Age and training intensity differently affect male runners' endocrine and sexual parameters.

Physical activity is widely recognized to improve health and its inclusion in daily life at all ages is highly recommended. Gonadal hormones are known to be affected by physical activity. The exercise-induced effects on male runners of different ages were investigated by dividing 31 runners by age (Young, Y, 30-55 years; Old, O, 56-70 years) and amount of training (Light, L, <50 km/week; Heavy, H, 50 or more km/week). To test the somatic, sexual, and psychological health aspects, the Aging Male's Symptoms Scale (AMS) and the International Index of Erectile Function-6 (IIEF-6) questionnaires were administered and blood samples were drawn for adrenocorticotropic hormone, testosterone (Total-TT), free testosterone (Free-T), cortisol (C), dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin determinations. Clinical evaluations and questionnaire results showed the presence in all groups of some subclinical symptoms and "Light" dysfunctions. TT in the old-heavy (OH) group was significantly lower than in the OL group (2.38 ± 0.18 ng/mL vs. 3.36 ± 0.44 ng/ml, P = 0.05). The TT/DHT ratio was significantly higher in YH than in OH (3.64 ± 0.16 vs. 2.92 ± 0.23, P < 0.05). TT was positively correlated with AMS sexual subscale and negatively correlated with IIEF-6. Physical activity can significantly affect andrological health and testosterone levels in runners at all ages. Thus, due to the important testosterone-mediated vital functions in men, the evaluation of these parameters would be indicated in old as well as in young subjects.

Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by dyskinesia, cognitive impairment and emotional disturbances, presenting progressive neurodegeneration in the striatum and intracellular mutant Huntingtin (mHTT) aggregates in various areas of the brain. Recombinant Adeno Associated Viral (rAAV) vectors have been successfully used to transfer foreign genes to the brain of adult animals. In the present study we report a novel in vivo rat HD model obtained by stereotaxic injection of rAAV serotype2/9 containing Exon1-Q138 mHTT (Q138) and Exon1-Q17 wild type HTT (Q17; control), respectively in the right and in the left striatum, and expressed as C-terminal GFP fusions to facilitate detection of infected cells and aggregate production. Immunohistochemical analysis of brain slices from animals sacrificed twenty-one days after viral infection showed that Q138 injection resulted in robust formation of GFP-positive aggregates in the striatum, increased GFAP and microglial activation and neurodegeneration, with little evidence of any of these events in contralateral tissue infected with wild type (Q17) expressing construct. Differences in the relative metabolite concentrations (N-Acetyl Aspartate/Creatine and Myo-Inositol/Creatine) were observed by H1 MR Spectroscopy. By quantitative RT-PCR we also demonstrated that mHTT induced changes in the expression of genes previously shown to be altered in other rodent HD models. Importantly, administration of reference compounds previously shown to ameliorate the aggregation and neurodegeneration phenotypes in preclinical HD models was demonstrated to revert the mutant HTT-dependent effects in our model. In conclusion, the AAV2/9-Q138/Q17 exon 1 HTT stereotaxic injection represents a useful first-line in vivo preclinical model for studying the biology of mutant HTT exon 1 in the striatum and to provide early evidence of efficacy of therapeutic approaches.

Perinatal 17α-ethinylestradiol exposure affects formalin-induced responses in middle-aged male (but not female) rats.

17α-Ethinylestradiol (EE), the main component of the contraceptive pill, is a synthetic estrogen found in rivers of the United States and Europe as an environmental contaminant. It is one of the most studied xenoestrogens due to its possible effect on the reproductive system. In the present study we evaluated the modulation of pain responses induced by formalin injection (licking, flexing, paw-jerk) in 8-month-old male and female offspring of female rats treated with two different doses of EE (4ng/kg/day or 400ng/kg/day) during pregnancy and lactation. Spontaneous behaviors and gonadal hormone levels were also determined. Both concentrations of EE induced an increase of pain behaviors in males only, i.e. higher flexing and licking of the formalin-injected paw than in OIL-exposed rats, during the second, inflammatory, phase of the formalin test. Grooming duration was increased by EE exposure in both males and females. Prenatal EE exposure (both concentrations) decreased estradiol plasma levels in the formalin-injected females but not in the males. These results underline the possibility that exposure to an environmental contaminant during the critical period of development can affect neural processes (such as those involved in pain modulation) during adulthood, indicating long-term changes in brain circuitry. However, such changes may be different in males and females.

Update in the Treatment of Pleural Tumors: Robotic Surgery Combined with Hyperthermic Intrathoracic Chemotherapy.

(1) Background. Intracavitary hyperthermic chemotherapy (HITHOC) remains part of the complex mosaic that is the multimodal approach for advanced stage thymoma and pleural malignancies. However, robotic pleurectomy/removal of pleural lesions in combination with intrathoracic chemotherapy is not currently being investigated. The aim of this study is to evaluate the safety of robotic pleurectomy/removal of relapses and HITHOC in patients with pleural recurrence of thymoma or MPM. (2) Methods: The data of nine consecutive patients affected by thymoma relapses or MPM who underwent robotic surgery in combination with HITHOC from February 2017 to November 2022 were collected and analyzed. Surgery performed prior to intrathoracic infusion of high-temperature chemotherapy consisted of removal of recurrences (three patients) or pleurectomy (six patients). All surgeries were performed with a four-port, fully robotic technique. (3) Results: No intraoperative complications occurred. No renal complications related to infusion were recorded. One patient, who underwent pleurectomy for MPM, had a grade II Clavien-Dindo postoperative complication. Oncological follow-up showed results in line with the literature. (4) Conclusions: With the limitation of the small number of patients, robotic surgery in combination with HITHOC seems to be safe in patients with pleural relapses of thymoma and early-stage MPM.

Unradical Surgery for Locally-Advanced Thymoma: Is it time to evolve Perspectives?

OBJECTIVES: Nearly-one-third of thymomas are locally-advanced at diagnosis. The traditional dogma that surgery is justified in case a complete resection can be achieved has remained unmovable until today. This study aimed to investigate feasibility and oncologic efficacy of incomplete resection for locally-advanced thymomas in a contest of multimodality therapy. MATERIALS AND METHODS: A retrospective analysis was conducted using data of prospectively maintained thymomas database in a single high-volume centre. Data on 285 consecutive patients undergoing surgery for stage III and IVa thymomas between 1995 and 2019 were reviewed. Patients who underwent incomplete resection with curative-intent (removal of at least 90% of tumour burden) were included. Long-term outcomes and predictors of cancer-specific survival (CSS) and progression-free survival (PFS) were analyzed. Secondary endpoint was to assess adjuvant therapy efficacy. RESULTS: The study included 79 patients, 60 with microscopic residual tumour (76%, R1) and 19 with macroscopic residual disease (24%, R2). Masaoka-Koga stage was: III in 41 patients (52%) and IVa in 38 (48%). Histology was B2-thymomas (n = 31, 39.2%) followed by B3 (n = 27, 34.2%). Five- and 10-years CSS was 88% and 80%. Seventy patients (90%) underwent adjuvant treatment; they showed CSS comparable to radical resected patients (5-years: 89.1% vs 98.9%, respectively; 10-years: 81.8% vs 92.7%, respectively, p = 0.43). The site of residual disease, Masaoka-Koga stage and WHO histology did not affect prognosis. Stepwise multivariable analysis confirmed adjuvant therapy as a favourable CSS prognostic factor (HR, 0.51; 95% CI, 0.33-0.79, p = 0.003). Stratifying by subgroups, R2-patients who received postoperative chemo(radio)therapy (pCRT) showed a significantly better prognosis than R2-patients treated by consolidation radiotherapy alone (10-years CSS: 60%, p < 0.001). CONCLUSION: In locally-advanced thymomas, whenever a radical surgery cannot be achieved, incomplete resection has proved to be effective in a contest of multimodality strategy, independently of WHO histology, Masaoka-Koga stage and site of residual disease.

Women in thoracic, cardiac and vascular surgery claim for a change in the working situation: an Italian national survey.

Background: Women's participation in the surgical workforce has increased. The aim of the study is to acquire objective data regarding practice, training, satisfaction, and discrimination of women surgeons working in cardiothoracic and vascular surgery in Italy. Methods: An 83-item questionnaire was distributed through social media and sent to e-mails of women surgeons from November through December 2020. A sub-analysis on women working in cardiac, thoracic, and vascular surgery was performed. Results: Overall, 222 respondents were included (48 cardiac, 62 thoracic, and 112 vascular surgeons). Thirty-six percent partially abandoned surgical activities in favor of other professional activities, not including the operating room. On average, our respondents took part in 33% of all surgical cases performed in their units; however, of 12 high complexity surgeries per month, less than one is performed by them. Only 7 female participants who answered the questionnaire were in leadership positions. Many respondents struggle with lack of mentorship and missing opportunities in operating room. A high percentage of women experienced discrimination due to their gender in their professional life, and 59% claimed to have been subject to sexual harassment. Conclusions: In Italy, women thoracic, cardiac, and vascular surgeons face lack of mentorship, opportunities in the operating room, and gender-related issues including some episodes of sexual harassment. Diversity, equity, and inclusion should become strategic priorities in all institutions. Among our respondents, surgical exposure is limited, which may deter a surgical career and play a crucial role in surgeons' dissatisfaction, that also include poor work-life-balance, and a large amount of administrative work. Surgical societies may address these issues by providing structured mentorship programs and networking opportunities. Societies' contributions might substantially impact supporting and retaining women at different stages of their careers.

Ticagrelor Enhances the Cardioprotective Effects of Ischemic Preconditioning in Stable Patients Undergoing Percutaneous Coronary Intervention: the TAPER-S Randomized Study.

BACKGROUND: Ticagrelor improves clinical outcomes in patients with acute coronary syndrome compared with clopidogrel. Ticagrelor also inhibits cell uptake of adenosine and has been associated with cardioprotective effects in animal models. We sought to investigate the potential cardioprotective effects of ticagrelor, as compared with clopidogrel, in stable patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: This was a Prospective Randomized Open Blinded End-points (PROBE) trial enrolling stable patients with coronary artery disease (CAD) requiring fractional flow reserve (FFR)-guided PCI of intermediate epicardial coronary lesions. ST-segment elevation at intracoronary (IC)-ECG during a two-step sequential coronary balloon inflations in the reference vessel during PCI was used as an indirect marker of cardioprotection induced by ischemic preconditioning. The primary endpoint of the study was the comparison of the delta (Δ) (difference) ST-segment elevation measured by intracoronary-ECG during two-step sequential coronary balloon inflations. RESULTS: Fifty-three patients were randomized to either clopidogrel or ticagrelor. The study was stopped earlier because the primary endpoint was met at a pre-specified interim analysis. ΔST-segment elevation was significantly higher in ticagrelor as compared to clopidogrel arms (p<0.0001). Ticagrelor was associated with lower angina score during coronary balloon inflations. There was no difference in coronary microvascular resistance between groups. Adenosine serum concentrations were increased in patients treated with ticagrelor as compared to those treated with clopidogrel. CONCLUSIONS: Ticagrelor enhances the cardioprotective effects of ischemic preconditioning compared with clopidogrel in stable patients with CAD undergoing PCI. Further studies are warranted to fully elucidate the mechanisms through which ticagrelor may exert cardioprotective effects in humans. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT02701140.

Food-Specific IgG4 Antibody-Guided Exclusion Diet Improves Conditions of Patients with Chronic Pain.

INTRODUCTION: Chronic pain is related to gastrointestinal (GI) functions because food components affect inflammation and pain through their action on the GI immune and/or neural system and because many analgesics interact with the gut to alter its structure and function. Immunoglobulin G4 (IgG4) are food-specific antibodies resulting from exposure of the gut immune system to nutrients. High IgG4 levels have been found to be associated with inflammation. METHODS: IgG4 were determined (both with the rapid test and enzyme-linked immunosorbent assay, ELISA) in men and women outpatients with chronic pain. All subjects were asked to exclude for 4 weeks all foods to which they had high blood levels of IgG4 antibodies. Pain and quality of life questionnaires were administered before (visit 1) and after (visit 2) the personalized exclusion diet period. Visual analogue scale (VAS), Italian Pain Questionnaire (QUID) and Margolis (MA) questionnaires were administered to determine pain intensity, pain features and pain extent, while Short Form Health Survey (SF-36) and Profile of Mood States (POMS) were used to test the quality of life and mood state. The nutritional status was evaluated in all subjects. Subject groups were women of reproductive age (pre-MW), women in menopause for at least 1 year (MW) and men. RESULTS: Fifty-four subjects with chronic pain (n = 12 neuropathic, n = 14 diffuse pain, n = 11 headache, n = 17 low back pain) completed the two visits and the 1-month exclusion diet. At visit 1, 47 (87%) subjects showed medium/high levels of IgG4 to at least one food. The foods showing the highest IgG4 values were eggs, dairy products, cereals and dried fruit. At visit 2, IgG4 levels were decreased, increased or unchanged. In all groups, the 4-week exclusion diet resulted in a significant reduction in all pain measures and an improvement of quality of life parameters. In particular, at visit 2, the VAS score determined in the morning decreased by more than 50%. CONCLUSIONS: A food elimination diet based on IgG4 antibody levels may be effective in reducing pain and improving quality of life in patients with chronic pain.

Estrogens and phytoestrogens in body functions.

Estrogens are the hormones of reproduction in women as well as of many other important functions in the male and female body. They undergo significant changes in the different phases of life, e.g. during puberty, pregnancy or at menopause/andropause. Phytoestrogens are natural non-steroidal phenolic plant compounds that can mimic the activity of estrogens and their beneficial effects in women and in men. This narrative review summarizes the literature on the physiological role of estrogens and the several potential health benefits of phytoestrogens, with particular attention given to the possible role of phytoestrogens in aging.

Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients.

BACKGROUND: In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available. METHODS: To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale-AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively). RESULTS: The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time. CONCLUSIONS: In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management.

Sex differences in the analgesic effects of ICI 182,780 and Flutamide on ureteral calculosis in rats.

To better define the involvement of gonadal hormones in the sex differences observed in experimental visceral pain, we administered antagonists of estrogen receptors (ICI 182,780 [ICI]) or androgen receptors (Flutamide [FLU]) to adult male and female rats suffering from artificial ureteral calculosis. Subjects were divided into groups and treated with one of the substances (ICI, FLU) or sweet almond oil (OIL, vehicle) for 5 days, starting 2 days before surgery. On day 3, animals underwent surgery, with half receiving an artificial calculosis (Stone) and half only a sham procedure. The animals' behavior (number and duration of ureteral crises) and blood hormone levels (estradiol and testosterone) were determined in all groups. In OIL-treated rats the number and duration of crises were higher in females than in males. The administration of ICI or FLU resulted in hormonal effects in males and behavioral effects in females. In males ICI treatment increased estradiol plasma levels and FLU increased testosterone plasma levels; in females ICI and FLU treatments both decreased the number and duration of the ureteral crises. These results, confirming previous findings of higher sensitivity of females than males to urinary tract pain, showed the modulatory effects of estrogen and androgen antagonists on the behavioral responses induced by pain but only in females.

Endocrine and behavioural effects of transdermal buprenorphine in pain-suffering women of different reproductive ages.

Chronic pain is a common problem in clinical practice and women are affected more often than men. Morphine is often used for long-term pain relief, but it induces side effects including endocrine alterations. The aim of the present study was to assess the behavioural and hormonal effects of transdermal buprenorphine in women suffering from persistent non-malignant pain. Hormones (LH, FSH, total and free testosterone, estradiol, cortisol) and pain measures (visual analogue scale, McGill Pain questionnaire, present pain intensity test) were evaluated at baseline and after 1, 3 and 6 months. Subjects were recruited in the Second University of Naples Pain Research Centre. Eighteen chronic pain women were included in the study, divided into pre- and post-menopausal groups. A transdermal buprenorphine patch (Buprenorphine TDS, 35 µg/h) was administered every 72 h. As expected, buprenorphine administration led to a decrease in pain intensity and no side effects suggestive of hypogonadism were recorded. Pain measures decreased at the first control visit (T1) in both groups. Total and free testosterone were not reduced by treatment (they tended to increase in both groups) while cortisol progressively recovered from the quite low levels detected at the beginning of treatment. These data confirm that buprenorphine is a safe and effective drug for pain relief in women. It is free from the adverse effects on gonadal hormones frequently associated with other opioid treatments. The lack of opioid-induced effects on gonadal hormones (i.e., hypogonadism) is important to guarantee safe long-term pain treatment.

Robotic thymectomy: A surgical point of view.

Robotic thymectomy is the most innovative surgical approach for treating disease of the anterior mediastinum. Robotic surgery offers low postoperative morbidity, faster recovery, shorter hospital stay, and better cosmetic results, without compromising surgical radicality. During the operation, the patient is placed in a supine position at the left edge of the operating table with the left hemithorax upward; the position is maintained with sandbags. The target area for the autodocking should be toward the jugulum. The first surgical step is to isolate the inferior thymic horns via the dissection that starts from the inferior portion of the mediastinal tissue and proceeds toward the right side, following the contralateral pleural reflection. Afterward, it is necessary to move toward the superior horns, following the phrenic nerve, the first landmark, to the innominate vein, our second landmark. Finally, we dissect the superior horns while searching for the thymic veins, which could appear atrophic, and clip the vessels to safely isolate the innominate vein. During this step, it is useful to use a retraction movement to progressively dissect the horns from the jugulum. The thymus gland is removed en bloc with the perithymus fat using an endoscopic bag inserted through the right port incision.

Robotic thymectomy for thymoma in patients with myasthenia gravis: neurological and oncological outcomes.

OBJECTIVES: The goal of this study was to analyse the outcomes in 53 patients with thymoma, 34 of whom had myasthenia gravis (MG), who were treated with robotic surgery. The oncological outcomes of the whole series of patients were analysed. Furthermore, because consistent data are not yet available in the literature, the main focus was the analysis of the neurological results of the patients affected by MG and thymoma. METHODS: The clinical outcomes of 53 patients with a diagnosis of thymoma who underwent robotic thymectomy between January 2014 and December 2019 in our institution were collected and evaluated; 34 of these patients had a concomitant diagnosis of MG. The neurological status of the patients was determined from a clinical evaluation according to the Osserman classification and on pre- and post-surgery Myasthenia Gravis Composite scores, whereas neurological clinical outcomes were assessed using the Myasthenia Gravis Foundation of America Post-Intervention Score. Reduction of steroid therapy was also considered. The recurrence rate, adjuvant radiotherapy and overall survival of the patients with a thymoma were evaluated. RESULTS: Neurological outcomes: improvement of the clinical conditions was obtained in 26 patients (76.5%) following the operation: complete stable remission was observed in 5 patients (14.7%), pharmacological remission in 10 (29.4%) and minimal manifestation in 11 (32.3%). Four patients (11.8%) exhibited no substantial change from the pretreatment clinical manifestations or reduction in MG medication and 4 (11.8%) patients experienced worsening of clinical conditions. In 21 patients (61.7%) a reduction of the dosage of steroid therapy was obtained. Oncological outcomes: at an average follow-up of 36 months, the overall survival was 96%, 4 patients (7.5%) had pleural relapses and 12 patients (22.6%) underwent postoperative radiotherapy, according to their stage. In accordance with Masaoka staging, 34% were in stage I, 56.6% in stage II and 9.4% in stage III. CONCLUSIONS: Our results suggest that robotic surgical treatment of patients with thymoma and concomitant MG is effective in improving the neurological outcomes. Moreover, the oncological results obtained in this series confirm the efficacy of robotic surgery for the treatment of thymic malignancies, with results in line with those of open surgery. However, due to the indolent growth of thymomas, further observations with longer follow-up are necessary.

Pain Study in X-Linked Adrenoleukodystrophy in Males and Females.

INTRODUCTION: X-linked adrenoleukodystrophy (ALD) is a metabolic disorder in which very long chain fatty acids (VLCFAs) are accumulated in the nervous system and adrenal cortex, impairing their functions. Three main variants are described in males: adrenomyeloneuropathy (AMN), a cerebral form (cALD or cAMN) and Addison's disease only (AD), while for females no classification is used. To evaluate pain and the functional state of afferent fibers, a series of tests was carried out in male and female patients. METHODS: Chronic pain occurrence and sensory phenotype profile were assessed in 30 patients (20 male: 10 AMN, 1 cAMN, 1 cALD, 8 AD; and 10 female). A set of instruments assessed the intensity, quality and extent of pain, while a battery of quantitative sensory testing (QST) procedures examined the functional status of Aß and Aδ fibers. Principal component analysis and hierarchical clustering with sensory responses input were used to identify distinct clusters. RESULTS: Nearly half of the subjects reported pain, with a high prevalence in females and male AMN patients. No sex differences in pain dimensions were found. The sensory responses were heterogeneous, differing among the clinical variants and between genders. Male AMN/cAMN/cALD patients showed the worst impairment. Aß and Aδ fibers were affected in males and females, but Aß fibers appeared undamaged in females when tactile sensitivity was tested. Abnormal responses were localized in the lower body district, according to the dying-back pattern of the neuropathy. Cluster analysis showed discrete clusters for each function examined, with well-interpretable sensory and clinical phenotypes. CONCLUSION: The study of pain and of the sensory profile appears to indicate a difference in the mechanisms underlying the AMN/cAMN/cALD and AD clinical forms and in the treatment of the respective generated pain types.

A risk stratification scheme for synchronous oligometastatic non-small cell lung cancer developed by a multicentre analysis.

BACKGROUNDS: Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. METHODS: The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan - Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. RESULTS: 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29-53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00-1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45-1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 - 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21-3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. CONCLUSIONS: Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease.

Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats.

BACKGROUND: The steroid hormone testosterone has been found to be greatly reduced by opioids in different experimental and clinical conditions. The purpose of this study on male rats was to determine the effects of a single injection of morphine (5 mg/Kg) on persistent pain (formalin test) and the single or combined effects on p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis. Testosterone was determined in the plasma and in the brain, morphine was assayed in the plasma. RESULTS: In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads. Morphine was detected in the blood of all morphine-treated rats even though there were no clear analgesic affects in the formalin-treated animals three hours after treatment. Testosterone was greatly reduced in the plasma and brain in morphine-treated subjects. CONCLUSIONS: It appears that morphine administration can induce long-lasting genomic effects in different body areas which contribute to the strong central and peripheral testosterone levels. These changes were not always accompanied by behavioral modifications.

The CB2 Agonist ß-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain.

Cannabinoids help in pain treatment through their action on CB1 and CB2 receptors. ß-caryophyllene (BCP), an ancient remedy to treat pain, is a sesquiterpene found in large amounts in the essential oils of various spice and food plants such as oregano, cinnamon, and black pepper. It binds to the CB2 receptor, acting as a full agonist. Sex differences in the BCP-induced analgesic effect were studied by exposing male and female rats to a persistent/repeated painful stimulation. To simulate treatment of a repeated inflammatory condition, after the first formalin injection (FT1; 50 µl, 2.5%), rats received BCP per os for 7 days at two dosages: 5 and 10 mg/kg dissolved in olive oil (OIL). The control group was treated with OIL for 7 days. On day 8, the formalin test was repeated (FT2) with a lower formalin concentration (50 µl, 1%). During the first and second formalin tests, pain-induced responses (licking, flexing, and paw jerk) and spontaneous behaviors were recorded and analyzed. In the FT1 (before the beginning of treatment with BCP), females displayed higher pain responses than did males in terms of flexing duration during the first part of the test (I phase and interphase), while during the second part (II phase early and late) males showed higher levels than did females in licking duration. In the FT2, the pain responses generally decreased in the BCP groups in a dose-dependent manner (i.e., greater effect of BCP10), with a more pronounced reduction in males than in females; moreover, the pain responses remained high in the OIL groups and in the female BCP5 group. In conclusion, long-term intake of BCP appears to be able to decrease pain behaviors in a model of repeated inflammatory pain in both sexes, but to a greater degree in males.

Effects of morphine on testosterone levels in rat C6 glioma cells: modulation by anastrozole.

Rat C6 glioma cells are commonly used to investigate the functions of glial cells. To evaluate the presence of testosterone and its metabolism in rat C6 glioma cells, we cultured them in media with or without the addition of testosterone propionate and anastrozole, a blocker of aromatase, the enzyme needed to transform testosterone into estradiol. The same procedure was repeated with morphine (10 and 100 microM), known to decrease testosterone levels in the brain (in rats) and plasma (in rats and humans). Confluent cells were exposed to the test media for 48 h and then collected. Cell pellets were used to determine testosterone by radioimmunoassay. The C6 cells contained detectable levels of testosterone and the levels increased with the addition of testosterone to the medium. Aromatase blockage by anastrozole increased cellular levels of testosterone regardless of the addition of exogenous testosterone. Both concentrations of morphine dose-dependently decreased testosterone levels in the C6 cells; this effect was also present with the contemporary administration of anastrozole. Our findings show that testosterone is present in rat C6 glioma cells and can be metabolized by aromatase. Moreover, the presence of morphine in the culture medium strongly decreased testosterone, demonstrating that the glia would be a target of the morphine-induced hypogonadal effect.

Effects of 17beta-estradiol on rat urinary bladder: gender differences in anoxia-glucopenia and reperfusion damage.

AIM: To study the effect of 17beta-estradiol (E(2)) as a neuroprotective agent in male and female rat urinary bladders subjected to anoxia-glucopenia and reperfusion (A/G-R) damage. METHODS: Rat urinary bladders were exposed to 1 hour of A-G and 2 hours of reperfusion (R). Intrinsic nerves underwent electrical field stimulation. The effect of E(2) on the contractile response and its recovery in R phase, was monitored by adding it to the bath medium, at different concentrations, 60 min before A-G, during the A-G and the first 30 min of R. Furthermore, on both genders, in vivo treatments with E(2), testosterone, IC1 182,780 and anastrozole were performed. RESULTS: After A-G the recovery of the nerve function in female bladders were significantly higher than in male. E(2) given both in vivo (increased of E(2) plasma levels were monitored) and in vitro, resulted to be neuroprotective in male bladder subjected to A-G/R damage. When rats were treated with anastrozole, a lower recovery of nerve responses both in male and female bladders was observed. Finally, treatments with E2 receptor antagonist ICI 182,780 increased E(2) plasma levels and showed to abolished E(2) neuroprotection, thus suggesting that E2 promotes neuronal survival likely through a rapid estrogen receptor mediated response. CONCLUSIONS: Male rat urinary bladder serves are more susceptible to A-G/R damage than female. E(2) exhibits neuroprotective properties and could be a lead for novel agents capable to protect the urinary bladder from ischaemia/reperfusion damage associated with urinary bladder disorders.