The Control of Hypothalamic Opioid Peptide Release

Abstract

It is generally agreed that one of the major factors involved in the response to stress is the 41 amino acid peptide corticotropin-releasing hormone (CRH) isolated by Vale and colleagues (Vale et al. 1981). This peptide is primarily known for its effect in stimulating the release of pituitary ACTH of which it appears to be the major modulator (Labrie et al. 1987). However, it has now become clear that CRH has a more general integrative role in the stress response. Thus, central administration of CRH produces a broad spectrum of autonomic and behavioral effects associated with stress. These include increased plasma levels of catecholamines and glucose (Brown et al. 1982), tachycardia and increased mean arterial pressure (Fisher et al. 1983), inhibited gastric acid secretion (Taché et al. 1983) and a variety of, generally locomotory, behavioral effects (Sutton et al. 1982; Vale et al. 1983). Furthermore, following acute or chronic stress, changes have been found in the levels of CRH-like immunoreactivity present in brain areas associated with stress responses (Chappell et al. 1986), coupled with increased synthesis and release of hypothalamic CRH (Haas and George 1988). At least one central response associated with stress (freezing behavior) can also be attenuated by the administration of a CRH receptor antagonist (Kalin et al. 1988). The mechanisms by which CRH elicits these effects are generally uncertain. However, since their discovery, the endogenous opioid peptides (EOPs) have been thought to play a major role in the reaction to stress (see Przewlocki et al., this Vol.) and a possible CRH-opioid interaction may therefore be envisaged. In support of this suggestion is the finding of a simultaneous co-expression of CRH and pro-opiomelanocortin (POMC) mRNA in specific regions of the brain (Thompson et al. 1987), implying an interaction between these systems. This would appear especially likely to occur in the hypothalamus, a region suggested to be the primary site of action for integrating the endocrine, autonomic and behavioral effects of CRH. The close neuroanatomical relationship between CRH and opioid neuronal systems would allow such a functional interaction between the two systems to occur. β-Endorphin (β-END) and CRH nerve terminals are present in close proximity in the medial basal hypothalamus and median eminence (Bloom et al. 1982; Swanson et al. 1983), while dynorphin_1–8 (DYN_1–8) and met-enkephalin (Met-ENK) have been reported to coexist with CRH in neurons in the paraventricular nucleus (Hökfelt et al. 1987; Roth et al. 1983); this is also the case for Met-ENK and CRH in the median eminence (Hisano et al. 1986).