Journal
JOURNAL OF NEUROSCIENCE
Volume 40, Issue 37, Pages 7080-7090Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1499-20.2020
Keywords
estrogen; nociceptor; prolactin; sex dimorphism; testosterone; translation regulation
Categories
Funding
- National Institute of Neurological Disorders and Stroke/National Institutes of Health [NS102161, NS065926, NS113457]
- National Institutes of Health/National Institute of General Medical Sciences [GM112747]
- University of Texas BRAIN Pilot Program [1503083]
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Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE(2) as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE(2) hypersensitivity was more persistent in females. This difference in PGE(2) response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using Delta PRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.
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