# Sex-specific regulation of local translation and chronic pain mechanisms in females

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2022 · $483,157

## Abstract

Despite recent advances in our understanding of pain mechanisms, there has been little-to-no overall
improvement in the clinical management of chronic pain. It is now recognized that effective chronic pain
management depends on key biological variables, especially patient sex. Hence, there is an urgent need to
customize chronic pain management schemes based on sex-specific pain mechanisms. Accordingly, our
long-term goal is to define sex-dependent mechanisms controlling pain chronicity, and utilize this knowledge
to develop sex-specific therapeutics for more effective chronic pain management. Gonadal hormones (GnH)
play a key role in sex-dependent regulation of pain mechanisms. There is a gap in knowledge pertaining to
how GnH regulate pain chronicity. The objective of this proposal is to identify regulatory mechanisms
recruited by GnH for sex-dependent control of pain chronicity. Based on the existing literature and our
preliminary data, we propose an entirely novel regulatory mechanism for sexual dimorphisms in chronic
pain plasticity wherein the transition from acute to chronic pain is governed by remote control of gene
function via GnH-dependent local translation. Our preliminary data suggests that the prolactin receptor (Prlr)
may be a linchpin in this mechanism. Prlr is locally translated in females but not males in nociceptor
terminals where it contributes strongly to pain plasticity exclusively in females. For instance, sensory
neuronal specific Prlr ablation leads to a suppression of IL-6-induced hypersensitivity only in females.
Moreover, Prolactin (PRL)-induced hyperalgesic priming, which models the transition from acute to chronic
pain, is dramatically enhanced in females compared to males. Therefore, our central hypothesis is that sex-
specific regulation of the transition to chronic pain occurs via continuous local translation in
nociceptor terminals of mRNAs such as Prlr, and this is fundamentally controlled by gonadal
hormones. The proposed study will: 1) greatly expand our knowledge of mechanisms controlling chronicity
of pain conditions in females; and 2) provide translational potential by offering therapeutic targets for sex-
based chronic pain management. Our hypothesis is tested by interconnected yet independent aims. Aim 1
defines the contribution of local translation in nociceptive terminals, GnH and Prlr in sex-dependent
regulation of hyperalgesic priming. Aim 2 examines the involvement of GnH in sex-specific local translation.
Aim 3 identifies Prlr sequence motifs controlling sex-specific local translation in nociceptor terminals. The
proposed study is innovative because it defines the conceptually novel sex-specific regulatory mechanisms
for neuronal plasticity underlying chronic pain in females with technically innovative mouse genetics. The
proposed research is significant as it advances our understanding of sex differences in chronic pain
mechanisms – an understudied area where increasing basic science knowledge has t...

## Key facts

- **NIH application ID:** 10317053
- **Project number:** 5R01NS102161-05
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** ARMEN N AKOPIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $483,157
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317053

## Citation

> US National Institutes of Health, RePORTER application 10317053, Sex-specific regulation of local translation and chronic pain mechanisms in females (5R01NS102161-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317053. Licensed CC0.

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