Hair glucocorticoids are not a historical marker of stress – exploring the time-scale of corticosterone incorporation into hairs in a rat model

Hair glucocorticoids are increasingly popular biomarkers, used across numerous research fields as a measure of stress. Although they are suggested to be a proxy of the average HPA axis activity spanning a period of weeks or months into the past, this theory has never been tested.In the present study, adrenalectomized rats with no endogenous (adrenal) glucocorticoid production were used to study how circulating glucocorticoid levels would be reflected in the glucocorticoid levels found in hair samples. By dosing the animals daily with high levels of corticosterone for seven days, while sampling hairs before, during, and after treatments, a timeline for glucocorticoid uptake into hairs was constructed. This kinetic profile was compared to two hypothetical models, and the theory that hair glucocorticoids are a record of historical stress had to be rejected.Corticosterone concentrations in hairs were found to increase within three hours of the first injection, the highest concentrations were found on the seventh day of treatments, and the decrease in concentrations post-treatment suggests rapid elimination. We speculate that hair glucocorticoid levels can only be used to characterize a stress-response for a few days following a postulated stressor.An updated model, where glucocorticoids diffuse into, along, and out of hairs needs to be adopted to reconcile the experimentally obtained data. The inescapable consequence of this updated model is that hair glucocorticoids become a marker of – and can only be used to study – recent, or ongoing, stress, as opposed to historical events, weeks or months in the past.

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

Background Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via β-adrenergic receptor (βAR) activation. The contribution of distinct βAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. Methods Here, the authors sought to determine the contribution of peripheral, spinal, and supraspinal βARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained βAR antagonists peripherally, spinally, or supraspinally alongside OR486. Results The authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 ± 0.24 vs. OR486 1.54 ± 0.08, mean ± SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 ± 0.22 vs. OR486 8.10 ± 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 ± 0.23 vs. OR486 5.91 ± 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective βAR antagonist propranolol, the β2AR antagonist ICI-118,511, or the β3AR antagonist SR59230A blocked the development of OR486-induced hypersensitivity. Conclusions Peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting βAR antagonists may benefit chronic pain patients.

Loss of hepatic aryl hydrocarbon receptor protein in adrenalectomized rats does not involve altered levels of the receptor’s cytoplasmic chaperones

The aryl hydrocarbon receptor (AHR) plays physiological roles and mediates adaptive and toxic responses to environmental pollutants. Adrenalectomized rats display decreased hepatic AHR protein levels, with no change in mRNA, and selectively impaired induction of cytochrome P450 1B1. This is similar to reported phenotypes for mice with hepatocyte-specific conditional deletion of AHR-interacting protein (AIP), a chaperone protein of the cytoplasmic AHR complex. In this study, we demonstrated that adrenalectomy (ADX) and acute dexamethasone (DEX) treatment do not alter hepatic AIP mRNA or protein levels. Also, hepatic protein levels of the 90 kDa heat shock protein and p23 were not altered by ADX or acute DEX treatment. These results suggest that the loss of rat hepatic AHR protein following ADX cannot be explained by changes in the levels of the receptor’s cytoplasmic chaperone proteins.

Possible Contribution of Mineralocorticoid Receptor Activation on Glucocorticoid-Induced Left Ventricular Remodeling in Adrenalectomized Rat

Background: Chronic glucocorticoid treatment induces the development of renal injury via mineralocorticoid receptor (MR) activation in bilaterally adrenalectomized rats. It has been hypothesized that glucocorticoid contributes to the development of left ventricular (LV) remodeling through MR activation in bilaterally adrenalectomized rats (ADX). Methods: ADX rats were maintained with 1%NaCl in drinking water and randomly treated as follows for 8 weeks: vehicle (n=7), bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO) (5 mg/kg/day, subcutaneous, n=7), and ADX + HYDRO + eplerenone (0.125% in chow; approximately 75 mg/kg/day, n=7). An osmotic minipump was implanted subcutaneously for continuous infusion of HYDRO. Results: As compared with control vehicletreated uninephrectomized rats, ADX+HYDRO treatment for 8 weeks significantly increased systolic blood pressure, LV weight, collagen content and mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and collagen type 1 and III. These changes were associated with increase in LV thiobarbituric acid reactive substances content, dihydroethidium fluorescence and mRNA levels of NADPH oxidase subunits. Treatment with a selective MR antagonist, eplerenone significantly attenuated HYDRO induced changes in LV parameters. HYDRO-induced increases in mRNA and protein levels of serum and glucocorticoid-regulated kinases 1 were prevented by eplerenone. Conclusion: These data suggest that chronic glucocorticoid treatment induces LV tissue remodeling through MR dependent mechanism in bilateral adrenalectomized rats. DOI: http://dx.doi.org/10.3329/jbsp.v8i1.16639 J Bangladesh Soc Physiol. 2013, June; 8(1): 6-15