Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation Graphical abstract Highlights d Oxytocin microinjected into ACC attenuates injury-related pain and anxiety responses d Oxytocin blocks the maintenance of pre-LTP, but not post-LTP d Oxytocin depolarizes the interneurons and decreases the ratio of E/I transmission d Activation of PVN-ACC pathway blocks pre-LTP and has analgesic and anxiolytic effects
Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.
Background/aim In terms of breast cancer risk, there is no consensus on the effect of uric acid (UA) levels. The aim of our study was to clarify the link between UA and breast cancer risk in a prospective case–control study and to find the UA threshold point. Methods We designed a case–control study with 1050 females (525 newly diagnosed breast cancer patients and 525 controls). We measured the UA levels at baseline and confirmed the incidence of breast cancer through postoperative pathology. We used binary logistic regression to study the association between breast cancer and UA. In addition, we performed restricted cubic splines to evaluate the potential nonlinear links between UA and breast cancer risk. We used threshold effect analysis to identify the UA cut-off point. Results After adjusting for multiple confounding factors, we found that compared with the referential level (3.5–4.4 mg/dl), the odds ratio (OR) of breast cancer was 1.946 (95% CI 1.140–3.321) (P < 0.05) in the lowest UA level and 2.245 (95% CI 0.946–5.326) (P > 0.05) in the highest level. Using the restricted cubic bar diagram, we disclosed a J-shaped association between UA and breast cancer risk (P-nonlinear < 0.05) after adjusting for all confounders. In our study, 3.6 mg/dl was found to be the UA threshold which acted as the optimal turning point of the curve. The OR for breast cancer was 0.170 (95% CI 0.056–0.512) to the left and 1.283 (95% CI 1.074–1.532) to the right of 3.6 mg/dl UA (P for log likelihood ratio test < 0.05). Conclusion We found a J-shaped association between UA and breast cancer risk. Controlling the UA level around the threshold point of 3.6 mg/dl provides a novel insight into breast cancer prevention.
The anterior cingulate cortex (ACC) is a key cortical region that plays an important role in pain perception and emotional functions. Previous studies of the ACC projections have been collected primarily from monkeys, rabbits and rats. Due to technological advances, such as gene manipulation, recent progress has been made in our understanding of the molecular and cellular mechanisms of the ACC-related chronic pain and emotion is mainly obtained from adult mice. Few anatomic studies have examined the whole-brain projections of the ACC in adult mice. In the present study, we examined the continuous axonal outputs of the ACC in the whole brain of adult male mice. We used the virus anterograde tracing technique and an ultrahigh-speed imaging method of Volumetric Imaging with Synchronized on-the-fly-scan and Readout (VISoR). We created a three-dimensional (3D) reconstruction of mouse brains. We found that the ACC projected ipsilaterally primarily to the caudate putamen (CPu), ventral thalamic nucleus, zona incerta (ZI), periaqueductal gray (PAG), superior colliculus (SC), interpolar spinal trigeminal nucleus (Sp5I), and dorsal medullary reticular nucleus (MdD). The ACC also projected to contralateral brain regions, including the ACC, reuniens thalamic nucleus (Re), PAG, Sp5I, and MdD. Our results provide a whole-brain mapping of efferent projections from the ACC in adult male mice, and these findings are critical for future studies of the molecular and synaptic mechanisms of the ACC and its related network in mouse models of brain diseases.
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