The role of the anteriolateral bed nucleus of the stria terminalis in stress-induced nociception

Abstract

The role of the anteriolateral bed nucleus of the stria terminalis in stress-induced nociception. Am J Physiol Gastrointest Liver Physiol 302: G1301-G1309, 2012. First published April 5, 2012; doi:10.1152/ajpgi.00501.2011.-Activation of the central amygdala (CeA) by corticosterone (CORT) induces somatic and colonic hypersensitivity through corticotrophinreleasing factor (CRF)-dependent mechanisms. However, the importance of the bed nucleus of the stria terminalis (BNST), part of the extended amygdala, on nociception remains unexplored. In the present study, we test the hypothesis that stimulation of the CeA by CORT induces somatic and colonic hypersensitivity through activation of the anteriolateral BNST (BNSTAL). Animals were implanted with micropellets of CORT or cholesterol (CHOL) onto the CeA or the BNSTAL. Mechanical sensitivity was quantified using electronic von Frey filaments, and colonic nociception was measured by quantifying a visceromotor response to graded colorectal distension. In situ hybridization was used to determine mRNA levels for CRF, CRF1, and CRF2 receptors in the BNSTAL. In a second group, animals were implanted bilaterally with 1) CORT or CHOL micropellets onto the CeA; and 2) cannulas localized to the BNSTAL to administer a CRF1 receptor antagonist (CP376395). Animals implanted with CORT onto the CeA, but not the BNSTAL, exhibited increased expression of CRF mRNA and increased CRF1-to-CRF2 receptor ratio in the BNST, as well as somatic and colonic hypersensitivity compared with CHOL controls. Infusion of CP376395 into the BNSTAL inhibited somatic and colonic hypersensitivity in response to elevated amygdala CORT. Somatic and colonic hypersensitivity induced by elevated amygdala CORT is mediated via a CRF1 receptor-dependent mechanism in the BNSTAL. The CeA through a descending pathway involving the BNSTAL plays a pivotal role in somatic and colonic nociception. amygdala; bed nucleus of the stria terminalis; corticosterone; corticotrophin-releasing factor; pain IRRITABLE BOWEL SYNDROME (IBS) is a gastrointestinal (GI) disorder characterized by abdominal pain and abnormal bowel habits that are worsened during periods of stress (26). While the precise etiology and pathophysiology are unknown, clinical studies suggest that hyperactivation in brain regions involved in pain processing, including the amygdala and the bed nucleus of the stria terminalis (BNST), play an important role in IBS symtomatology (31,39). In previous preclinical studies, stereotaxic implants of corticosterone (CORT; cortisol in humans) onto the dorsal margin of the central amygdala (CeA) at pharmacological doses induced IBS-like symptoms, including anxiety-like behavior, abnormal colonic motility, and heightened somatic and colonic pain sensitivity (14,27). In the same model, elevation of amygdala CORT increased corticotrophinreleasing factor (CRF) mRNA in the CeA and the BNST (37, 38). Thus, although clinical and preclinical evidence implicates important roles of stress activation of the CeA and BNST in GI pathologies,...

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…Stereotaxic bilateral implantation of cannulae into the BNST AL was performed as previously described (Tran et al, 2012c). Briefly, animals were anesthetized with a ketamine (100 mg/kg i.p.…”

“…A somatic mechanical threshold was determined using an electronic von Frey (IITC, Woodland Hills, CA) as previously described Myers et al, 2005;Tran and Greenwood-Van Meerveld, 2012b;Tran et al, 2012c). Animals were acclimated to the procedure room for 30 min before unrestrained placement on an elevated mesh floor (12 mm  12 mm grid) in a clear plastic enclosure apparatus (21  27  15 cm) for an additional 30 min.…”

“…Instrumentation for visceral sensitivity assessment was performed as previously described (Greenwood-Van Meerveld et al, 2001;Johnson et al, 2012;Myers et al, 2005;Tran et al, 2013;Tran and Greenwood-Van Meerveld, 2012b;Tran et al, 2012c). Briefly, rats were fasted for 16-18 h to ensure that the colon was free of fecal pellets, allowing for the insertion of the colonic balloon catheter.…”

“…Blood samples were collected to evaluate CORT and ACTH levels. The time (approximately 0900-1100 hours) was selected to be consistent with our previous experiments investigating the BNST AL (Tran et al, 2012c), and is a period that CORT levels are known to be constant and minimal (Allen and Kendall, 1967), which improves resolution when examining stress responses. Approximately 1 ml of trunk blood was collected and centrifuged at 2500 g for 10 min.…”

“…Moreover, our previous study demonstrated that the central amygdaloid nucleus (CeA) has a pivotal role in somatic and colonic nociception, through a descending pathway involving the anteriolateral BNST (BNST AL ; Tran et al, 2012c). However, the precise mechanisms of CRF in the BNST AL regulating comorbid anxiety and hyperalgesia in response to a chronic stressor are unclear.…”