Ovarian Hormone-dependent and Spinal ERK Activation-regulated Nociceptive Hypersensitivity in Female Rats with Acid Injection-induced Chronic Widespread Muscle Pain

Ju-Hsin Chang,Yu-Cheng Liu,Yeong-Ray Wen,Shih-Ying Tsai,Yen-Jing Zeng,Kuen-Bao Chen,Chi-Yuan Li

doi:10.1038/s41598-019-39472-z

Ju-Hsin Chang, Yu-Cheng Liu + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-39472-z

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Abstract

Symptoms of chronic widespread muscle pain (CWP) meet most of the diagnostic criteria for fibromyalgia syndrome, which is prevalent in females. We used an acid injection-induced muscle pain (AIMP) model to mimic CWP. After female rats received an ovariectomy (OVX), acid saline solution was injected into the left gastrocnemius muscle. Time courses of changes in pain behaviours and p-ERK in the spinal cord were compared between groups. Intrathecal injections of oestradiol (E2) to the OVX group before two acid injections and E2 or progesterone (P4) injections in male rats were compared to evaluate hormone effects. We found that repeated acid injections produced mechanical hypersensitivity and enhanced p-ERK expression in the spinal dorsal horn. OVX rats exhibited significantly less tactile allodynia than did the rats in the other groups. The ERK inhibitor U0126 alleviated mechanical allodynia with lower p-ERK expression in the sham females but did not affect the OVX rats. Intrathecal E2 reversed the attenuated mechanical hypersensitivity in the OVX group, and E2 or P4 induced transient hyperalgesia in male rats. Accordingly, our results suggested that ovarian hormones contribute to AIMP through a spinal p-ERK-mediated pathway. These findings may partially explain the higher prevalence of fibromyalgia in females than males.

Highlights

Symptoms of chronic widespread muscle pain (CWP) meet most of the diagnostic criteria for fibromyalgia syndrome, which is prevalent in females
Our results revealed that ovarian hormones contribute to acid injection-induced muscle pain (AIMP) through a spinal p-ERK-mediated pathway
Saline injection did not alter withdrawal thresholds (Fig. 10). These findings demonstrated that male rats treated with intrathecal ovarian hormones developed acute and short mechanical hypersensitivity for at least 24 h

Summary

Introduction

Symptoms of chronic widespread muscle pain (CWP) meet most of the diagnostic criteria for fibromyalgia syndrome, which is prevalent in females. Our results suggested that ovarian hormones contribute to AIMP through a spinal p-ERK-mediated pathway These findings may partially explain the higher prevalence of fibromyalgia in females than males. Several hypotheses regarding pathophysiology of CWP have been proposed, such as central sensitization[7,8]; pain disinhibition[9,10]; peripheral sensitization[11]; increases in nociceptive substances[12]; up-regulation of an acid-sensing ion channel (ASIC3) in muscle[13] and in dorsal root ganglia[14]; and elevated cytokines levels[15,16] None of these pathways can adequately explain the sex difference in pain pathologies. This model is widely used to mimic CWP or FMS in humans

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