Role of gap junctions in chronic pain

Wu, Ann Chen; Green, Colin; Rupenthal, Ilva D.; Moalem‐Taylor, Gila

doi:10.1002/jnr.22764

Cited by 56 publications

(37 citation statements)

References 92 publications

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“…Several cell-specific subtypes of connexins (Cx) have been found 56 and connexin 43 (Cx43) is the primary component of intercellular gap junction connections in astrocytes 5,12,16,17 . The expression of Cx43 in spinal dorsal horn following chemotherapy was assessed by western blotting.…”

Section: Resultsmentioning

confidence: 99%

Spinal Astrocyte Gap Junctions Contribute to Oxaliplatin-Induced Mechanical Hypersensitivity

Yoon

Robinson

Zhang

et al. 2013

The Journal of Pain

111

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Spinal glial cells contribute to the development of many types of inflammatory and neuropathic pain. Here the contribution of spinal astrocytes and astrocyte gap junctions to oxaliplatin-induced mechanical hypersensitivity was explored. The expression of glial fibrillary acidic protein (GFAP) in spinal dorsal horn was significantly increased at day 7 but recovered at day 14 after oxaliplatin treatment, suggesting a transient activation of spinal astrocytes by chemotherapy. Astrocyte-specific gap junction protein connexin 43 was significantly increased in dorsal horn at both day 7 and day 14 following chemotherapy but neuronal (connexin 36) and oligodendrocyte (connexin 32) gap junction proteins did not show any change. Blockade of astrocyte gap junction with carbenoxolone prevented oxaliplatin-induced mechanical hypersensitivity in a dose-dependent manner and the increase of spinal GFAP expression, but had no effect once the mechanical hypersensitivity induced by oxaliplatin had fully developed. These results suggest that oxaliplatin chemotherapy induces the activation of spinal astrocytes and this is accompanied by increased expression of astrocyte-astrocyte gap junction connections via connexin 43. These alterations in spinal astrocytes appear to contribute to the induction but not the maintenance of oxaliplatin-induced mechanical hypersensitivity. Combined these results suggest that targeting spinal astrocyte/astrocyte-specific gap junction could be a new therapeutic strategy to prevent oxaliplatin-induced neuropathy.

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Section: Resultsmentioning

confidence: 99%

Spinal Astrocyte Gap Junctions Contribute to Oxaliplatin-Induced Mechanical Hypersensitivity

Yoon

Robinson

Zhang

et al. 2013

The Journal of Pain

111

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“…Hightened astrocyte-astrocyte communication following SCI, through gap junction networks, may result in extensive Ca 2+ waves, and long range signaling via the release of ATP. This could directly excite nociceptive neurons, by binding to neuronal P2 receptors, in addition to causing the glial-mediated release of proinflammatory cytokines or pronociceptive molecules, such as ATP, prostaglandin or glutamate, in local or peritraumatic tissue (Evans et al 2006; Stout et al 2002; Wu et al 2012). Furthermore, decoupling of gap junctions has been previously shown greatly reduced the concentrations of IL-1 and IL-6 in tissues and in the CSF, which as a result inhibited the development of mechanical allodynia and heat hyperalgesia after nerve injury (Spataro et al 2004).…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Kress

Han

et al. 2012

Glia

173

156

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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.

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“…neurons, astrocytes), allowing rapid intercellular exchange of small molecules including ions, second messengers, nutrients and metabolites [2; 40; 50; 55]. A characteristic example is the transients and oscillatory waves of cytoplasmic Ca 2+ in astrocytes elicited by neuronal activity that may propagate to adjacent and/or distant astrocytes through gap junctions and hemichannels [1; 13; 36].…”

Section: Introductionmentioning

confidence: 99%

The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats

Wang

Cao

Chiang

et al. 2014

Pain

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Glial cells are being increasingly implicated in mechanisms underlying pathological pain and recent studies suggest glial gap junctions involving astrocytes may contribute. The aim of the present study was to examine the effect of a gap junction blocker carbenoxolone (CBX) on medullary dorsal horn (MDH) nociceptive neuronal properties and facial mechanical nociceptive behavior in a rat trigeminal neuropathic pain model involving partial transection of the infraorbital nerve (p-IONX). p-IONX produced facial mechanical hypersensitivity reflected in significantly reduced head withdrawal thresholds that lasted for over 3 weeks. p-IONX also produced central sensitization in MDH nociceptive neurons that was reflected in significantly increased receptive field size, reduction of mechanical activation threshold and increases in noxious stimulation-evoked responses. Intrathecal CBX treatment significantly attenuated the p-IONX-induced mechanical hypersensitivity and the MDH central sensitization parameters, compared to intrathecal vehicle treatment. These results provide the first documentation that gap junctions may be critically involved in orofacial neuropathic pain mechanisms.

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Role of gap junctions in chronic pain

Cited by 56 publications

References 92 publications

Spinal Astrocyte Gap Junctions Contribute to Oxaliplatin-Induced Mechanical Hypersensitivity

Spinal Astrocyte Gap Junctions Contribute to Oxaliplatin-Induced Mechanical Hypersensitivity

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

The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats

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