Research ReportInhibition by dexmedetomidine of the activation of spinal dorsal horn glias and the intracellular ERK signaling pathway induced by nerve injury☆
Highlights
► We investigated the effects of dexmedetomidine (DEX) in a rat model of neuropathic pain ► Repeated intraperitoneal injections of DEX at tolerable doses relieved the hyperalgesia induced by partial sciatic nerve ligation ► The analgesic effect of DEX may be ascribed to inhibition of spinal dorsal horn glial cell hypertrophy and activation of the ERK signaling pathway.
Introduction
Dexmedetomidine (DEX) is a potent and highly selective agonist of α2-adrenergic receptors with good analgesic properties in acute inflammatory pain (Xu et al., 2010), postoperative pain (Shimode et al., 2003), and even neuropathic pain unresponsive to opioid analgesics (Malmberg et al., 2001, Xu et al., 2000). The α2-adrenergic receptor (α2AR) consists of three highly homologous subtypes, the α2A, α2B, and α2C subtypes. Activation of any one of these receptor subtypes can inhibit the release of noradrenaline. Although it has been shown that α2A-adrenergic receptor agonists exert sedative effects by suppressing noradrenaline release from the locus ceruleus (De Sarro et al., 1987), Engelhard et al. (2002) found that α2AR agonists produce antinociceptive effects without affecting noradrenaline release. Therefore, the mechanism of their analgesic effect is unclear.
Numerous studies have demonstrated that astrocytes and microglias in the central nervous system (CNS) can be activated by noxious stimuli, including nerve injury, inflammation, and tumor invasion, and play an important role in the maintenance of long-term chronic pain (Hansson, 2006, McMahon and Malcangio, 2009, Ren and Dubner, 2008, Watkins et al., 2001). Activated microglias appear in the early stage of pain, while activated astrocytes emerge later and last longer than activated microglias (Mika et al., 2009, Xu et al., 2007). Following nerve injury, activated glial cells exhibit hyperplasia and hypertrophy, and release inflammatory factors such as adenosine triphosphate (ATP), cyclo-oxygenase-2 (COX-2), interleukin (IL)-1, and IL-6 which amplify pain signals or sensitize neighboring neurons, and are involved in peripheral or central nervous sensitization. Therefore, specific inhibition of glial activation can reduce the hyperalgesia induced by surgical trauma (Obata et al., 2006).
Activated glial cells exert their effects by activation of multiple intracellular signaling pathways. Extracellular signal-regulated kinase (ERK), as one of the classical mitogen-activated protein kinase (MAPK) signaling pathways, may be activated by Ca2+, protein kinase C (PKC), and growth factors, and regulate cell activities, including their proliferation, differentiation and mitosis. ERK is also recognized to play a crucial role in neuronal plasticity by modulating gene expression and cytoplasmic protein phosphorylation (Dai et al., 2002, Ji et al., 2002, Obata et al., 2004). In rats with surgically-induced nerve injury, Zhuang et al. (2005) reported that ERK activates sequentially in neurons, astrocytes, and microglias of the spinal dorsal horn. On post-surgery Day 2, ERK is predominantly activated in microglias, but by Day 21 it is mainly in astrocytes, which is different from its activation in acute inflammation. Phospho-ERK (pERK) activates glial cells, stimulates the production and release of inflammatory molecules, and amplifies pain signals (Falsig et al., 2004, Ma and Quirion, 2002), which suggests that activation of the intracellular ERK signaling pathway in spinal dorsal root glial cells in the late stage of chronic pain is closely associated with the maintenance and development of chronic pain.
As well as neurons, the membranes of glial cells also express α2ARs in the CNS (Mori et al., 2002, Peng et al., 2003). In the rat brain, α2ARs in presynaptic membranes are only about 20% of the total number of α2ARs (Heal et al., 1993). The physiological function of α2ARs in glial cells is as yet unclear. It has been reported that changes of glial fibrillary acid protein (GFAP) expression in astrocytes are functionally linked to α2ARs (Conway et al., 1998). However, the effects of DEX on the activation of glial cells and the intracellular ERK signaling pathway induced by neuropathic pain have yet to be clarified.
The aim of the present study was to investigate the effects of repeated intraperitoneal (IP) injections of DEX at tolerable dose levels on pain hypersensitivity in a rat neuropathic pain model (induction of pain by partial sciatic nerve ligation [PNSL]), and on the activation of spinal dorsal root glial cells and the intracellular ERK signaling pathway.
Section snippets
Results
As stated in Section 4 (Experimental procedures), the study animals were randomly divided into seven groups of 10 rats each: a control group; the P7 group (studied 7 days after undergoing PSNL); D1 group (continuously treated with DEX 20 μg/kg for 7 days); D2 group (continuously treated with DEX 40 μg/kg for 7 days); P14 group (studied 14 days after PSNL); D3 group (continuously treated with DEX 20 μg/kg for 14 days); and D4 group (continuously treated with DEX 40 μg/kg for 14 days).
Discussion
This study showed that administration of DEX 40 μg/kg by repeated IP injections for 7 days and 14 days in rats significantly relieved the thermal and mechanical hyperalgesia induced by PSNL. Repeated IP injections of DEX 40 μg/kg for 14 days significantly inhibited the hypertrophy of astrocytes and activation of the ERK signaling pathway in the spinal dorsal horn glias of PSNL rats. However, DEX had no effect on the activation of microglias induced by nerve injury. Treatment with repeated IP
Animals and reagents
Seventy adult Sprague–Dawley rats (200–250 g) were used (provided by Guangdong Province Medicine Experimental Center; animal certification No: SCXK ‘yue’ 2008-0002). Following the IASP guidelines for pain research in animals, all animal studies were approved by the Animal Care and Use Committee at Sun Yat–Sen University, and were in accordance with the University's guidelines for the care and use of laboratory animals. The animals were habituated for 3 days at the Sun Yat-Sen University animal
Acknowledgments
This work was supported by the Natural Science Foundation of Guangdong Province (No. 7001595). The authors thank the Department of Pharmacology, Sun Yat-Sen University for guidance and assistance with this work.
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Contributors: Ling Liu and Fengtao Ji contributed equally to this work.