].…”

Section: Discussionmentioning

confidence: 99%

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Chen

Huang

et al. 2014

Marine Drugs

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Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.

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“…These findings, together with early observations that inflammatory mediators are involved in neuropathic pain (Watkins et al, 1994, 1995; DeLeo et al, 1997) and the discovery that the microglial reaction in the spinal cord and the development of neuropathic pain timely coincide (Colburn et al, 1997, 1999; Coyle, 1998) have raised the assumption that microglia are involved in neuropathic pain development (Watkins et al, 2001). It is clear today that inhibition of various microglia-specific receptors or effector molecules prevents the development of neuropathic pain (Jin et al, 2003; Schäfers et al, 2003; Tsuda et al, 2003; Terayama et al, 2008; Clark et al, 2009, 2010).…”

Section: Microglia In Neuropathic Painmentioning

confidence: 94%

Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain

Biber

Boddeke

2014

Front. Cell. Neurosci.

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The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.

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Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior

Cited by 266 publications

References 53 publications

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain

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