Reversal of TRESK Downregulation Alleviates Neuropathic Pain by Inhibiting Activation of Gliocytes in the Spinal Cord

Abstract

Despite the consensus that activation of TWIK-related spinal cord K (TRESK) might contribute to the pathogenesis of chronic pain, the specific mechanisms underlying the transfer and development of pain signals still remain obscure. In the present study, we validated that TRESK was expressed in neurons instead of glial cells. Furthermore, in the SNI model of neuropathic pain (NP), downregulation of TRESK in spinal cord neurons resulted in upregulation of connexin 36 (Cx36) and connexin 43 (Cx43), both being subtypes of gap junctions in the spinal cord, with gliocytes in the spinal cord activated ultimately. Compared with SNI rats, intrathecal injection of TRESK gene recombinant adenovirus significantly downregulated the expression levels of Cx36 and Cx43 and suppressed the activation of gliocytes in the spinal cord, with hyperalgesia significantly reduced. In conclusion, TRESK contributes to the pathogenesis of NP by upregulation of synaptic transmission and activation of gliocytes.

Role of Connexin 36 in Autoregulation of Oxytocin Neuronal Activity in Rat Supraoptic Nucleus

“…The postburst inhibition during suckling can be explained by burst-evoked increase in extracellular potassium (Leng et al., 1988) and high potassium-evoked expansion of astrocytic processes in the presence of high level of OT (Wang & Hatton, 2009). Because activation of potassium channels is negatively correlated with the expression of Cx36 (Medina-Ceja & Ventura-Mejia, 2010; Lebreton et al., 2015; Zhou et al., 2017), it is reasonable to propose that the burst firing dampens the activity of Cx36 and that results in the inhibition. During extended time of OT treatment, the expression of protein kinase A is increased (Wang et al., 2017) as result of prostaglandin activation of EP receptor (Shibuya et al., 2000) and reduced pERK1/2 inhibition of protein kinase A expression (Zhong et al., 2003), while filamentous actin network is disrupted (Wang & Hatton, 2007b).…”

Two‐pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26

“…K2P18 channels mediate the largest component of the background K + current in DRG neurons (Tulleuda et al, 2011; Plant, 2012), but the channel is down‐regulated in animals with spinal cord injury. This phenotype is associated with significantly decreased thresholds for withstanding mechanical pain (allodynia), activation of astrocytes and microglia and up‐regulation of connexin‐36 and connexin‐43, components of neuronal and astrocyte‐oligodendrocyte gap junctions respectively (Zhou et al, 2017). Down‐regulation of K2P18 in nerve injury occurs in combination with an increase in MAPK, ERK and p38, which are also implicated in the pathogenesis of neuropathic pain.…”

The Background K+ Channel TRESK in Sensory Physiology and Pain

“…The study showed that, similarly to other ion channels and particularly some K + channels [10], peripheral injury or axotomy reduces the expression of TRESK, consequently enhancing sensory neuron excitability. Other studies reported similar effects using different models of chronic neuropathic or inflammatory pain [21,40,41]. Interestingly and despite the fact that sensory neuron primary culture is a common model used in many studies, ganglia dissociation produces an inevitably axotomy where neurons become injured.…”

“…Despite the data is not conclusive, it seems that the involvement of the channel in the development of inflammatory pain is rather limited. Models of neuropathic pain (complete axotomy, spared nerve injury or spinal nerve ligation) have shown a marked reduction of TRESK expression in the DRGs, which likely contributes to the enhanced mechanical and thermal hypersensitivity [18,40,44,48]. Recovery of TRESK expression levels by viral transfection partially reversed mechanical allodynia [40,44].…”

“…Models of neuropathic pain (complete axotomy, spared nerve injury or spinal nerve ligation) have shown a marked reduction of TRESK expression in the DRGs, which likely contributes to the enhanced mechanical and thermal hypersensitivity [18,40,44,48]. Recovery of TRESK expression levels by viral transfection partially reversed mechanical allodynia [40,44]. A similar TRESK downregulation in DRGs has been reported in a model of cancer-associated pain and overexpression of the channel suppresses tumor-induced neuronal hyperexcitability and pain hypersensitivity in this bone metastasis model [41].…”