Estrogen effects on pain sensitivity and neuropeptide expression in rat sensory neurons

While a number of chronic pain conditions are much more prevalent in women than men, the role of estrogen in regulating nociception remains unclear. Estrogen receptors (ER) are known to be expressed in various parts of the nociceptive pathway, including in the small-sized primary sensory neurons of the dorsal root ganglion (DRG). This study evaluated the effects of long term estrogen replacement on pain sensitivity and neuropeptide expression in the DRG of female Sprague Dawley rats. The goal was to evaluate whether estrogen modulates nociceptive neuropeptides in the DRG in a manner consistent with its effects on pain sensitivity. Our results show that long term (28 days) ovariectomy (ovx) of adult rats induces a profound thermal and mechanical hyperalgesia of the hindpaw and tail compared to ovariectomized animals that were continuously estrogen-treated (ovx+E). Significant changes in the expression of two neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), were observed using immunocytochemistry and in situ hybridization (ISH) in the small lumbar DRG neurons which contain ER. CGRP and SP were differentially regulated by estrogen, with SP showing a significant downregulation at both the peptide and mRNA levels while CGRP and its mRNA were increased in the DRG of estrogen-treated animals. We also evaluated the development of mechanical allodynia after partial sciatic nerve injury and found that both ovx and ovx+E animals developed significant allodynia within a week of the partial nerve injury, which continued for at least one month. The estrogen-treated animals showed a partial amelioration of the extent of the allodynia at 2 weeks post injury. Overall, the results suggest that estrogen has significant anti-nociceptive actions that can be directly correlated with changes in expression of two peptides in the small nociceptive ERalpha expressing neurons of the DRG.