Role of NaV1.6 and NaVβ4 Sodium Channel Subunits in a Rat Model of Low Back Pain Induced by Compression of the Dorsal Root Ganglia

Abstract

Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. In this study, we used siRNA-mediated knockdown of the pore-forming Na V 1.6 and regulatory Na V β4 sodium channel isoforms that have been previously implicated in a different model of low back pain caused by locally inflaming the L5 DRG. Knockdown of either subunit markedly reduced spontaneous pain and mechanical and cold hypersensitivity induced by DRG compression, and reduced spontaneous activity and hyperexcitability of sensory neurons with action potentials <1.5 msec (predominately cells with myelinated axons, based on conduction velocities measured in a subset of cells) 4 days after DRG compression. These results were similar to those previously obtained in the DRG inflammation model and some neuropathic pain models, in which sensory neurons other than nociceptors seem to play key roles. The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by Na V β4 knockdown in either model. The Na V 1.6 channel, and the Na V β4 subunit that can regulate Na V 1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.

Intervertebral foramen injection of plerixafor attenuates CCD-induced low back&nbsp;pain&nbsp;in&nbsp;rats through down-regulation of Nav1.8 and Nav1.9

“…In the present study, we used the CCD model induced by inserting a stainless steel rod between vertebrae holes (L4 and/or L5) which has been proven to be a typical model that mimics the clinical etiology and various symptoms of low back pain 3 . In line with previous studies, we identi ed four different pain behaviors in the ipsilateral hindpaw of CCD rats, including mechanical hyperalgesia, thermal hyperalgesia, mechanical allodynia and cold allodynia [22,29], which occurred as early as 1 day after surgery and maintained at least for 14 days.…”

“…As shown in the Fig.2A and Fig.2B, intraganglionar CXCR4 siRNA microinjection remarkably reduced CXCR4 expression in compressed DRG comparing with scrambled siRNA injection group. Previous studies have shown that CCD induces obvious mechanical and thermal pain sensitivity in the ipsilateral hindpaw as measured by the von Frey test and thermal stimuli, mechanical allodynia as measured by the paw withdrawal responses to a light cotton wisp stroking and cold allodynia as measured by increased withdrawal to acetone stimuli [22]. These multiple pain behaviors were also occurred as early as 1 day post CCD and maintained at least for 14 days (Fig.2).…”

“…We speculated that the protracted analgesic effect was largely because of the plerixafor not only reduced the expression of Nav1.8 and Nav1.9, but also has the ability to relieve in ammation in compressed DRG which was also a pivotal mechanism for neuronal hyperexcitability and chronic pain. In supporting, recent studies have demonstrated that the pro-in ammatory cytokines dramatically up-regulated accompanying with several anti-in ammatory cytokines down-regulated in compressed DRG [22], while plerixafor has been proven to be able to reducing the expression of TNF-α, IL-1β, IL-6 and in ammatory cell in ltration in the nervous system [10,35]. Collectively, the above characteristics and advantages of plerixafor make it an effective and applicable therapeutic medicine for neuropathic pain.…”

“…Taking together, these ndings evidenced that CXCR4-Nav1.8/Nav1.9 axis in compressed DRG was involved in CCD-induced low back pain. Recently, another study demonstrated that NaV1.6 and regulatory NaVβ4 sodium channel in compressed DRG also play key roles in low back pain [22]. Besides, TRPV4, voltage-gated potassium current and hyperpolarization-activated cation current were all reported to be correlated with CCD-induced low back pain [30,32,33].…”

“…Emerging data veri ed that the CCD causes an increase in the excitability of the cell bodies of compressed DRG neurons and the CCD-induced spontaneous activity and/or lowered rheobase of DRG neurons was accompanied, and possibly caused by, an increased expression of voltage-gated sodium currents (VGSCs) [19][20][21]. Recent research proved that knockdown of NaV1.6 and regulatory NaVβ4 sodium channel markedly reduced spontaneous pain and mechanical and cold hyperalgesia induced by CCD, indicating that targeting the VGSCs may have therapeutic value for low back pain [22]. However, the roles of two other distinct VGSCs identi ed in DRG neurons, Nav1.8 which plays an important role in action potential generation, and Nav1.9 which contribute to setting the resting membrane potential and to neuronal excitability [23], have not yet been explored in CCD-induced low back pain.…”