The Role of the Anteriolateral Bed Nucleus of the Stria Terminalis (BNST) 1 in Stress-Induced Nociception

Background : Activation the induces somatic and colonic hypersensitivity through corticotrophin-releasing factor 26 (CRF)-dependent mechanisms. However, the importance of the bed nucleus of the stria 27 terminalis (BNST), part of the extended amygdala, on nociception remains unexplored. 28 In the current study we test the hypothesis that stimulation of the CeA by CORT induces 29 somatic and colonic hypersensitivity through activation of the anteriolateral BNST 30 (BNST AL ). Methods: Animals were implanted with micropellets of CORT or cholesterol 31 (CHOL) onto the CeA or the BNST AL . Mechanical sensitivity was quantified using 32 electronic von Frey filaments, and colonic nociception was measured by quantifying a 33 visceromotor response (VMR) to graded colorectal distension (CRD). In situ 34 hybridization was used to determine mRNA levels for CRF, CRF 1 , and CRF 2 receptors 35 in the BNST AL . In a second group, animals were implanted bilaterally with 1) CORT or 36 CHOL micropellets onto the CeA and 2) cannulas localized to the BNST AL to administer 37 a CRF 1 receptor antagonist (CP376395). Results: Animals implanted with CORT onto 38 the CeA, but not the BNST AL , exhibited increased expression of CRF mRNA and 39 increased CRF 1 :CRF 2 receptor ratio in the BNST as well as somatic and colonic 40 hypersensitivity compared to CHOL controls. Infusion of CP376395 into the BNST AL 41 inhibited somatic and colonic hypersensitivity in response to elevated amygdala CORT. Summary: Somatic The results our study demonstrated that somatic and colonic hypersensitivity induced by elevated amygdala CORT is mediated, at least in part, via a CRF 1 receptor dependent mechanism in the BNST AL . Taken together, our findings may provide important insight into the brain circuitry involved in GI pathologies as IBS. demonstrated that, when compared to CHOL, there was heightened somatic and colonic sensitivity in animals with micropellets containing pharmacological concentrations of CORT implanted over the CeA. However, no changes in somatic or colonic sensitivity were observed when micropellets of CORT or CHOL bathed the BNST AL . These findings suggest that modulation of the CeA by CORT plays a role in modulating somatic and colonic sensitivity whereas directly elevating CORT in the BNST AL has little influence on somatic or colonic sensitivity. Since previous studies have shown that elevated amygdala CORT induced an increase in CRF mRNA in the BNST AL [38], we explored the role of CRF in the BNST AL following modulation of the amygdala by elevated CORT. Our results showed that in addition to increasing CRF mRNA in the BNST AL , there was an increase in the CRF 1 :CRF 2 receptor ratio, implicating a potential role for CRF signaling by the BNST AL in response to elevating levels of CORT in the CeA. To further investigate the functional role of CRF in the BNST, we investigated the effect of a selective CRF 1 receptor antagonist infused directly into the BNST AL in rats with CORT-implanted over the CeA. Infusion of 290 CP376395 into the BNST AL resulted in an inhibition of the somatic and colonic hypersensitivity induced by elevated amygdala CORT. Together our results highlight an important mechanism that may be involved in the emotional processing of pain in which the BNST AL , through a CRF-dependent mechanism, mediates somatic and colonic hypersensitivity induced by exposure of the CeA to elevated levels of CORT. that animals primed with 1, a CRF receptor agonist, into BNST an increase in anxiety-like behavior, which could be reversed by a 1 investigate the role of CRF in the regulation of colonic somatic hypersensitivity within the BNST AL a CRF 1 receptor antagonist infused the BNST. that the CRF 1 receptor antagonist colonic pain that