The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

even less so. It was therefore impossible for the functionally minded neuro­ scientist to design and execute experiments taking this heterogeneity into consideration. Even pharmacological studies with these peptides were difficult to interpret in a physiological framework. In 1982, thanks mainly to the recombinant DNA techniques, we learned that all these peptides belong to three genetically distinct peptide families, as we describe below. We now know a great deal more about their anatomy, and we are beginning to clarify their biosynthetic pathways. Suddenly, we can think in terms of circuits rather than in "humors" or in black boxes. In our study offunction, we can no longer ignore the multiple systems, any more than the student of monoamines can ignore differences between dopaminergic and noradrenergic systems. Less clear, but equally critical, is the issue of multiple opioid receptors. Unquestionably, the heterogeneity exists. What remains to be established is whether each of the three families of opioids has its own receptor, or whether a given family can interact with more than one SUbtype, and each receptor subtype with more than one family. More critical to physiology is whether

Endogenous Opioids: Biology and Function

Anatomy of CNS opioid receptors

In the guinea pig ileum myenteric plexus--longitudinal muscle preparation, dynorphin-(1--13) and the prototypical kappa agonist ethylketocyclazocine had equally poor sensitivity to naloxone antagonism and showed selective cross protection in receptor inactivation experiments with the alkylating antagonist beta-chlornaltrexamine. In binding assays with membranes from guinea pig brain, ethylketocyclazocine and dynorphin-(1--13) amide were more potent in displacing tritium-labeled ethylketocyclazocine than in displacing typical mu and delta opioid receptor ligands. In the two preparations studied, the dynorphin receptor appears to be the same as the kappa opioid receptor.

http://science.sciencemag.org/content/sci/215/4531/413.full.pdf

Dynorphin is a specific endogenous ligand of the kappa opioid receptor.

The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the β 2 -adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.

/pdf/functional-selectivity-and-classical-concepts-of-vqiyeua91s.pdf

Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Acute ethanol administration increased methionine-enkephalin (met-enkephalin) and β-endorphin levels in distinct areas of the rat brain, whereas chronically supplied ethanol caused a depression of met-enkephalin and β-endorphin levels in most of the brain areas investigated. The β-endorphin content of the intermediate/posterior lobe of the pituitary of rats and guinea pigs decreased by 70%. Withdrawal of ethanol resulted in a complete recovery of endorphin levels in brain and pituitary within two weeks. Whether the observed alterations in endorphin concentrations are causally related to the primary mechanisms under-lying alcohol dependence is uncertain, since no obvious signs of physical dependence were observed in treated animals.

Acute and chronic ethanol treatment changes endorphin levels in brain and pituitary

The suppressive effect of opioid administration on secretion of luteinizing hormone (LH) probably originates primarily in the hypothalamus1–5. Furthermore, the endogenous ligands of the opiate receptors (endorphins) seem to exert a tonic inhibition on the hypothalamic–pituitary–LH axis, as blockade of opiate receptors by the narcotic antagonist naloxone causes a pronounced increase in the release of LH3,4. However, it is unknown which of the particular endorphins present in the hypothalamus is responsible for this tonic inhibition. In addressing this issue we hypothesized that a similar effect to that obtained by blocking receptors with naloxone would be achieved by reducing the concentration of a specific endorphin at the receptors using antibodies against specific opioid peptides. We report here that both anti-β-endorphin antibodies and anti-dynorphini1-13 antibodies, when injected into the arcuate nucleus of the mediobasal hypothalamus (MBH) of immature female rats, caused an increase in serum LH. Anti-methionine-enkephalin (Met-enkephalin) antibodies did not affect LH levels. We conclude that β-endorphin and dynorphin rather than Met-enkephalin have a role in regulation of LH secretion in immature female rats. These may represent the first data ascribing a specific physiological function to a particular endorphin

Beta-endorphin and dynorphin control serum luteinizing hormone level in immature female rats.

Selective receptors for β-endorphin on the rat vas deferens

The epsilon-opiate receptor of the electrically stimulated rat vas deferens has been characterized by means of beta-endorphin, its fragments and derivatives thereof, as well as by its tolerance development. The data provide evidence for the uniqueness of the epsilon-receptor as compared to mu- and delta-receptors of the guinea-pig ileum and the mouse vas deferens, respectively. It appears that an activation of the epsilon-receptor requires at least the beta-endorphin sequence 1-21, which sharply contrasts with the relatively high sensitivity of mu- and delta-receptors to much shorter fragments of this opioid peptide. Furthermore, after chronic exposure of rats to etorphine, the isolated vas deferens shows a dramatic loss of sensitivity to mu-receptor agonists, but only a moderate decrease in sensitivity to beta-endorphin. The presented data contribute to the characterization of a distinct novel type of opiate receptor, the epsilon-receptor.

Pharmacological characterization of the epsilon-opiate receptor.

Studies with isolated tissues have provided strong indications for a multiplicity of opiate receptors 1–4. To satisfy the definition of cross-tolerance (tolerance to a specific opioid implying tolerance to all opioids), chronic exposure to an opiate agonist should cause tolerance and dependence in all opiate-sensitive systems. On the other hand, if multiplicity of opiate receptors is defined in terms of multiple recognition sites whose activation by specific opioids cause independent responses, then development of cross-tolerance is less likely. The mouse vas deferens (MVD) provides a useful model to test these considerations. This tissue contains δ-opiate receptors, for which D-Ala2-D-Leu5-enkephalin (DADL) represents the most selective agonist, as well as μ-receptors, for which sufentanyl appears highly selective3,5–7. We report here that isolated vasa deferentia of mice chronically treated with DADL are 800-fold less sensitive to this δ-receptor agonist, whereas there is no cross-tolerance to μ-receptor agonists. On the other hand, chronic exposure of mice to sufentanyl renders their vasa deferentia more than 1,000-fold less sensitive to sufentanyl, but affects their sensitivity to DADL insignificantly. Apparently, such highly tolerant preparations exhibit no detectable sign of dependence when challenged with naloxone or clonidine. These findings favour the notion that opiate tolerance and dependence dissociate in the MVD.

Selective development of tolerance without dependence in multiple opiate receptors of mouse vas deferens

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