Nav1.7 and Nav1.8: Role in the pathophysiology of pain

Abstract

Chronic pain is a significant unmet medical problem. Current research regarding sodium channel function in pathological pain is advancing with the hope that it will enable the development of isoform-specific sodium channel blockers, a promising treatment for chronic pain. Before advancements in the pharmacological field, an elucidation of the roles of Na_v1.7 and Na_v1.8 in the pathophysiology of pain states is required. Thus, the aim of this report is to present what is currently known about the contributions of these sodium channel subtypes in the pathophysiology of neuropathic and inflammatory pain. The electrophysiological properties and localisation of sodium channel isoforms is discussed. Research concerning the genetic links of Na_v1.7 and Na_v1.8 in acquired neuropathic and inflammatory pain states from the scientific literature in this field is reported. The role of Na_v1.7 and Na_v1.8 in the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability highlights the importance of these channels in the development of pathological pain. However, further research in this area is required to fully elucidate the roles of Na_v1.7 and Na_v1.8 in the pathophysiology of pain for the development of subtype-specific sodium channel blockers.

Keywords: Nav1.7; Nav1.8; dorsal root ganglion; hyperexcitability; inflammatory pain; neuropathic pain; nociceptors; sodium channel; voltage-gated sodium channels.

Figure 1.

The structure and states of Na_v channels. (a) The secondary structure of the α-subunit of VGSCs. The pore forming α-subunit is arranged into four domains (DI-DIV) each with six transmembrane alpha helices (S1–S6). The S4 segments are voltage sensors containing positively charged ions. The intracellular loop between DIII and DIV is believed to be the fast inactivation gate. (b) The three distinct states of VGSCs, with the inactivated closed state present with either fast inactivation (within milliseconds) or slow inactivation (seconds) kinetics, which differs among VGSC isoforms.

Figure 2.

Proposed mechanisms of the role of Na_v1.7 and Na_v1.8 in the pathophysiology of neuropathic pain and inflammatory pain. (a) Nerve injury leads to an increased number of kinases such as p38 MAPK and ERK1/2. This leads to the modulation of Na_v1.7 channels which are upregulated as a result of nerve injury. This contributes to increased generation of ectopic discharge. In the acute phase following nerve damage, Na_v1.8 is downregulated in injured neurons and upregulated in neighbouring uninjured neurons, which contributes to increased spontaneous discharge. In the chronic phase via a form crosstalk between injured and intact neurons Na_v1.8 is also upregulated in injured neurons resulting in a further increase and maintenance of the ectopic discharge. This leads to spontaneous pain and hypersensitivity. (b) Inflammatory cells and mediators are present at increased numbers at the site of tissue injury and inflammation. This results in an increased number of kinases that phosphorylate and modulate the Na_v1.7 and Na_v1.8 channels, which are upregulated in nociceptors innervating the damaged tissue. This leads to an increase in ectopic action potentials. Together, these mechanisms result in spontaneous pain and hypersensitivity, that is, hyperalgesia and allodynia. PKA: protein kinase A; PKC: protein kinase C; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; DRG: dorsal root ganglion.