Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat

Neonatal pain has been suggested to contribute to the development and/or persistence of adult pain. Observations from animal models have shown that neonatal inflammation produces long-term changes in sensory neuron function, which can affect the susceptibility of adults to develop persistent pain. We used a preclinical model of transition to chronic pain, hyperalgesic priming, in which a previous inflammatory stimulus triggers a long-lasting increase in responsiveness to pro-algesic mediators, prototypically prostaglandin E-2 (PGE(2)), to investigate if post-natal age influences susceptibility of adult rats to develop chronic pain. Priming was induced by tumor necrosis factor alpha (TNF alpha), in male and female rats, 1, 2, 3, 4, 5 or 7 weeks after birth. When adults (8 weeks after birth), to evaluate for the presence of priming, PGE(2) was injected at the same site as TNF alpha. In males that had received TNF alpha at post-natal weeks 1, 2 or 3, priming was attenuated compared to the 4-, 5- and 7-week-old treated groups, in which robust priming developed. In contrast, in females treated with TNF alpha at post-natal week 1, 2, 3, or 4, but not at 5 or 7, priming was present. This age and sex difference in the susceptibility to priming was estrogen-dependent, since injection of TNF alpha in 3-week-old males and 5-week-old females, in the presence of the estrogen receptor antagonist ICI 182,780, did produce priming. These results suggest that estrogen levels, which vary differently in males and females over the post-natal period, until they stabilize after puberty, impact pain as an adult. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.