Article

Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord

Department of Neurobiology, Parker University Research Institute, Dallas, TX 75229, USA.
Pain (Impact Factor: 5.21). 09/2011; 152(11):2605-15. DOI: 10.1016/j.pain.2011.08.003
Source: PubMed

ABSTRACT

Adenosine triphosphate-sensitive potassium (K(ATP)) channels are suggested to be involved in pathogenesis of neuropathic pain, but remain underinvestigated in primary afferents and in the spinal cord. We examined alterations of K(ATP) channels in rat spinal cord and tested whether and how they could contribute to neuropathic pain. The results showed that protein expression for K(ATP) channel subunits SUR1, SUR2, and Kir6.1, but not Kir6.2, were significantly downregulated and associated with thermal hyperalgesia and mechanical allodynia after sciatic nerve injury. Spinal administration of a K(ATP) channel opener cromakalim (CRO, 5, 10, and 20 μg, respectively) prevented or suppressed, in a dose-dependent manner, the hyperalgesia and allodynia. Nerve injury also significantly increased expression and phosphorylation of connexin 43, an astroglial gap junction protein. Such an increase of phosphorylation of connexin 43 was inhibited by CRO treatment. Furthermore, preadministration of an astroglial gap junction decoupler carbenoxolone (10 μg) completely reversed the inhibitory effects of CRO treatment on the hyperalgesia and allodynia and phosphorylation of NR1 and NR2B receptors and the subsequent activation of Ca(2+)-dependent signals Ca(2+)/calmodulin-dependent kinase II and cyclic adenosine monophosphate (cAMP) response element binding protein. These findings suggest that nerve injury-induced downregulation of the K(ATP) channels in the spinal cord may interrupt the astroglial gap junctional function and contribute to neuropathic pain, thus the K(ATP) channels opener can reduce neuropathic pain probably partly via regulating the astroglial gap junctions. This study may provide a new strategy for treating neuropathic pain using K(ATP) channel openers in the clinic.

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    • "Expression of Cx43 was not found in either neurons (Fig. 1D) or microglia (Fig. 1E). In the current study, punctuate immunostaining of Cx43 was detected around astrocytes, suggesting pericellular localization, which is consistent with previous findings (Rouach et al., 2008; Wu et al., 2011). Also, as previous reported, Cx43 was expressed not only on glial cell bodies but also processes (Giaume et al., 2010). "

    Full-text · Dataset · Aug 2015
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    • "Expression of Cx43 was not found in either neurons (Fig. 1D) or microglia (Fig. 1E). In the current study, punctuate immunostaining of Cx43 was detected around astrocytes, suggesting pericellular localization, which is consistent with previous findings (Rouach et al., 2008; Wu et al., 2011). Also, as previous reported, Cx43 was expressed not only on glial cell bodies but also processes (Giaume et al., 2010). "
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    ABSTRACT: Spinal cord astrocytes are critical in the maintenance of neuropathic pain. Connexin 43 (Cx43) expressed on spinal dorsal horn astrocytes modulates synaptic neurotransmission, but its role in nociceptive transduction has yet to be fully elaborated. In mice, Cx43 is mainly expressed in astrocytes, not neurons or microglia, in the spinal dorsal horn. Hind paw mechanical hypersensitivity was observed beginning 3 days after partial sciatic nerve ligation (PSNL), but a persistent downregulation of astrocytic Cx43 in ipsilateral lumbar spinal dorsal horn was not observed until 7 days post-PSNL, suggesting that Cx43 downregulation mediates the maintenance and not the initiation of nerve injury-induced hypersensitivity. Downregulation of Cx43 expression by intrathecal treatment with Cx43 siRNA also induced mechanical hypersensitivity. Conversely, restoring Cx43 by an adenovirus vector expressing Cx43 (Ad-Cx43) ameliorated PSNL-induced mechanical hypersensitivity. The sensitized state following PSNL is likely maintained by dysfunctional glutamatergic neurotransmission, as Cx43 siRNA-induced mechanical hypersensitivity was attenuated with intrathecal treatment of glutamate receptor antagonists MK801 and CNQX, but not neurokinin-1 receptor antagonist CP96345 or the Ca(2+) channel subunit α2δ1 blocker gabapentin. The source of this dysfunctional glutamatergic neurotransmission is likely decreased clearance of glutamate from the synapse rather than increased glutamate release into the synapse. Astrocytic expression of glutamate transporter GLT-1, but not GLAST, and activity of glutamate transport were markedly decreased in mice intrathecally injected with Cx43-targeting siRNA but not non-targeting siRNA. Glutamate release from spinal synaptosomes prepared from mice treated with either Cx43-targeting siRNA or non-targeting siRNA was unchanged. Intrathecal injection of Ad-Cx43 in PSNL mice restored astrocytic GLT-1 expression. The cytokine tumor necrosis factor (TNF) has been implicated in the induction of central sensitization, particularly through its actions on astrocytes, in the spinal cord following peripheral injury. Intrathecal injection of TNF in naïve mice induced the downregulation of both Cx43 and GLT-1 in spinal dorsal horn, as well as hind paw mechanical hypersensitivity, as observed in PSNL mice. Conversely, intrathecal treatment of PSNL mice with the TNF inhibitor etanercept prevented not only mechanical hypersensitivity but also the downregulation of Cx43 and GLT-1 expression in astrocytes. The current findings indicate that spinal astrocytic Cx43 are essential for the maintenance of neuropathic pain following peripheral nerve injury and suggest modulation of Cx43 as a novel target for developing analgesics for neuropathic pain. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Brain Behavior and Immunity
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    • "Recent studies have indicated that Cx43 and Kir6.1 are part of the same functional unit, which regulate various stress related cell survival functions. Nerve injury-induced down regulation of the K þ (ATP) channels in the spinal cord has been found to interrupt the astroglial gap junction function mediated by Cx43 [19]. Moreover, mitochondrial K þ (ATP) channels in cardiomyocytes have been linked to confer cytoprotection against necrotic and apoptotic cell injury. "
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    Full-text · Dataset · Jul 2014
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