Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding effective, non-hormonal and long-term treatments for endometriosis still remains one of the most significant challenges in the field. Corticotropin releasing hormone (CRH) is one of the main signaling peptides within the hypothalamic pituitary adrenal (HPA) axis released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of two types of CRH receptors: CRHR1 and CRHR2. Our aim was to determine if blocking CRHR1 with antalarmin will reduce endometriosis progression. In experiment 1 we induced endometriosis in female rats by suturing uterine horn tissue next to the intestinal mesentery and allowed to progress for 7 days. We determined that after 7 days, there was a significant increase in CRHR1 within endometriotic vesicles as compared to normal uterus. In Experiment 2, we induced endometriosis and administered either antalarmin (20 mg/kg, i.p.) or vehicle during the first 7 days after surgery. A separate group of sham surgery rats served as non-endometriosis controls. Endometriosis was allowed to progress until 60 days after surgery, at which time rats were tested for anxiety behaviors. At the time of sacrifice, endometriotic vesicles, uterus and blood were collected. Treatment with antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 mRNA within endometriotic vesicles but not of glucocorticoid receptor. Endometriosis did not change anxiety behaviors in the open field and zero-maze tests and prior antalarmin administration did not modify this. Our data provides the first in-vivo demonstration for use of CRHR1 antagonist for the treatment of endometriosis opening the possibility for further exploring CRH signaling as a treatment target for this debilitating disease.
Maternal separation (MS) early in life is related to an increase in anxiety and depressive-like behaviors and neurobiological alterations mostly related to alterations in hypothalamic pituitary adrenal (HPA) axis reactivity. Environmental enrichment (EE) has been used to ameliorate the effects of MS. However, the outcomes of this intervention at different developmental periods after MS have not been studied. We subjected male and female Sprague–Dawley pups to MS and subsequently compared the effects of EE started either in the pre-pubertal period [postnatal day (PND) 22] or adulthood (PND 78). Anxiety and depressive-like behaviors as well as in hippocampal synaptic density and basal corticosterone, oxytocin, and vasopressin levels were measured. Our results support the beneficial effects of adulthood EE in decreasing anxiety in males as well as promoting synaptic density in ventral hippocampal CA3. Males displayed higher levels of vasopressin while females displayed higher oxytocin, with no changes in basal corticosterone for any group after EE.
Current mitigation strategies for orofacial pain in combat casualties rely predominantly on opioid and non‐steroidal anti‐inflammatory drugs, resulting in adverse effects such as nausea, apnea, and dependency. New effective pain control therapies are needed to support patient recovery, particularly in austere environments where access to medical care may be limited. Our study proposed that a combination of adenosine, lidocaine and magnesium (ALM), a recently developed drug for trauma, would significantly decrease pain responsiveness and inflammation in a mouse model of hind paw injury. Injury was induced by subcutaneously administering capsaicin or Complete Freund's Adjuvant (CFA) into the dorsal surface of the hind paw. Male SKH1‐Hrhr mice between the ages of 5‐ to 8‐weeks (n=95) were randomly assigned to three injury/assessment groups. The first group received a capsaicin‐induced injury to assess acute pain and inflammation in response to the injury. The second and third groups received CFA‐induced injury with 3‐hour and 24‐hour assessment, respectively, for chronic pain and inflammation response. Additionally, each group contained treatment subgroups of 10 animals each: (1) no injury (negative control); (2) injury only (positive control); (3) injury+lidocaine; and (4) injury+ALM. Pain assessment in the acute group was performed by behavioral observations. To evaluate changes in pain perception in the chronic pain response groups, we performed the von Frey behavioral test. Plasma was collected prior to euthanasia for cytokine multiplex analysis. Behavioral effects and multiplex analysis were analyzed by one‐way ANOVA with repeated measures and Tukey's post hoc comparison test. Data are represented as mean±SD with significance as alpha<0.05. Results showed that acute pain responses in the ALM+injury and lidocaine+injury groups were attenuated compared to the negative control group, with significantly decreased time spent in grooming (p<0.0001) and grooming events (p=0.0004 and p=0.0010), respectively. However, in the chronic pain response assessment at 3 and 24 hours, no significant differences were found within or between experimental groups. Immunoreactivity levels of the cytokines IL‐2, IL‐6, IFN‐γ and TNF‐α in the injury+ALM group, compared to positive and negative control groups, showed no statistically significant differences at any time point of the study. These findings suggest that injury interventions with ALM can decrease acute pain responsiveness but are ineffective at mitigating chronic pain and related immune responses.
Endometriosis is a chronic inflammatory disorder in which endometrial tissue is found outside the uterine cavity. Previous reports suggest that there is a dysregulation of the hypothalamic pituitary adrenal axis during the progression of endometriosis. Our previous report showed that a short-term treatment with antalarmin, a corticotrophin releasing hormone receptor type 1 (CRHR1) antagonist decreases the number and size of endometriotic vesicles in the auto-transplantation rat model of endometriosis. Our current goal was to examine the mRNA expression of intra-adrenal receptors to better understand the mechanisms of the hypothalamic pituitary adrenal (HPA) axis involvement in endometriosis. We used two groups of female rats. The first received sham surgery or endometriosis surgery before collecting the adrenals after 7 days of the disease progression. The second group of animals received endometriosis surgery and a treatment of either vehicle or antalarmin (20 mg/kg, i. p.) during the first 7 days after endometriosis induction and then the disease was allowed to progress until day 60. Rats with sham surgery served as controls. Results showed that the mRNA expression of the mineralocorticoid (MRC2) receptor was lower in the rats after 7 days of endometriosis surgery and in rats with endometriosis that received antalarmin. In addition, the CRHR1 was significantly elevated in animals that received antalarmin and this was counteracted by a non-significant elevation in CRHR2 mRNA. The glucocorticoid receptor mRNA within the adrenals was not affected by endometriosis or antalarmin treatment. This report is one of the first to explore intra-adrenal mRNA for receptors involved in the HPA axis signaling as well as in the sympatho-adrenal signaling, calling for additional research towards understanding the role of the adrenal glands in chronic inflammatory diseases such as endometriosis.
Endometriosis is a disorder in which the development of uterine‐lining tissue is found outside the uterine cavity causing infertility, pain and stress. Previous studies have shown that stress can negatively affect the progression of the disease. Under the control of the hypothalamic pituitary adrenal (HPA) axis, circulating glucocorticoids regulate immune and stress responses by binding to the glucocorticoid receptors (GR). Our objective was to determine if GR is altered in the brain hippocampal area of rats with endometriosis. We focused on the hippocampus as this is one of the main brain areas that display GR. In addition, hippocampal GR play a significant role in HPA axis hyperactivity. Endometriosis was induced in female rats (n=16) by suturing uterine horn tissue next to the intestinal mesentery and the disease was allowed to progress for 60 days, during which rats were exposed to either environmental enriched conditions (increased social groups, larger enclosures, toys and nesting) or normal housing conditions. Sham rats (n=8) had only sutures in the intestinal mesentery and were exposed to normal housing conditions. At the time of sacrifice, endometriotic vesicles, uterus and brains were collected. A single labeling with DAB immunohistochemistry was performed to analyze the levels of GR in the Cornus amon (CA1 and CA3) and Dental Gyrus (DG) of the hippocampus. We have previously documented that environmental enrichment can significantly reduce the progression of endometriosis resulting also in decreased GR expression within endometriotic vesicles compared to nonenriched rats. Results show that rats with endometriosis had 60% increased GR integrated density in CA1 and DG regions of the rat hippocampus compared to sham controls. Non‐enriched animals had double the integrated density of GR in the dorsal CA3 compared to sham controls and this increase was dampened by environmental enrichment. Our data suggest that interventions that decrease stress can provide some benefit to return GR activity to baseline levels in both, peripheral tissues and also in brain structures involved in stress regulation.Support or Funding InformationNIH‐K07AT008027This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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