Chronic stress-induced effects of corticosterone on brain: direct and indirect.

Acutely, glucocorticoids act to inhibit stress-induced corticotrophin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) secretion through their actions in brain and anterior pituitary (canonical feedback). With chronic stress, glucocorticoid feedback inhibition of ACTH secretion changes markedly. Chronically stressed rats characteristically exhibit facilitated ACTH responses to acute, novel stressors. Moreover, in adrenalectomized rats in which corticosterone was replaced, steroid concentrations in the higher range are required for facilitation of ACTH responses to occur after chronic stress or diabetes. Infusion of corticosterone intracerebroventricularly into adrenalectomized rats increases basal ACTH, tends to increase CRF, and allows facilitation of ACTH responses to repeated restraint. Therefore, with chronic stressors, corticosterone seems to act in brain in an excitatory rather than an inhibitory fashion. We believe, under conditions of chronic stress, that there is an indirect glucocorticoid feedback that is mediated through the effects of the steroid +/- insulin on metabolism. Increased energy stores feedback on brain to inhibit hypothalamic CRF and decrease the expression of dopamine-beta-hydroxylase in the locus coeruleus. These changes would be expected to decrease the level of discomfort and anxiety induced by chronic stress. Moreover, central neural actions of glucocorticoids abet the peripheral effects of the steroids by increasing the salience and ingestion of pleasurable foods.

Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: a chronic stress paradigm.

Body temperature and pituitary-adrenal responses to restraint (15 min or 4 h) stress were evaluated in nondependent and morphine-dependent rats. Male Sprague-Dawley rats were treated twice daily with increasing doses of morphine (10-100 mg/kg, s.c.) for 16 days. Transmitters were implanted in the peritoneal cavity to monitor body temperature and blood was collected for hormone assays. Acute withdrawal from chronic morphine treatment was associated with reduced body weight, increased adrenal weight and decreased thymus weight. Sixteen days after termination of chronic morphine treatment, rats had recovered normal adrenal size, but still displayed marked thymus involution and reduced body weight. Restraint-induced hyperthermia was attenuated in morphine-dependent rats that had undergone 12-h withdrawal. Sixteen days after withdrawal, rats still had not fully recovered the hyperthermic response to restraint. Chronic morphine treatment resulted in a marked elevation of basal corticosterone concentrations. Despite the negative-feedback effects of elevated basal corticosterone concentrations, morphine-dependent rats that had undergone 12-h withdrawal displayed a potentiated and prolonged corticosterone response to restraint stress. In contrast, rats that had undergone 8-day and 16-day morphine withdrawal had recovered normal basal pituitary-adrenal activity, but displayed significantly reduced and shorter adrenocorticotropic hormone and corticosterone responses to restraint. These results suggest that chronic morphine dependence is a chronic stressor, resulting in profound and long-lasting changes in the temperature and pituitary-adrenal responses to acute restraint stress in a time-dependent manner. This morphine-dependence model may be useful in understanding the role that hormonal stress responses play in the maintenance and relapse to opioid use in humans.

Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid negative-feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: possible mechanisms involved in facilitated and attenuated stress responses.

Chronic morphine treatment produces profound and long-lasting changes in the pituitary-adrenal responses to stressful stimuli. The purpose of the present study was to explore the mechanisms involved in these altered stress responses. Chronic morphine administration increased basal plasma concentrations of corticosterone and adrenocorticotropic hormone (ACTH), which peaked at 36 h after the final morphine injection and returned to normal levels within 84-h. Whole brain glucocorticoid receptor protein expression was reduced (approximately 70%) in morphine-treated rats 4-h after the final morphine injection and these levels recovered within 16-h. Twelve hours following morphine withdrawal, rats displayed normal ACTH, but potentiated and prolonged corticosterone responses to restraint stress. Both the ACTH and corticosterone responses to restraint in acutely withdrawn rats were insensitive to dexamethasone. Furthermore, acutely withdrawn rats displayed reduced ACTH but prolonged corticosterone responses to peripheral corticotropin releasing hormone (CRH) administration. These findings suggest that the normal ACTH and enhanced corticosterone responses to stress in acutely withdrawn rats involved decreased sensitivity of negative-feedback systems to glucocorticoids, reduced pituitary responsivity to CRH, and enhanced sensitivity of the adrenals to ACTH. Eight days following morphine withdrawal, rats displayed dramatically reduced ACTH, but normal corticosterone responses to restraint stress. These rats displayed enhanced sensitivity to dexamethasone and normal pituitary-adrenal responses to CRH. These data suggest that the reduced ACTH responses to stress in 8-day withdrawal rats involved increased sensitivity of negative-feedback systems to glucocorticoids as well as reduced CRH and/or AVP function in response to stress. Taken together, the results of this study illustrate some of the mechanisms mediating altered stress responsivity in rats that have received chronic morphine treatment.

The steroid 17alpha-acetoxy-6-dimethylaminomethyl-21-fluoro-3-ethoxy-pregna-3, 5-dien-20-one (SC17599) is a selective mu-opioid agonist: implications for the mu-opioid pharmacophore.

The steroid SC17599 (17alpha-acetoxy-6-dimethylaminomethyl-21-fluoro-3-ethoxypregna -3, 5-dien-20-one) has mu-opioid actions in vivo. The ability of SC17599 to interact with opioid receptors has been studied using radioligand and [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) binding assays. SC17599 bound to mu-opioid receptors in SH-SY5Y neuroblastoma cells and to recombinant receptors expressed in rat C6 glioma cells and Chinese hamster ovary cells with good affinity and with greater than 100-fold selectivity for mu- over both delta- and kappa-opioid receptors. Binding was much reduced when aspartate 147 in the wild-type mu-opioid receptor was replaced with asparagine. The affinity of SC17599 for the mu-opioid receptor was decreased in the presence of sodium ions, indicating agonist activity. SC17599 stimulated the binding of [(35)S]GTPgammaS in a naloxone-reversible manner with good potency and maximal effect equivalent to that of the mu-opioid agonists fentanyl and [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. In rat brain membranes, SC17599-mediated stimulation of [(35)S]GTPgammaS binding was reversed by the antagonist naltrexone. SC17599 lacks an aromatic ring and para-hydroxyl substituent considered critical in the pharmacophore for mu-opioids. The structural relationship between SC17599 and more traditional opioid ligands was investigated through genetic algorithm-based modeling techniques for pharmacophore generation (GASP) and ligand-receptor docking (GOLD). The relatively planar and electron-rich A ring of the steroid compensated for the lack of aromaticity. Modeling of ligand-receptor docking showed that both morphine and SC17599 occupy the same binding pocket within the transmembrane helix bundle of the mu-opioid receptor and that the relationship between their binding modes largely mimicked the pharmacophore alignment.

Antinociceptive and other behavioral effects of the steroid SC17599 are mediated by the mu-opioid receptor.

The objective of the present investigation was to evaluate the behavioral effects of SC17599 (17alpha-acetoxy-6-dimethylaminomethyl-21-fluoro-3-ethoxypregna -3, 5-dien-20-one) in mice and to determine if these effects are selectively mediated by opioid receptors. Although less potent than morphine, SC17599 produced dose-dependent antinociception in both the acetic acid-induced writhing and warm water tail-withdrawal assays. Pretreatment with the opioid antagonist naltrexone and the noncompetitive mu-opioid receptor-selective antagonist methocinnamox, but not the delta-opioid receptor-selective antagonist naltrindole or the kappa-opioid receptor-selective antagonist nor-binaltorphimine, antagonized the antinociceptive effects of both SC17599 and morphine. Similarly to morphine, administration of SC17599 induced the Straub tail response in a dose-dependent and naltrexone-sensitive manner. At the highest doses studied, unlike morphine, SC17599 did not alter locomotor activity. The steroid SC17599 is structurally a very unusually selective mu-opioid agonist that produces behavioral effects, which are similar, but not identical, to those of morphine.