Archives

  • 2018-07
  • 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
  • One difficulty in studying gp is that it

    2021-11-29

    One difficulty in studying gp120 is that it binds to more than one receptor. Understanding how Epiberberine respond to gp120 is complex because of this promiscuity. In an attempt to establish the contribution of CXCR4 in the antagonistic effect of gp120 on morphine-induced antinociception, AMD3100 was administered directly into the PAG prior to gp120 and morphine. It was found that AMD3100 (Donzella et al., 1998) interacts with and blocks CXCR4, the main co-receptor used by T-tropic viruses (Schols et al., 1997a, Schols et al., 1997b). In previous studies, AMD3100 was shown to inhibit the replication of T-tropic HIV strains or clinical isolates in T-cell lines, such as MT-4, MOLT-4, or CEM cells (De Vreese et al., 1996, De Clercq, 1994). In addition, the interaction between CXCL12 and CXCR4 can be blocked by AMD3100 (Schols et al., 1997a, Schols et al., 1997b). Our present data show that pretreatment with AMD3100 prevents the effect of gp120 on morphine-induced antinociception and indicates that the inhibitory effect of gp120 is mediated by CXCR4 in the PAG. That the pretreatment with AMD3100 was able to restore the analgesic effects of morphine suggests that chemokine blockers might be used as a strategy to restore opioid functions, particularly in neuroinflammatory conditions such as the presence of gp120 in the brain. The effect of gp120 could occur in one of two ways. The most direct mechanism would be for gp120 to bind directly to the chemokine receptors on the neurons and thereby inhibit the induction of morphine-induced analgesia. The alternative mechanism would be for gp120 to bind to microglia and release chemokines, which would bind to the chemokine receptors to cause the effect on opioid receptors. Although this study was not designed to determine which of these two pathways is in operation, it demonstrates conclusively that CXCR4 is involved in the antagonism of gp120 on morphine-induced analgesia. Our laboratory has reported electrophysiological evidence for heterologous desensitization between the mu opioid receptor and CXCR4 in the PAG at the single-cell level (Heinisch et al., 2011). Specifically, we demonstrated that chemokines, including CXCL12, can prevent mu-opioid receptor-mediated PAG neuron hyperpolarization and reduction of input resistance. In a similar manner, the current study (Fig. 7) showed that gp120 pretreatment blocked both morphine-mediated hyperpolarization as well as morphine-mediated reduction in input resistance in these neurons, which strongly support the in vivo results from the antinociceptive tests (cold-water tail-flick test and hot-plate test). These findings from both behavioral experiments and electrophysiology experiments demonstrate for the first time that gp120 reduces morphine antinociception in the PAG and that morphine’s effect can be restored by antagonism of CXCR4 receptors expressed in the brain of rats.
    Acknowledgments
    Introduction HIV infection of target cells is a multi-stage process involving the entry, replication, and budding of virus. Presently, many strategies have been developed for HIV therapy depending on distinct stages of the process, among which blocking HIV entry is a well-known, important one. Many entry inhibitors or drugs have been developed in the treatment of HIV infection by blocking the interactions of HIV envelop glyprotein gp120 with cell-surface CD4 or coreceptors, or HIV envelop protein gp41-mediated membrane fusion [1], [2], [3], [4]. However, the interactions of the inhibitors or drugs with CD4 or gp120 or gp41 remain poorly understood. Soluble CD4 (sCD4) and CD4-mimetic compounds are well known to inhibit HIV entry in vitro or in vivo [5], [6], [7], [8]. It has been reported that sCD4 selectively inhibited HIV replication and syncytium formation [9] or inactivated HIV by inducing the release of gp120 [10], [11]. Recently, sCD4 and CD4 mimics were found to inhibit HIV infection by inducing a short-lived activated state of gp120 and spontaneously and irreversibly transforming gp120 into a non-functional conformation from the relatively long-lived activated intermediate induced by cell-associated CD4 [12]. Neutralizing antibodies against gp120 or cell-associated CD4 are also well-known HIV entry inhibitors and antibody-based vaccines [13], [14], [15]. These antibodies inactivate or neutralize or block the invading HIV virus by interacting with gp120 on viral surface or cell-surface CD4 on CD4+ lymphocytes.