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.
Highlights
The most common complication of herpes zoster (HZ) is postherpetic neuralgia (PHN) which has been defined as severe pain occurring 1 month after rash onset and persisting for more than 3 months [1]
varicella zoster virus (VZV) infection induced mechanical allodynia which was resistant to antiviral therapy No difference in paw withdrawal threshold was observed between naive rats (2563.5 g) and mock infected rats (24.563.4 g), and the paw withdrawal threshold of these two groups maintained at basal level through the period tested
It is still unclear how latent VZV infection interacts with the nervous system to induce pain behavioural changes, the underlying pathophysiological mechanisms of PHN may be similar to other forms of neuropathic pain
Summary
The most common complication of herpes zoster (HZ) is postherpetic neuralgia (PHN) which has been defined as severe pain occurring 1 month after rash onset and persisting for more than 3 months [1]. PHN is often prolonged, responds poorly to current analgesics such as anticonvulsants, tricyclic antidepressants, opioids and non-steroidal anti-inflammatory drugs (NSAIDS) [2]. PHN can result in impaired sleep, emotional distress and depression which patients may suffer for years [3]. Continued inflammation was observed in biopsy studies of some PHN patients, whereas PHN is resistant to NSAIDS, suggesting that inflammatory response per se is not sufficient to induce PHN [4,5]. It has been pointed out that PHN shares some characteristics of neuropathic pain [6]. Up-regulation of some neuropeptide, calcium channel and sodium channel has been observed in dorsal root ganglia of PHN rat model. Systemic treatment with gabapentin or the sodium channel blockers could to some extent reverse PHN [7]. There is still no ideal explanation on the neural mechanisms underlying PHN
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