Hyperalgesia in the Psychological Stress-Induced Fibromyalgia Model Shows Sexual Dimorphism Mediated by LPA1 and LPA3

Since the initial report indicating that LPA(1) signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA(1/3) antagonists have demonstrated that LPA(1) and LPA(3) signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA(1/3) 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(1)- and LPA(3)-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA(1/3) 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 na & iuml;ve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA(1/3)-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA(1/3)-mediated peripheral immune mechanisms.