Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • UNC2025 receptor br Involvement of gap junctions and

    2022-01-21


    Involvement of gap junctions and Panx1 in spinal cord processing of pain information Several studies indicated that GJs in the CNS contribute to pain. A common finding in such studies is that intrathecal administration of GJ blocker attenuates pain behavior. For example, intrathecal CBX attenuated nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection [35] and by spinal nerve ligation (SNL) in rats [36]. Surprisingly, the latter group reported that spinal Cx43 was reduced in SNL, and intrathecal application of Cx43 siRNA alleviated SNL hypersensitivity [37]. This apparent paradox was explained by proposing that the function of Cx43 channels increased despite their lower expression levels. A major caveat of all studies using intrathecal application of drugs is that they readily diffuse to the sensory ganglia [38]. Thus, such application may not distinguish between central and peripheral drug actions. As mentioned above, oxaliplatin treatment leads to neuropathic pain and sensitization in sensory ganglia. It also leads to gap junction changes in the spinal cord, with reactive gliosis and upregulated Cx43 all appearing as hypersensitivity develops between 1 and 2 weeks after treatment [39]. These effects were prevented by intrathecal CBX pre-treatment, but not by CBX administration after CINP was established. In a rat sciatic inflammatory neuropathy (SIN) model, intrathecal CBX dose-dependently reversed allodynia and mirror-image pain, while in the CCI model CBX only affected mirror-image pain [40]. Further insight into mirror-image pain has come from a recent study showing that spinal cord UNC2025 receptor injection led to bilateral pain responses and bilaterally increased Cx43 expression in spinal cord [41]. The mechanism appears to be inflammation-related. As many as 80% of spinal cord injury (SCI) patients suffer from pain and it has been proposed that changes in spinal cord GJs contribute to the spread and severity of the damage; for review see [42] and for recent work on animal models see [43].
    Pannexin1 in sensory ganglia Pannexins (Panx) are membrane channels related to GJ, but they do not form cell-to-cell channels and they are highly permeable to ATP [44], [45]. Panx1 expression and impact on peripheral pain sensitivity were reported at scientific meetings in 2012 and summarized in a review [46]. However, the first published account of Panx1 expression in sensory ganglia was the report of high levels of Panx1 expression in TG, where it was localized to both sensory neurons and SGCs [47]. Panx1 increased in TG in the CFA orofacial pain model [48]. Moreover, mice in which Panx1 was globally deleted did not develop allodynia following CFA; selective Panx1 deletion in glia (GFAP-cre/Panx1ff) prevented hypersensitivity similarly to the global knockout, whereas targeting neuronal deletion (NFH-cre) only resulted in a slight delay in onset of hypersensitivity that did not persist or develop into allodynia. Measurement of Ca2+ signaling in SGCs or neurons revealed that both cell types were hyperactive, and their response to ATP was exaggerated in the pain model. Thus, glial and neuronal Panx1 appear to play major, but distinct, roles in development of allodynia in this pain model. There have been several other reports associating Panx1 expression and/or function with pain. In a study on nodose ganglion, Panx1 and Cx43 were reported to be exclusively expressed in neurons and glia, respectively [49]. Both gap junction and Panx1 drugs modified vagal sensory nerve activity, from which they concluded that SGC Cx43 hemichannels played a role in neuronal excitation. However, reduced activity of Panx1 channels through pharmacological blockade or in the Panx1 null mouse also attenuated the response, suggesting that Panx1 likely also plays a role in excitation. Moreover, Panx1 was subsequently detected in nodose ganglion SGCs as well as in sensory neurons, and its expression increased in the LPS injection model of systemic pain [28].