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Kappa opioid receptor agonists produce sexually dimorphic and prolactin-dependent hyperalgesic priming

兴奋剂 内分泌学 内科学 痛觉超敏 痛觉过敏 伤害感受器 κ-阿片受体 类阿片 催乳素 医学 阿片受体 孤菲肽受体 受体 阿片肽 伤害 激素
作者
Caroline Machado Kopruszinski,Moe Watanabe,Ashley L. Martinez,Luiz Henrique Moreira de Souza,David W. Dodick,Aubin Moutal,Volker Neugebauer,Frank Porreca,Edita Navratilova
出处
期刊:Pain [Lippincott Williams & Wilkins]
卷期号:164 (6): e263-e273 被引量:10
标识
DOI:10.1097/j.pain.0000000000002835
摘要

Abstract Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. Mice received 3 daily doses of U-69593 or nalfurafine as a “first-hit” stimulus followed by assessment of periorbital tactile allodynia. Sixteen days after the first KOR agonist administration, animals received a subthreshold dose of inhalational umbellulone, a TRPA1 agonist, as the second-hit stimulus and periorbital allodynia was assessed. Cabergoline, a dopamine D2 receptor agonist, was used to inhibit circulating PRL in additional cohorts. Prolactin receptor isoforms were quantified in the V1 region of the trigeminal ganglion after repeated doses of U-69593. In both sexes, KOR agonists increased circulating PRL and produced allodynia that resolved within 14 days. Hyperalgesic priming, revealed by umbellulone-induced allodynia in animals previously treated with the KOR agonists, also occurred in both sexes. However, repeated U-69593 downregulated the PRLR long isoform in trigeminal neurons only in female mice. Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.
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