Administration of estrogen shortly after ovariectomy mimics the anti-nociceptive action and change in 5-HT1A-like receptor expression induced by calcitonin in ovariectomized rats

Although many clinical reviews are consistent with the view that hormone replacement therapy should be recommended for increasing bone mass of osteoporotic patients, calcitonin administration is preferable to hormone replacement therapy for the alleviation of pain accompanying osteoporosis, despite the fact that osteoporosis and the accompanying pain are accelerated by the reduction in estrogen levels. Distinct from the clinical view, animal studies have shown that estrogen treatment reduces ovariectomy-induced hyperalgesia, although the mechanism of this phenomenon is unknown. The discrepancy in clinical and animal study outcomes may be due to the timing of administration of estrogen after depletion of the hormone. To address this possibility, the anti-nociceptive effect of estrogen was compared with calcitonin using the tail withdrawal test in rats injected with estrogen or calcitonin at 3 weeks (short term) or 15 weeks (long term) after ovariectomy. Furthermore, we analyzed the change in [3H]8-OH-DPAT binding in the spinal cord, addressing whether estrogen exerts its anti-nociceptive effect by the expression of 5-HT receptors attributable to calcitonin-induced analgesia, as has been reported in our previous animal studies. The present study demonstrates that the administration of estrogen injected in the short term, but not long term, after ovariectomy mimicked the effects of calcitonin-induced anti-nociception and prevention of ovariectomy-induced decrease in 5-HT receptor expression in the spinal cord, although the effects of calcitonin were observed regardless of the timing of calcitonin injection. These results suggest that the estrogen receptor is downregulated gradually after ovariectomy. Disappearance of the estrogen receptor may be one of the reasons that estrogen is not recommended for the treatment for chronic pain associated with osteoporosis.