1. 2022;25;E1239-E1248The Involvement of CaV1.2 in Estrogenic Modulation of Morphine Antinociception in Rats Under Uterine Cervix Pain
   Animal Study
   Li-Hong Sun, MD, Qi Xu, PhD, Lin Jin, MD, Li-Dan Jin, MD, Qing Chen, MD, Hui Wu, PhD, and Xin-Zhong Chen, PhD.

BACKGROUND: Morphine is one of the preferred drugs for the clinical treatment of pain. Both clinical and preclinical studies have reported sexual dimorphism in morphine analgesia. Different circulating levels of estrogen could be involved in sex differences in response to morphine analgesia. In our previous research, we found that capsaicin injection into the cervix of rats caused acute visceral pain that could be relieved by morphine. The role of estrogen in morphine analgesia in rats under uterine cervix pain and its underlying mechanisms remain to be explored.

OBJECTIVES: The present study aims to investigate the effect of estrogen on morphine analgesia and its underlying mechanism in rats under uterine cervix pain.

STUDY DESIGN: Controlled animal study.

SETTING: University laboratory.

METHODS: First, we compared the analgesic effect of morphine in ovariectomized rats with uterine cervix pain with or without estrogen replacement. Then, the changes in the expression of opioid receptors and L-type voltage-gated calcium channels (L-type-VGCC, LTCC) at the spinal level were detected by real-time quantitative polymerase chain reaction. Finally, we investigated the effect of the manipulation of spinal LTCC (L-type CaV1.2 calcium channel, L-type CaV1.3 calcium channel) on the estrogen-mediated inhibition of morphine analgesia.

RESULTS: Our study shows that morphine antinociception is  diminished in rats with uterine cervix pain that are treated with estrogen. Estrogen treatment increases the expression of spinal CaV1.2 and CaV1.3, while only anti-CaV1.2 treatment impaired estrogenic suppression of morphine antinociception.

LIMITATIONS: More underlying mechanisms of the role of spinal CaV1.2 in modulating estrogen-mediated inhibition of morphine analgesia need to be explored in future research.

CONCLUSIONS: This is the first evidence that spinal CaV1.2 is involved in estrogenic modulation of morphine antinociception in rats under uterine cervix pain. Our results will provide new ideas and references for estrogen-related differential prescription of opioids.

KEY WORDS: Estrogen, morphine, pain, analgesia, LTCC, CaV1.2, uterine cervix, opioid