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

Abstract

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 level 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 ERα expressing neurons of the DRG.

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

“…Furthermore, several previous studies have established the ability of estradiol exposure to produce facial and peripheral allodynia in animal models. Importantly, our model demonstrates recruitment of similar downstream mechanisms of inflammation (Liverman, 2007), and vasodilation (Sarajari and Oblinger, 2010) exhibited in other work, indicating that our model causes similar results of facial allodynia following treatment with estradiol.…”

“…It is established that estradiol receptors are present in trigeminal nociceptors and studies have demonstrated that binding of estradiol leads to downstream activation of extracellular signal regulated kinase (ERK), a known inflammatory response pathway (Liverman, et al, 2009). Furthermore, it has been shown that estradiol exposure can lead to other nociceptive-related downstream effects; including, increased primary neuron activity (Cairns, et al, 2001, Cairns, et al, 2002), increased allodynia (Liverman, et al, 2009), altered sodium gated channel activity (Wang, et al, 2013), and enhanced vasodilation (Levy and Burstein, 2011, Sarajari and Oblinger, 2010). …”

“…Several previous studies have examined how estradiol exposure alters behavioral outcomes and gene expression related to pain disorders; including, increased hind paw allodynia following partial sciatic nerve ligation (Sarajari and Oblinger, 2010), increased TRP channel activation after injection of complete Freund’s adjuvant bilaterally into the temporomandibular joint (Wu, et al, 2010), and changes in craniofacial pain (Cairns, 2007). This study was designed to further clarify the underlying mechanisms behind estradiol signaling in migraine and discuss how this compares to BPA exposure.…”

Blocking TNF-α with infliximab alleviates ovariectomy induced mechanical and thermal hyperalgesia in rats

“…It is widely recognized that estrogen depletion leads to hyperalgesia, and estrogen replacement exhibits analgesic effect [8,9,24]. In the present study, we observed significant hyperalgesia to mechanical and thermal stimuli in estrogen deficient rats (group Ovx-1), which was consistent with previous studies.…”

“…As the important role of estrogen in regulation of pain has been widely recognized [7], studies have demonstrated that estrogen modulates pain via their effects on the peripheral nervous system (PNS), central nervous system (CNS), skeletal, immune and cardiovascular systems [5]. Mechanical and thermal hyperalgesia have been induced in estrogen deficiency animals, and this hyperalgesia could be alleviated by estradiol replacement [8,9].…”