Spinal Astrocytic Activation Is Involved in a Virally-Induced Rat Model of Neuropathic Pain

Abstract

Postherpetic neuralgia (PHN), the most common complication of herpes zoster (HZ), plays a major role in decreased life quality of HZ patients. However, the neural mechanisms underlying PHN remain unclear. Here, using a PHN rat model at 2 weeks after varicella zoster virus infection, we found that spinal astrocytes were dramatically activated. The mechanical allodynia and spinal central sensitization were significantly attenuated by intrathecally injected L-α-aminoadipate (astrocytic specific inhibitor) whereas minocycline (microglial specific inhibitor) had no effect, which indicated that spinal astrocyte but not microglia contributed to the chronic pain in PHN rat. Further study was taken to investigate the molecular mechanism of astrocyte-incudced allodynia in PHN rat at post-infection 2 weeks. Results showed that nitric oxide (NO) produced by inducible nitric oxide synthase mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal dorsal horn neurons to strengthen pain transmission. Taken together, these results suggest that spinal activated astrocytes may be one of the most important factors in the pathophysiology of PHN and “NO-Astrocyte-Cytokine-NMDAR-Neuron” pathway may be the detailed neural mechanisms underlying PHN. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for clinical management of PHN.

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

“…11 Short-term effects on VZV pain in the rats by agents such as astrocyte toxin, iNOS inhibitors, NO scavengers, IL1 receptor antagonist, cytokine inhibitor, NMDA receptor antagonists and non-competitive NMDA receptor antagonist have also been reported, but these require intraperitoneal or intrathecal administration, routes not particularly suited to human treatment. 11–13 The single peripheral administration of vHPPE abrogated VZV-induced nocifensive behaviors completely at high doses (Figures 2b and d). We argue that this is the first strategy to show a prolonged effect on VZV-induced pain behaviors with single dosing and relatively simple administration.…”

“…10–13 Animals inoculated at the footpad with VZV-infected cells develop long-term chronic nocifensive behaviors similar to those exhibited by PHN patients, including MA, thermal hyperalgesia (TH) and anxious-like behaviors. 12 VZV-infected animals show a viral dose-dependent increase in sensitivity with the expression of some VZV proteins in neurons colocalizing with peripherin, neurofilament 200 and neuropeptide y in ipsilateral but not contralateral ganglia.…”

“…11 It has been established that pain behaviors developing in the VZV-inoculated rat model do not respond to acyclovir blockade of viral replication, which mirrors the observations that pain in the majority of human PHN patients is not alleviated by antiviral therapy. 6,9,12–14 Although the pain indices that develop in the rat differ from human PHN in that it follows an acute primary infection rather than a reactivation from latency, the rat model has proved highly useful for preclinical assessment of many current and novel drug treatment strategies, 11–13 and many treatments in the rat echo the response of some PHN patients. Animals treated with gabapentin, morphine, sodium channel blockers (mexiletine and lamotrigine) or tricyclic antidepressant (amitriptiline) showed significant reduction in hypersensitivity.…”

Neuronal changes induced by Varicella Zoster Virus in a rat model of postherpetic neuralgia

“…MA is defined as pain resulting from what is considered to be normally innocuous stimuli. The rat model has permitted the evaluation of novel and established pharmacological agents for treatment of VZV induced pain, and we have used the rat model to establish gene therapy strategies for the treatment of VZV-induced pain (Garry et al, 2005; Guedon et al, 2014; Hasnie et al, 2007; Medhurst et al, 2008; Zhang et al, 2011). However, virus infection in the rat model has not been extensively evaluated.…”

Activated Glia Increased the Level of Proinflammatory Cytokines in a Resiniferatoxin-Induced Neuropathic Pain Rat Model

“…The doses of all agents used in this study were based on relevant and our previous researches. 4,[12][13][14][15] Western Blotting…”