Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury

Abstract

Chronic neuropathic pain is a frequent consequence of spinal cord injury (SCI). Yet despite recent advances, up-stream releasing mechanisms and effective therapeutic options remain elusive. Previous studies have demonstrated that SCI results in excessive ATP release to the peri-traumatic regions and that purinergic signaling, among glial cells, likely plays an essential role in facilitating inflammatory responses and nociceptive sensitization. We sought to assess the role of connexin 43 (Cx43) as a mediator of CNS inflammation and chronic pain. To determine the extent of Cx43 involvement in chronic pain, a weight-drop SCI was performed on transgenic mice with Cx43/Cx30 deletions. SCI induced robust and persistent neuropathic pain including heat hyperalgesia and mechanical allodynia in wild-type control mice, which developed after 4 weeks and was maintained after 8 weeks. Notably, SCI-induced heat hyperalgesia and mechanical allodynia were prevented in transgenic mice with Cx43/Cx30 deletions, but fully developed in transgenic mice with only Cx30 deletion. SCI-induced gliosis, detected as upregulation of glial-fibrillary-acidic- protein (GFAP) in the spinal cord astrocytes at different stages of the injury, was also reduced in the knockout mice with Cx43/Cx30 deletions, when compared to littermate controls. In comparison, a standard regimen of post-SCI treatment of minocycline attenuated neuropathic pain to a significantly lesser degree than Cx43 deletion. These findings suggest Cx43 is critically linked to the development of central neuropathic pain following acute SCI. Since Cx43/Cx30 is expressed by astrocytes, these findings also support an important role of astrocytes in the development of chronic pain.

Connexin Hemichannels in Astrocytes: An Assessment of Controversies Regarding Their Functional Characteristics

“…However, the Cx43 crystal structure is of a limited resolution and the authors thus point out that with a higher resolution, in which the amino acid side chains would be visible, the Cx43 central pore may be as narrow as 5 Å [114], which would put severe limitations to the range of permeable solutes. There is evidence in favor of Cx30 and Cx43 acting as an ATP permeation pathway both in cell experiments [42,53,67,98,115] and in (patho) physiological contexts [80,[116][117][118]. This feature has, however, been questioned and assigned to other transport proteins and/or reduced cytosolic ATP concentration in the Cx43 −/− astrocytes [91].…”

Gap Junction Coupled Cells, Barriers and Systemic Inflammation

“…In inflammation that causes disruption of tight junctions a down regulation of Cx43 occurs in the gap junction regions and an up regulation of Cx43 in the hemichannels [39,40].…”

Involvement of Gap Junction Proteins in Infectious Diseases Caused by Parasites

“…Under physiological conditions, HCs are involved in the regulation of cell volume [33], vascular tone [34], hemostasis [35], and neuroglia paracrine interactions [36], among others. However, HCs have been the focus of interest because of their relevance in pathological conditions, including metabolic inhibition [37], stroke [38], myocardial infarction [39,40], ischemic neuronal death [41], spinal cord injury [42], diarrhoea during infectious enteric disease [5], and keratitis-ichthyosis-deafness syndrome [43].…”