Ueda Hiroshi, Neyama Hiroyuki, Dozono Naoki, Aoki Junken, Chun Jerold
Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Cells. 2025 Jul 4;14(13):1022. doi: 10.3390/cells14131022.
Since the initial report indicating that LPA signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA antagonists have demonstrated that LPA and LPA signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA signaling in the intermittent psychological stress induced-related FM-like model called intermittent psychological stress (IPS)-induced generalized pain (IPGP) model where the hyperalgesia in IPGP mice was abolished in LPA- and LPA-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA antagonist Ki16425 consistently prevented hyperalgesia. However, intracerebroventricular treatments with Ki16425 abolished hyperalgesia in male, but not female, mice. Notably, intrathecal treatments of Ki16425 did not prevent hyperalgesia. Further studies revealed that splenocytes derived from female IPGP mice could initiate hyperalgesia via adoptive transfer in naïve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA-mediated peripheral immune mechanisms.
自从最初的报告表明溶血磷脂酸（LPA）信号传导在引发神经损伤诱导的神经性疼痛（NeuP）中起关键作用以来，随后使用基因敲除小鼠和LPA拮抗剂的研究表明，LPA和LPA信号传导会影响NeuP和纤维肌痛（FM）模型。在本研究中，我们在间歇性心理应激诱导的类似FM的模型（称为间歇性心理应激（IPS）诱导的全身性疼痛（IPGP）模型）中确定了涉及LPA信号传导的痛觉过敏性别差异，在该模型中，IPGP小鼠的痛觉过敏在LPA基因敲除小鼠和LPA受体敲除小鼠中消失。通过腹腔内（i.p.）注射LPA拮抗剂Ki16425进行药物干预可持续预防痛觉过敏。然而，脑室注射Ki16425可消除雄性小鼠而非雌性小鼠的痛觉过敏。值得注意的是，鞘内注射Ki16425不能预防痛觉过敏。进一步的研究表明，来自雌性IPGP小鼠的脾细胞可通过在未致敏小鼠中进行过继转移引发痛觉过敏，当供体小鼠预先用Ki16425（i.p.）处理时，这种效应会消失。因此，这些研究确定了IPGP潜在的大脑中雄性特异性LPA介导的机制，以及不同的LPA-LPA介导的外周免疫机制。
