Pannexin 1: A novel participant in neuropathic pain signaling in the rat spinal cord

Abstract

Pannexin 1 (panx1) is a large-pore membrane channel expressed in many tissues of mammals, including neurons and glial cells. Panx1 channels are highly permeable to calcium and adenosine triphosphatase (ATP); on the other hand, they can be opened by ATP and glutamate, two crucial molecules for acute and chronic pain signaling in the spinal cord dorsal horn, thus suggesting that panx1 could be a key component for the generation of central sensitization during persistent pain. In this study, we examined the effect of three panx1 blockers, namely, 10panx peptide, carbenoxolone, and probenecid, on C-reflex wind-up activity and mechanical nociceptive behavior in a spared nerve injury neuropathic rat model involving sural nerve transection. In addition, the expression of panx1 protein in the dorsal horn of the ipsilateral lumbar spinal cord was measured in sural nerve-transected and sham-operated control rats. Sural nerve transection resulted in a lower threshold for C-reflex activation by electric stimulation of the injured hindpaw, together with persistent mechanical hypersensitivity to pressure stimuli applied to the paw. Intrathecal administration of the panx1 blockers significantly depressed the spinal C-reflex wind-up activity in both neuropathic and sham control rats, and decreased mechanical hyperalgesia in neuropathic rats without affecting the nociceptive threshold in sham animals. Western blotting showed that panx1 was similarly expressed in the dorsal horn of lumbar spinal cord from neuropathic and sham rats. The present results constitute the first evidence that panx1 channels play a significant role in the mechanisms underlying central sensitization in neuropathic pain.

Pannexin-1 Up-regulation in the Dorsal Root Ganglion Contributes to Neuropathic Pain Development

“…However, the conclusion of the authors is entirely on the basis of the use of pharmacological agents that may not specifically block Panx1 channels (37). Also, the authors assume that the analgesic effect produced by intrathecal administration of Panx1 blockers is through inhibition of Panx1 in the spinal cord (36). However, neither spinal nerve ligation (used in our study) nor sural nerve transection (36) has any effect on Panx1 expression level in the rat spinal cord.…”

“…A recent study has reported that intrathecal injection of Panx1 blockers reduces pain hypersensitivity caused by sural nerve transection in rats (36). However, the conclusion of the authors is entirely on the basis of the use of pharmacological agents that may not specifically block Panx1 channels (37).…”

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

“…Diverse strategies aimed at blocking HC activity using genetic or pharmacological tools have thus been developed [25][26][27][28]. Most of them suppress Cx43 expression and/or function, which are considered the main HC constituent in astrocytes [7] by knocking-out Cx43 gene, for instance, using anti-sense tools, antibodies or mimetic peptides.…”

“…Meanwhile, glutamate and ATP can also promote activation of neuronal NMDA and purinergic receptors, further leading to Ca 2+ overload and the activation of intracellular neurotoxic cascades resulting in neurodegeneration [18]. This is summarized in Figure 1.Diverse strategies aimed at blocking HC activity using genetic or pharmacological tools have thus been developed [25][26][27][28]. Most of them suppress Cx43 expression and/or function, which are considered the main HC constituent in astrocytes [7] by knocking-out Cx43 gene, for instance, using anti-sense tools, antibodies or mimetic peptides.…”

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

“…Each Cx member displays a specific temporal (developing CNS versus mature CNS) and spatial (cell-specific and regionspecific) expression pattern, and each cell type contains a unique Cx portfolio (Table 1). Of note, a detailed overview of the Cx and Panx expression profile in the developing and mature CNS is beyond the scope of this review, and we refer the reader to primary and secondary literature sources [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] for more information. Six Cx subunits oligomerize to form a hemichannel (HC), which subsequently docks head-to-head with an apposed HC on a neighboring cell to form a GJC at cell-cell contact regions (Fig.…”