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    • Milligan et al demonstrated the important

    2022-05-11

    Milligan et al. [31] demonstrated the important role of TNF-α, IL-6 and IL-1β in the development of mechanical hyperalgesia induced by intrathecal injection of gp120. Because of this work, we decide to produce and purify gp120 to develop biological systems to study pain and behavior in rodents. Intrathecal administration of gp120 induced mechanical hyperalgesia in rats [30] and also in mice. Our results are in agreement with Milligan et al. [30] as shown by the ability of injection of gp120 at doses of 50, 300, and 500pg to induce mechanical hyperalgesia at 3h after injection. The immune response to HIV infection is a cell intrinsic, innate immune response [35]. In the innate immune response pathway, recognition of glycoproteins by Toll-like receptors (TLRs) induces inflammatory cytokine expression via activation of NF-kB [36]. Of the several TLRs, gp120 acts through interaction with TLR-2 and TLR-4. In a previous study, L-α-Aminoadipic Acid to TLR-2 and -4 blocked the ability of soluble gp120 to induce the nuclear translocation of NF-kB and production of TNF-α and other inflammatory cytokines in primary genital epithelial cells [37]. This induction probably involves a direct gp120 interaction with these TLRs, since in the presence of heparin sulfate (HS), soluble gp120 bound to TLR-2 and -4 on beads. Thus a tri-molecular complex of gp120, HS and TLR-2 or -4 was proposed to activate the innate immune response pathway, which in turn could induce cytokine expression and downstream behavioral effects. Although it has been shown that gp120 activates toll-like receptors [37], this was not measured directly in the current study and the role of the toll-like receptors in the current work remains a hypothesis. Therefore, we cannot say if limonene reduces either TLR-2 and TLR-4 activation or signaling downstream from these receptors following gp120 injection, and more studies are necessary to clarify this point. Limonene was demonstrated previously to have antidepressant and antihyperalgesic activity in a neuropathic pain model in animals and for that reason the current study tested the protective effect of limonene on the action of inflammatory cytokines and gp120. To our knowledge, the current study is the first to show that oral administration (10mg/kg) of limonene prevented gp120-induced mechanical hyperalgesia in mice. The present work has also shown that prior administration of limonene decreases IL-1β and IL-10 produced in whole blood by intrathecal injection of gp120. Moss et al. [4] showed that gp120 significantly increased the expression of 25 cytokine-related genes in bone marrow-derived macrophage, some of which have been implicated in other painful polyneuropathies. HIV infection and administration of soluble gp120 induced inflammasome activation in microglia and the release of IL-1β [38]. These steps have been demonstrated to be related to cortical neuronal loss and complex neurobehavioral deficits. IL-1β release, in turn, is capable of inducing the synthesis of other cytokines. TNF-α and IL-1β [39] are well known to change sensitivity to mechanical stimuli after spinal cord administration. The intrathecal administration of IL-1β (5–5000pg) or TNF-α (5–5000ng) produced a significant increase in the frequency of withdrawal responses indicative of allodynia and hyperalgesia [39]. Because limonene prevented the observed gp120 actions, and because mechanical hyperalgesia induced by gp120 administered by the spinal cord route is related to the actions of TNF-α and IL-1β, we decided to test the effects of limonene against hyperalgesia caused by TNF-α and IL-1β. In our work, the spinal injection of TNF-α induced mechanical hypersensitivity and limonene inhibited TNF-α-induced mechanical hyperalgesia. IL-1β increased the development of hyperalgesia. Oral administration of limonene reduced the mechanical hyperalgesia induced by IL-1β and TNF-α. Previous studies have shown that limonene reduces the activation of NF-κB in a rat colitis model and NF-kB expression in a doxorubicin-induced stress model [24], [40]. The ability of limonene to reduce the inflammatory response may result from the reported ability of limonene and its endogenous metabolite, perillyl alcohol [41], to block the activation of NF-kB in cultured cells, as shown by their ability to block NF-kB binding to DNA [42], [43]. Thus the main pathway by which limonene blocks TNF-α and IL-1β expression could be a block of activation of NF-kB. In this case, the failure of limonene to block the regulation of SOD and HSP90 could reflect an independence of expression of these proteins from NF-kB activation. We cannot, however, exclude that other pathways activate the cytokines.