Abstract
Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing. The present study investigated whether hormonal depletion alters the nociceptive, depressive-like and learning behaviors in experimental rats after ovariectomy (OVX), a common method to deplete animals of their gonadal hormones. OVX rats developed thermal hyperalgesia in proximal and distal tail that was established 2 weeks after OVX and lasted the 7 weeks of the experiment. A robust mechanical allodynia was also occurred at 5 weeks after OVX. In the 5th week after OVX, dilute formalin (5%)-induced nociceptive responses (such as elevating and licking or biting) during the second phase were significantly increased as compared to intact and sham-OVX females. However, chronic constriction injury (CCI) of the sciatic nerve-induced mechanical allodynia did not differ as hormonal status (e.g. OVX and ovarian intact). Using formalin-induced conditioned place avoidance (F-CPA), which is believed to reflect the pain-related negative emotion, we further found that OVX significantly attenuated F-CPA scores but did not alter electric foot-shock-induced CPA (S-CPA). In the open field and forced swimming test, there was an increase in depressive-like behaviors in OVX rats. There was no detectable impairment of spatial performance by Morris water maze task in OVX rats up to 5 weeks after surgery. Estrogen replacement retrieved OVX-induced nociceptive hypersensitivity and depressive-like behaviors. This is the first study to investigate the impacts of ovarian removal on nociceptive perception, negative emotion, depressive-like behaviors and spatial learning in adult female rats in a uniform and standard way.
Highlights
Circulating ovarian hormones play a pivotal role in reproductive behavior and sexual differentiation, they contribute to emotion, memory, neuronal survival and the perception of somatosensory stimuli [1,2,3]
Intact female rats were primarily classified as in proestrus, estrus, metestrus or diestrus on the day of testing according to the cellular characteristics of their vaginal smears
Baseline measures of paw withdrawal thresholds (PWTs) to von Frey hairs on both hindpaws did not differ across estrous phases (One-way ANOVA, Left: F 3,39 = 0.0916, p = 0.964; Right: F3,39 = 0.0732, p = 0.974) (Fig. 1A)
Summary
Circulating ovarian hormones play a pivotal role in reproductive behavior and sexual differentiation, they contribute to emotion, memory, neuronal survival and the perception of somatosensory stimuli [1,2,3]. Ovarian hormones have been shown to alter nociceptive behaviors using a variety of models [4,5,6,7,8]. Depending on the type of noxious stimulation, behavioral test employed, species and strain of the animal and periods from ovariectomy (OVX), gonadectomy increased [4,7,9], decreased [10,11] or had no effect [12] on nociceptive responses. Ovarian hormones have been suggested to regulate affective disorders and learning memory beyond their role in pain modulation [3]. The increased risk of affective disorders in women is related to hormonal changes who are premenstrual, postpartum and hypoestrogenic due to the medical surgery or menopause [15]. Data from animal experiments have shown that OVX increases depressive-like behavior in several tasks [16,17]. Very low estradiol levels or very high levels were associated with impaired spatial ability [18,19]
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