Examination of the contribution of Nav1.7 to axonal propagation in nociceptors

Abstract

Na v 1.7 is a promising drug target for the treatment of pain. However, there is a mismatch between the analgesia produced by Na v 1.7 loss-of-function and the peripherally restricted Na v 1.7 inhibitors, which may reflect a lack of understanding of the function of Na v 1.7 in the transmission of nociceptive information. In the periphery, the role of Na v 1.7 in transduction at nociceptive peripheral terminals has been comprehensively examined, but its role in axonal propagation in these neurons is less clearly defined. In this study, we examined the contribution of Na v 1.7 to axonal propagation in nociceptors using sodium channel blockers in in vivo electrophysiological and calcium imaging recordings in mice. Using the sodium channel blocker tetrodotoxin (TTX) (1-10 mM) to inhibit Na v 1.7 and other tetrodotoxin-sensitive sodium channels along the sciatic nerve, we first showed that around two-thirds of nociceptive L4 dorsal root ganglion neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. By contrast, nearly all large-sized cutaneous afferents (95%-100%) were blocked by axonal TTX. Many cutaneous nociceptors resistant to TTX were polymodal (57%) and capsaicin sensitive (57%). Next, we applied PF-05198007 (300 nM-1 mM) to the sciatic nerve between stimulating and recording sites to selectively block axonal Na v 1.7 channels. One hundred to three hundred nanomolar PF-05198007 blocked propagation in 63% of C-fiber sensory neurons, whereas similar concentrations produced minimal block (5%) in rapidly conducting A-fiber neurons. We conclude that Na v 1.7 is essential for axonal propagation in around twothirds of nociceptive cutaneous C-fiber neurons and a lower proportion (#45%) of nociceptive neurons innervating muscle.

Modulation of activity-dependent excitability changes in subclasses of primary afferent nociceptors

“…In line with this idea, presumably Na V 1.8 mediated TTX-r conduction has been shown in C-fibers 252,250,240,410 , and these results are substantiating the body of evidence showing TTX-r axonal AP conduction in somatosensory C-fibers of distal nerve segments 269,84,67 . Furthermore, in support of the aforementioned theory and coherent with recent studies on murine nociceptors 187 , these experiments also demonstrate that differences in TTX sensitivity exist between the various Cnociceptors: Whereas conduction in CMs is blocked even after a low concentration of intra-dermally injected TTX (100 nM), activation thresholds changes in CMis, but none of these fibers are blocked by TTX injections during 5 Hz rectangular electrical stimulation 252 . Considering that Na V 1.8 is essential to generate TTX-r APs 276 , these results are confirming previous studies showing that this Na V isoform is highly expressed in CMi-, but less in CM nociceptors 399 .…”

In vivo calcium imaging shows that satellite glial cells have increased activity in painful states

“…However, we know from our own work ( Supplementary Fig. 1 ) and that of others 17 , 20 , 36 that electrical stimulation of the sciatic nerve very robustly induces activation of the vast majority of neurons within a field of view during our calcium imaging setup.…”

“…For the latter, 5 µl of AAV9 pAAV-Syn- GCaMP6s -WPRE.SV40 virus (Addgene, Watertown, MA, USA, #100843-AAV9) was injected into C57BL/6J pups 3–6 days after birth as previously described. 36 …”

Regulation of pain neurotransmitters and chondrocytes metabolism mediated by voltage-gated ion channels: A narrative review

“…They regulate the release of pain-causing neurotransmitters and the excitability of neurons, thereby affecting the occurrence and development of pain [ 38 , 39 ]. The sodium channel expressed in peripheral neurons is mainly Nav1.7, and Nav1.7 is more obviously expressed in nociceptive sensory neurons than non-nociceptive sensory neurons [ 40 , 41 ]. Nav1.7 knockout mice exhibited reduced mechanical and inflammatory pain through failure to initiate peripheral terminal action potentials, failure to transmit action potentials to secondary neurons in the spinal cord, and defective neurotransmitter release [ 42 ].…”