Journal article
Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain
The journal of pain, Vol.26, 104723
01/2025
DOI: 10.1016/j.jpain.2024.104723
PMID: 39522853
Abstract
Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in mice.
This article presents novel mechanisms testosterone’s protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.
●Testosterone in females prevents the increase in SERT protein in the RVM after muscle pain.●SERT inhibition in the RVM reduces hyperalgesia in female mice, blocked by 5-HT2A inhibitor.●Androgen receptor mRNA is found on 5-HT2A and SERT mRNA positive cells in the RVM.
Details
- Title: Subtitle
- Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain
- Creators
- Ashley N. Plumb - University of IowaJoseph B. Lesnak - University of IowaLynn Rasmussen - University of IowaKathleen A. Sluka - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The journal of pain, Vol.26, 104723
- DOI
- 10.1016/j.jpain.2024.104723
- PMID
- 39522853
- NLM abbreviation
- J Pain
- ISSN
- 1526-5900
- eISSN
- 1528-8447
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health: AR073187, NS045549, GM067795 Foundation for Physical Therapy Research Promotion of Doctoral Studies (PODS) I
This work was supported by the National Institutes of Health AR073187 (KAS), NIH NS045549 (ANP), Foundation for Physical Therapy Research Promotion of Doctoral Studies (PODS) I (JBL), NIH GM067795 (JBL). The study and its contents are the authors' sole responsibility.
- Language
- English
- Date published
- 01/2025
- Academic Unit
- Iowa Neuroscience Institute; Nursing; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology
- Record Identifier
- 9984748258802771
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