Modulation of limbic noradrenergic circuits by cannabinoids

Tese de doutoramento MedicinaThe endocannabinoid system has been implicated in the regulation of several physiological functions. The widespread distribution of the endocannabinoid system in the central nervous system (CNS) accounts for many effects attributed to cannabinoids. Importantly, cannabinoids have been shown to modulate mood, cognition and memory. There is growing evidence suggesting that cannabinoids can interact with the noradrenergic system. Noradrenergic transmission in the CNS has also been implicated in the regulation of mood, cognition and memory. In the present work, the hypothesis that cannabinoids can impact noradrenergic transmission in the limbic system was examined. Firstly, localization of the cannabinoid receptor type 1 (CB1r) was performed in the nucleus accumbens (Acb) and in the nucleus of the solitary tract (NTS), using immunohistochemical techniques, to clarify the anatomical substrates underlying potential interactions. It was shown that CB1r is present in noradrenergic neurons of the NTS. In addition, CB1r was found in the Acb but rarely in noradrenergic terminals. Furthermore, the effects of cannabinoid administration on adrenergic receptor (AR) expression in the Acb were studied. Western blot analysis of accumbal tissue revealed that exogenous administration of the synthetic cannabinoid WIN 55,212-2 decreases α2A- and β1-AR expression. Finally, the importance of norepinephrine (NE) in cannabinoid-induced behaviors was tested. Using the place conditioning paradigm and the elevated zero maze (EZM), the effects of cannabinoids on aversion and anxiety, respectively, were tested following depletion or blockade of noradrenergic transmission in the Acb or in the bed nucleus of the stria terminalis (BNST). Using an immunotoxin approach, NE depletion restricted to the Acb, but not BNST, blocked the expression of aversion to WIN 55,212-2. Depletion of NE had no effect on WIN 55,212-2-induced anxiety. Moreover, the fact that blockade of β1-AR in the Acb prevents WIN 55,212-2-induced aversion suggests that noradrenergic transmission via β1-AR is critical for eliciting this behavior. In conclusion, the present work provides new evidence supporting the idea that cannabinoids can impact noradrenergic transmission in the limbic system. In addition, cannabinoid-induced aversion is dependent on intact noradrenergic transmission in the Acb. Taken together, the studies provide herein clarify the anatomical and neurochemical substrates for cannabinoid actions in the CNS.O sistema endocanabinóide tem sido implicado na regulação de várias funções fisiológicas. A dispersa distribuição do sistema endocanabinóide no sistema nervoso central (SNC) explica os muitos efeitos atribuídos aos canabinóides. De realçar que tem sido demonstrado que os canabinóides modelam o humor, cognição e memória. Existe uma crescente evidência sugerindo uma interacção entre o sistema endocanabinóide e o sistema noradrenérgico. Por seu lado, transmissão noradrenérgica no SNC tem sido implicada na regulação do humor, cognição e memória. No presente trabalho, a hipótese de que os canabinóides podem afectar a transmissão noradrenérgica no sistema límbico foi examinada. Inicialmente, a localização do receptor dos canabinóides tipo 1 (CB1r) no núcleo accumbens (Acb) e no núcleo do tracto solitário (NTS) foi efectuada utilizando técnicas de imunohistoquímica, de forma a clarificar os substratos anatómicos subjacente a potenciais interacções. Foi demonstrado que CB1r está presente em neurónios noradrenérgicos do NTS. Para além disso, CB1r foi encontrado no Acb mas raramente em terminais noradrenérgicos. Adicionalmente, os efeitos da administração de canabinóides na expressão de receptores adrenérgicos no Acb foram estudados. Análise por western blot de tecido do Acb revelou que administração exógenea do canabinóide sintético WIN 55,212-2 diminui a expressão dos receptores adrenérgicos α2A e β1. Finalmente, a importância da noradrenalina (NA) nos comportamentos induzidos pelos canabinóides foi testada. Utilizando o paradigma de “place conditioning” e o teste “elevated zero maze” (EZM), os efeitos dos canabinóides na aversão e anxiedade foram testados após depleção ou bloqueio da transmissão noradrenérgica no Acb ou no núcleo da estria terminalis (BNST). Utilizando uma imunotoxina, a depleção restrita de NA no Acb, mas não no BNST, bloqueou a aversão ao WIN 55,212-2. Enquanto que depleção de NA não teve nenhum efeito na anxiedade provocada por WIN 55,212- 2. Mais, o facto de o bloqueio do receptor adrenérgico β1 no Acb prevenir a aversão induzida por WIN 55,212-2 sugere que a transmissão noradrenérgica via este receptor é fundamental para a expressão deste comportamento. Em conclusão, o presente trabalho fornece nova evidência suportando a ideia de que os canabinóides podem afectar a transmissão noradrenérgica no sistema límbico. Mais, a aversão induzida por canabinóides é dependente da transmissão noradrenérgica no Acb. Em conjunto, os estudos apresentados neste trabalho esclarecem os substratos anatómicos e neuroquímicos das acções dos canabinóides no SNC

What is in? pneumoperitoneum after sexual intercourse

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Extensive subcutaneous emphysema as a presentation of ischemic colitis

Introduction . Subcutaneous emphysema is usually benign and self-limited; however, it may be associated with a life-threating situation. Case Report . An elderly woman with progressive malaise with extensive subcutaneous emphysema (cervical to abdominal wall) was observed at the emergency department. Colonic perforation was diagnosed and the patient underwent surgery. Intraoperatively, necrosis and perforation of the sigmoid colon into the retroperitoneum were found and a Hartmann procedure was performed. Conclusion . Cervical and thoracic subcutaneous emphysema may be the first sign of intra-abdominal lesion

Epigastric pain: incarceration or rotation?

Introduction: Acute intrathoracic gastric volvulus occurs when the stomach has a twist mesenteroaxial/organoaxial or chest cavity resulting in a dilatation or rupture of the diaphragmatic hiatus or diaphragmatic hernia. The purpose of this work is to show a interesting case of gastric volvulus in a patient with several comorbidities. Case Report: A 77-year-old female with past history of hiatal hernia and mental disease associated with diabetes and atrial fibrillation. Patient went to the emergency department due to vomiting associated with blood. Analytical parameters (WBC, HGB, PCR, metabolic panel and liver function), showed no significant alterations. Thoracic X-ray revealed an enlarged mediastinum due to herniation of the stomach. A computed tomography (CT) scan confirmed intrathoracic localization of the gastric antrum with twist. Patient’s symptoms were relieved by nasogastric intubation and analgesia. After six months, the patient is still asymptomatic. Conclusion: In general, the treatment of an acute gastric volvulus requires an emergent surgical repair. In patients who are not surgical candidates (with comorbidities or an inability to tolerate anesthesia), endoscopic reduction should be attempted. Chronic gastric volvulus may be treated non-emergently, and surgical treatment is increasingly being performed using a laparoscopic approach. In this case, it is a chronic form that was solved with the placement of the nasogastric tube. A nasogastric decompression is an option in the chronic form of hiatal hernia associated to gastric volvulus in patients with serious comorbidities

Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion

The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the 1-adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents.This work was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007

Omental whirl associated with bilateral inguinal hernia: a case report

INTRODUCTION: Torsion of the omentum is a rare cause of abdominal pain. It is clinically similar to common causes of acute surgical abdomen and is often diagnosed during surgery. Inguinal hernia is a common condition but not frequently related with torsion of the omentum. CASE PRESENTATION: A 40-year-old Caucasian man came to our emergency department with abdominal pain of the left quadrant and abdominal distension for 2 days. His medical history included an untreated left inguinal hernia in the last year. Computed tomography revealed densification of mesocolon with left omentum "whirl" component and other signs of omental torsion. During an exploratory laparoscopy, a wide twist of his omentum with necrotic alterations that extended to the bilateral inguinal hernial content was observed. Omentectomy and surgical repair of bilateral inguinal hernia were performed. CONCLUSIONS: Torsion of the omentum is a rare entity and usually presents a diagnostic challenge. The use of abdominal computed tomography can help diagnosing torsion of the omentum preoperatively and, thus, prevents a surgical approach. Nonetheless, some cases of torsion of the omentum require surgical repair. Accordingly, a laparoscopic approach is minimally invasive and efficient in performing omentectomy.(undefined

Contribution of limbic norepinephrine to cannabinoid-induced aversion

RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007)

Anatomical, biochemical, and behavioral evidence for cannabinoid modulation of noradrenergic circuits: role of norepinephrine in cannabinoid-induced aversion

The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Recent evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. This chapter summarizes our current knowledge regarding the anatomical substrates underlying regulation of noradrenergic circuitry by the endocannabinoid system. It then presents biochemical and functional evidence showing an important effect of cannabinoid modulation on adrenergic receptor signaling. Finally, the impact of this interaction with respect to specific behaviors is explored, demonstrating that norepinephrine is a critical determinant of cannabinoid-induced aversion, which adds another dimension to how central noradrenergic circuitry is regulated by the cannabinoid system.(undefined

Muscularis and submucosa plus mucosa layers length in small intestine.

<p>(A) Muscularis and (B) submucosa plus mucosa layers at 1, 3 and 8 months old. There were no differences between groups. <i>iuGC</i>, <i>in utero</i> glucocorticoid exposed animals. (A) n = 6, 4, 6 CTR and n = 5, 10, 7 <i>iuGC</i>. (B) n = 6, 7, 6 CTR and n = 5, 9, 7 <i>iuGC</i>.</p

<i>In utero</i> glucocorticoid exposure decreases the length of small intestine at 24 hours, 1 and 3 months old.

<p>(A) The length of small intestine is shorter in <i>iuGC</i> rats at 1 and 3 months old, n = 6, 17, 6 CTR and n = 9, 10, 7 <i>iuGC</i>. (B) Stomach length in control and <i>iuGC</i> animals, n = 10, 9, 6 CTR and n = 10, 11, 7 <i>iuGC</i>. (C) The length of colon in control and <i>iuGC</i> animals, n = 10, 9, 6 CTR and n = 10, 11, 7 <i>iuGC</i>. (D) Small Intestine is shorter in <i>iuGC</i> animals at 24 hours of life, n = 4 CTR and n = 13 <i>iuGC</i>. <i>iuGC</i>, <i>in utero</i> glucocorticoid exposed animals. *<i>P</i> <0.05, *** <i>P</i> <0.001.</p