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

## TL;DR

The study shows that pain responses in a fibromyalgia-like model differ between males and females, with LPA1 and LPA3 signaling playing a key role.

## Contribution

The study reveals sexual dimorphism in LPA1/3 signaling mechanisms underlying stress-induced fibromyalgia-like pain.

## Key findings

- Hyperalgesia in the IPGP model was abolished in LPA1- and LPA3-knockout mice.
- Intracerebroventricular LPA1/3 antagonism prevented hyperalgesia in males but not females.
- Female IPGP splenocytes induced hyperalgesia in naïve mice, blocked by systemic LPA1/3 antagonism.

## Abstract

Since the initial report indicating that LPA1 signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA1/3 antagonists have demonstrated that LPA1 and LPA3 signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA1/3 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 LPA1- and LPA3-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA1/3 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 naïve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA1/3-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA1/3-mediated peripheral immune mechanisms.