Increased Na_v1.7 expression in the dorsal root ganglion contributes to pain hypersensitivity after plantar incision in rats

Abstract

Postoperative pain remains a complex problem that is difficult to manage in the clinical context, seriously affecting rehabilitation and the quality of life of patients after surgery. Nociceptors, of which the cell bodies are located in the dorsal root ganglion, are crucial for initiating and conducting the pain signal. The peripheral voltage-gated sodium channels, including Nav1.7, which is mainly expressed in the dorsal root ganglion, are key to understanding the mechanism underlying postoperative pain. Nav1.7, in particular, of which mutations in the encoding gene (SCN9A) can determine whether pain occurs, has aroused most attention. Previous studies have shown that Nav1.7 in dorsal root ganglion is critical for the development of inflammatory pain and some neuropathic pain. However, the expression of Nav1.7 in the dorsal root ganglion after surgery and its role in postoperative pain hypersensitivity remain unclear. Therefore, in this study, in order to gain a better understanding of the role of dorsal root ganglion Nav1.7 in pain hypersensitivity following operation, we dynamically examined the pain-related behavior and expression of Nav1.7 in L4−L6 dorsal root ganglion before and after plantar incision in rats (an acute postoperative pain model). After plantar incision, the mechanical and thermal pain threshold decreased significantly, the cumulative pain score was increased significantly, meanwhile quantitative polymerase chain reaction and Western blotting results showed that expression of Nav1.7 in L4−L6 dorsal root ganglion was enhanced significantly. After pretreatment using SCN9A-RNAi-LV delivered via an intrathecal tube, immunohistochemistry showed that increased expression of Nav1.7 in L4−L6 dorsal root ganglion after plantar incision was inhibited, as also confirmed by quantitative polymerase chain reaction and Western blotting. Moreover, pain hypersensitivity was alleviated. These results suggested that Nav1.7 of L4−L6 dorsal root ganglion plays an important role in the development of pain hypersensitivity after plantar incision.

Voltage‐gated sodium channel 1.7 expression decreases in dorsal root ganglia in a spinal nerve ligation neuropathic pain model

“…Studies have shown that deficits in expression and/or function of Nav1.7 may have analgesic effects: Nav1.7 conditional knockout and Nav1.7 blocker protoxin II modulated pain in burn injury models; inhibition of NaV1.7 was effective in treating inflammatory and neuropathic pain in mice . By contrast, the enhancement of Nav1.7 function leads to pain: Enhanced expression of Nav1.7 in L4‐L6 DRGs contributed to pain hypersensitivity after plantar incision; prostaglandin E2 induced up‐regulation of Nav1.7 that was involved in inflammatory pain in rats …”

Neuropathic pain: Spotlighting anatomy, experimental models, mechanisms, and therapeutic aspects

“…The schematic drawing shows the central neurite of a primary order dorsal root ganglion neuron and a synapse of such a neuron with a second‐order neuron in the dorsal horn of the spinal cord. The scheme summarises alterations of the voltage‐gated sodium channels (Na V , orange), the adenosine triphosphate (ATP)‐dependent activity of the sodium‐potassium adenosine triphosphatase (Na + /K + ATPase, red), the N ‐methyl‐D‐aspartate receptor (NMDAR, green), the sodium‐potassium‐chloride cotransporter 1 (NKCC1, light blue) the auxiliary voltage‐gated channel subunit α2δ‐1 (purple) and the potassium‐chloride cotransporter 2 (KCC2, dark blue) in the first‐order dorsal root ganglia neurons ( 1 Chang et al., 2017, 2 Sun et al., 2018, 3 Blesneac et al., 2018, 4 Alsaloum et al., 2019, 5 Meents et al., 2019, 6 Qu et al., 2019, 7 Duggett et al., 2017, 8 Yan et al., 2013, 9 McGuinness et al., 2010, 10 Hasbargen et al., 2010, 11 Tan et al., 2020, 12 Luo et al., 2001, 13 Newton et al., 2001, 14 Tachiya et al., 2018, 15 Boroujerdi et al., 2008, 16 Nguyen et al., 2009, 17 Zhou & Luo, 2014).…”

“…Besides Na V 1.7, special focus was laid on Na V 1.8, and Na V 1.9. Following injury or chemotherapy, secretion of signal molecules may upregulate the expression of Na V 1.7 in rats and humans, and cause an enhanced excitability (Chang et al., 2017; Sun et al., 2018). Other findings suggest that de novo expression of Na V 1.8 is reduced in patients after peripheral nerve injury, while already present channels accumulate at the injury sites (Coward et al., 2000).…”

“…Increased levels of the voltage‐gated sodium channels Na V 1.7 and Na V 1.8 were furthermore detected in a mild severity mice model of SMA, showing mechanical allodynia, thermal allodynia, and hyperalgesia (Qu et al., 2019). Three of the studies mentioned above, were able to show that overexpression of voltage‐gated sodium channels is accompanied by a reduced threshold potential of the cell (Chang et al., 2017; Qu et al., 2019; Sun et al., 2018). Due to the lowered threshold, minor stimuli may cause action potentials and consequently allodynia.…”

Upregulation of Nav1.7 by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain

“…Studies have shown that dorsal root ganglion (dRG) neurons are closely associated with neuropathic pain. changes in neurotrophic factors, inflammatory factors and expression Upregulation of Na v 1.7 by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain JUN-JIE TIAN 1,2* , cHAO-YANG TAN 1,3* , QIN-YI cHEN 1,4* , YING ZHOU 1,5 , ZU-WEI QU 6 , MENG ZHANG 7,8 , KE-TAO MA 1,9 , WEN-YAN SHI 1,9 , LI LI 10 and JUN-QIANG SI 1,9,11 of various ion channels in dRG neurons result in increased excitability of dRG neurons, which underlie the development of neuropathic pain (3)(4)(5)(6)(7). Voltage-gated sodium channels (VGScs or Na v s) have been classified into nine different subtypes (Na v 1.1-1.9), seven of which are expressed on human dRG neurons (Na v 1.1-1.3 and Na v 1.6-1.9).…”