During activation of the HPA axis, secretion of CRH and catecholamines also increases the secretion of BEP in the hypothalamus. In a feedback mechanism, BEP regulates the secretion of CRH in a hypothalamic region called the paraventricular nucleus (PVN) (Plotsky 1986). In the PVN, the BEP-releasing neurons act on CRH-releasing neurons and inhibit CRH release, thus regulating the activity of the stress system (Plotsky et al. 1993). BEP acts by binding to δ- and μ-opioid receptors; accordingly, treatment with a μ-opioid receptor antagonist results in increased CRH release (Boyadjieva et al. 2006). BEP affects immune-system function through a variety of mechanisms. By binding to δ- and μ-opioid receptors BEP modulates neurotransmission in sympathetic and parasympathetic neurons via neuronal circuitry within the PVN, ultimately resulting in activation of NK-cell cytolytic functions in the spleen (Boyadjieva et al. 2006, 2009; Sarkar et al. 2011). If incubated with human bone marrow mononuclear cells or NK-enriched cell populations, BEP enhances NK activity (Mathews et al. 1983). In animal models, chronic BEP infusion into the blood vessels in the brain enhances NK-cell activity in vivo,
