Involvement of spinal microglia and interleukin-18 in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI

Li, Shuangshuang; Zhang, Wei-Shi; Ji, Dong; Zhou, Yalan; Li, Hui; Yang, Jiale; Xiong, Yang; Zhang, Yu‐Qiu; Xu, Hua

doi:10.1016/j.neulet.2013.12.012

Cited by 27 publications

(22 citation statements)

References 24 publications

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“…44,45 We show that a reduction in spinal norepinephrine results in long term increases in spinal glial activation following peripheral nerve injury, similar to previous studies in our lab that examined earlier time points. 27 Consistent with our findings, noradrenergic receptor agonists have been shown to inhibit glial activation in vivo in rodent neuropathic pain models 46,47 and in vitro in spinal microglia 48 and astrocyte cultures 49 . Enhanced glial activation after injury likely results from increased primary afferent release of stimulating factors ( e.g.…”

Section: Discussionsupporting

confidence: 88%

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

et al. 2015

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Background Chronic post-surgical pain (CPSP), a significant public health problem, occurs in 10-50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of CPSP. The relationship between CPM and recovery from surgery has not been examined in preclinical models. Methods CPM was assessed in individual rats and correlated with each animal’s time course of recovery of hypersensitivity following partial spinal nerve ligation (pSNL). The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β hydroxylase conjugated saporin (DβH-saporin) to ablate these pathways. Behavioral hypersensitivity, static weight bearing and spinal glial activation were measured after pSNL. Results The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001, r = 0.660). CPM induced release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or DβH-saporin. DβH-saporin also slowed recovery and enhanced spinal glial activation following pSNL surgery. Ongoing activation of these pathways was critical to sustained recovery, since intrathecal DβH-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. Conclusions Collectively, these studies provide a clear back-translation from clinical observations of CPM and CPSP and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

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Section: Discussionsupporting

confidence: 88%

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

et al. 2015

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“…There are three highly homologous subtypes of the α 2 -adrenoceptor: α 2 A, α 2 B, and α 2 C. Dexmedetomidine, a highly selective α 2 -adrenoceptor agonist, has been used for conscious sedation and as an adjunct for clinical anesthesia [8910]. In animal experiments, dexmedetomidine has been shown to produce analgesic effects in models of neuropathic pain, but the mechanisms underlying these effects remain largely unknown [111213]. …”

Section: Introductionmentioning

confidence: 99%

“…Moreover, P2X7 receptors are involved in regulating microglial activation via the release of cytokines [19]. Recently, spinal microglia were shown to be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to chronic constriction injury of the sciatic nerve (CCI) [12]. However, no study has examined the effects of dexmedetomidine on P2X7R activation and the related analgesic effects.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

et al. 2018

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α2-Adrenoceptor agonists attenuate hypersensitivity under neuropathic conditions. However, the mechanisms underlying this attenuation remain largely unknown. In the present study, we explored the potential roles of purinergic receptor 7 (P2X7R)/extracellular signal-regulated kinase (ERK) signaling in the anti-nociceptive effect of dexmedetomidine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. An animal model of CCI was adopted to mimic the clinical neuropathic pain state. Behavioral hypersensitivity to mechanical and thermal stimuli was determined by von Frey filament and Hargreaves' tests, and the spinal P2X7R expression level and ERK phosphorylation were analyzed using western blot analysis and immunohistochemistry. In parallel with the development of mechanical and thermal hyperalgesia, a significant increase in P2X7R expression was noted in the ipsilateral spinal cord on day 7 after CCI. Intrathecal administration of dexmedetomidine (2.5 µg) for 3 days not only attenuated neuropathic pain but also inhibited the CCI-induced P2X7R upregulation and ERK phosphorylation. Intrathecal dexmedetomidine administration did not produce obvious effects on locomotor function. The present study demonstrated that dexmedetomidine attenuates the neuropathic pain induced by CCI of the sciatic nerve in rats by inhibiting spinal P2X7R expression and ERK phosphorylation, indicating the potential therapeutic implications of dexmedetomidine administration for the treatment of neuropathic pain.

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“…However, accumulating evidence suggests that glial cells also play an important role in the initiation and maintenance of chronic pain. [1][2][3] Robust activation of spinal glia, especially microglia and astrocytes, has been observed in various models of neuropathic pain. 1 2 w3-w9 Activated glia release proinflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6), which facilitate pain transmission.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Spinal Microglia and Astrocytes Contributes to the Anti-Allodynic Effect of Electroacupuncture in Neuropathic Pain Induced by Spinal Nerve Ligation

Liang

Qiu

et al. 2016

Acupunct Med

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Involvement of spinal microglia and interleukin-18 in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI

Cited by 27 publications

References 24 publications

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

Inhibition of Spinal Microglia and Astrocytes Contributes to the Anti-Allodynic Effect of Electroacupuncture in Neuropathic Pain Induced by Spinal Nerve Ligation

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