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A Larcher

Publications and source records attributed to A Larcher.

At least 19 recordsLinked to original sources
PubMed2000

Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine.

BACKGROUND: It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity. METHODS: The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed. RESULTS: Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia. CONCLUSIONS: Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.

Analgesics, Opioid↗
PubMed1999

Evidence for opiate-activated NMDA processes masking opiate analgesia in rats.

The acute interaction between opioid receptors and N-methyl-D-aspartate (NMDA) receptors on nociception was examined in rats using tail-flick and paw-pressure vocalisation tests. When injected at various times (1 to 6 h) after morphine (5 to 20 mg/kg, i.v.) or fentanyl (4x40 microgram/kg, i.v.), the opioid receptor antagonist naloxone (1 mg/kg, s.c.) not only abolished the opiate-induced increase in nociceptive threshold, but also reduced it below the basal value (hyperalgesia). The noncompetitive NMDA receptor antagonist MK-801 (0.15 or 0.30 mg/kg, s.c.) prevented the naloxone-precipitated hyperalgesia and enhanced the antinociceptive effects of morphine (7.5 mg/kg, i.v.) and fentanyl (4x40 microgram/kg, i.v.). These results indicate that the antinociceptive effects of morphine and fentanyl, two opiate analgesics widely used in humans in the management of pain, are blunted by concomitant NMDA-dependent opposing effects which are only revealed when the predominant antinociceptive effect is sharply blocked by naloxone. This study provides new rationale for beneficial adjunction of NMDA receptor antagonists with opiates for relieving pain by preventing pain facilitatory processes triggered by opiate treatment per se.

Analgesics, Opioid↗
PubMed1999

Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity.

From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. We recently showed that a single heroin administration induces an enhanced pain sensitivity for several days, a phenomenon which is prevented by the non-competitive N-methyl-D aspartate receptor antagonist MK-801. Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.

Analgesics, Opioid↗
PubMed1998

Genomic and non-genomic mechanisms of oxytocin receptor regulation.

Our recent studies have shown that regulation of uterine oxytocin (OT) binding involves at least two different mechanism: Estradiol (E2)-induced upregulation is accompanied by an increase in OT receptor (OTR) mRNA accumulation, implying that the E2 effect is mediated via increased OTR gene transcription and/or OTR mRNA stabilization. In contrast, P (P)-induced OTR down-regulation occurs via a novel non-genomic mechanism, involving a direct interaction of P with the OTR at the level of the cell membrane. We found that P specifically binds to the OTR and inhibits its ligand binding and signalling functions. Physiological levels of P repress in vitro the ligand binding capacity (Bmax) of the OTR by > 50%. When expressed in CHO cells, the OTR provides a high affinity (Kd: 20nM) membrane binding site for P. OT-induced inositol phosphate production and intracellular calcium mobilization is inhibited 85% and 90%, respectively, by P. These effects are specific as signalling and binding functions of the closely related V1a vasopressin receptor remain unaffected by P, and as other, related steroids are devoid of any effect on OTR binding or signalling functions. The present observation of a specific interaction of a steroid with a G-protein-linked receptor defines a new mechanism of non-genomic steroid action and uncovers a novel level of crosstalk between steroid and peptide hormone action.

Animals↗
PubMed1998

Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems.

Mechanisms underlying the development of acute tolerance to the analgesic effect of opiates were investigated. In the rat tail-flick test, administration of naloxone (1 mg/kg, s.c.) 40 min after heroin (1 mg/kg, s.c.) was shown to induce hyperalgesia, indicative of a short-onset, opiate-activated pain facilitatory systems masking the opiate analgesia. Pretreatment with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate blocked, in a dose-dependent manner, the naloxone-induced hyperalgesia and potentiated the heroin-induced analgesia. Using a schedule of two successive injections of 1 mg/kg heroin, acute tolerance was indicated by a marked reduction (-52%) in analgesia induced by the second dose. After pretreatment with dizocilpine maleate, the acute tolerance was abolished and the analgesic effects of both injections of heroin were strongly potentiated. These observations indicate that acute tolerance appears after the first exposure to opiates and stems from opiate activation of N-methyl-D-aspartate-dependent pain facilitatory systems.

Analgesics, Opioid↗
PubMed1998

Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time.

Acute dependence, defined as a precipitation of somatic signs by an antagonist, may occur after a single administration of an opiate drug. Because hyperalgesia is a consistent sign of the withdrawal syndrome, we tested the effectiveness of heroin, an opiate used by addicts, to induce pain facilitation even after a first exposure to the drug. In opiate-naive rats, subcutaneous injection of heroin induced analgesia followed by allodynia, a decrease in pain threshold. This latter phenomenon was observed in the absence of noxious stimuli and lasted several days. An N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 prevented such long-lasting allodynia. These results suggest that allodynia is an early sign reflecting neural plasticity associated with the development of dependence.

Animals↗
PubMed1995

Simultaneous activation of spinal antiopioid system (neuropeptide FF) and pain facilitatory circuitry by stimulation of opioid receptors in rats.

Neuropeptide FF (NPFF) is a mammalian FMRFamide-like octapeptide with antiopioid properties that inhibits morphine-induced analgesia but also produces hyperalgesia. In the present study, a series of three experiments was carried out to investigate the interactions between opioid receptor stimulation and antiopioid systems. First, by using in vitro superfusion system with rat spinal cord slices, we showed that morphine stimulated NPFF release in a dose-dependent manner. The stimulating effect which was observed with morphine concentrations as low as 100 fM reached a maximum at 0.1 nM, then decreased and was ineffective at 10 microM. The morphine-induced release of NPFF was abolished by naloxone (1 microM) but unaltered by tetrodotoxin. Second, by an in vivo approach, we showed that a single heroin administration (2.5 mg/kg, s.c.) elicited in 30 min a drastic drop (38%) in spinal NPFF content. In a third experiment, we evaluated the capacity of naloxone in revealing an antiopioid component associated with opioid receptor stimulation. The administration of naloxone (1 mg/kg, s.c..) 25 min following that of heroin (2.5 mg/kg, s.c.) not only abolished the heroin-induced increase of tail-flick latency, but also lowered it under the basal value by 30%. These results indicate that opioid receptor stimulation activates both pain inhibitory and pain facilitatory systems in which NPFF may play a significant role and that opiate-induced analgesia is always partly masked.

Animals↗
PubMed1995

Effects of retinoic acid and estrogens on oxytocin gene expression in the rat uterus: in vitro and in vivo studies.

We and others have previously identified functional estrogen (E) and retinoic acid (RA) response elements in the human and rat oxytocin (OT) gene promoters. Whereas there is no direct evidence for a significant role of E or RA in the regulation of rat hypothalamic OT gene expression, we have recently demonstrated that in vivo administration of E strongly stimulates uterine OT gene expression. Here, we show that in vivo administration of RA similarly induces a significant increase in uterine OT gene expression. Moreover, we report that the E and RA effects are reproducible in vitro. Using short-term uterine organ explant cultures derived from 18-day pregnant rats, we found that E (50 nM) and RA (0.4 nM) increased OT mRNA levels 5.2- and 3-fold, respectively, suggesting a direct action of these agents on uterine OT gene expression. Finally, we analyzed uterine E and RA receptor gene expression during pregnancy. Using semi-quantitative Northern blot analysis, we found that mRNAs encoding the E receptor, the RA receptor alpha and RA receptor beta are present in rat uterus and that their levels rise by 3.7-, 3.6- and 5.8-fold, respectively, between day 14 of gestation and term. Taken together, the data suggest that, at term, the rat uterus has an increased capacity to respond to E and RA, and that both agents may be involved in mediating the dramatic increase of OT mRNA accumulation observed in the uterus at term.

Animals↗
PubMed1995

Oxytocin receptor gene expression in the rat uterus during pregnancy and the estrous cycle and in response to gonadal steroid treatment.

It is well established that uterine oxytocin receptors (OTRs) are strongly up-regulated immediately before parturition as well as in response to estrogen (E2) administration. Progesterone (P4), on the other hand, induces a rapid down-regulation. We recently cloned the rat OTR gene and characterized its expression in the rat uterus. In this study, we examined the regulation of OTR messenger RNA (mRNA) levels in rat uterus during pregnancy, the estrous cycle, and in response to gonadal steroid treatment. OTR mRNA levels increased more than 25-fold during gestation: 4.5-fold during the first 21 days and 6-fold within 24 h between day 21 and the onset of parturition. Uterine OTR mRNA levels fell rapidly by 85% within 24 h following parturition. By in situ hybridization, OTR mRNA was localized specifically to the longitudinal and circular layers of the myometrium but was not detected in the endometrium. During the estrous cycle, OTR mRNA levels increased 2-fold between metestrus and proestrus, whereas oxytocin (OT) binding rose more than 10-fold within this same interval. Treatment of ovariectomized rats with E2 lead to a significant increase in both OTR mRNA levels (4.4-fold) and OT binding (< 6-fold). Cotreatment with P4 strongly reduced OT binding by 75% (P < 0.01) but did not significantly affect the E2-induced rise in OTR mRNA (11% decrease, P > 0.1). Our data suggest that the increased expression of OT binding sites observed at the onset of labor and at proestrus is mediated, at least in part, by an E2-induced up-regulation of OTR gene expression. However, it also appears that OTR mRNA levels are not the sole determinants of uterine OT binding. Specifically, P4-mediated OTR down-regulation cannot be explained by an effect on OTR mRNA accumulation and may involve novel mechanisms acting at translational or posttranslational levels.

Animals↗
PubMed1995

Gonadal steroid regulation of oxytocin and oxytocin receptor gene expression.

By Northern blot analysis and in situ hybridization, we have determined that, at term, the rat uterine epithelium represents a major site of oxytocin (OT) gene expression. OT mRNA levels increase > 150-fold during pregnancy and, at term, exceed hypothalamic OT mRNA by a factor of 70. By cryoultramicroscopy, OT immunoreactivity was localized to transport vesicles in the apical compartment of uterine epithelial cells. Estrogens (E) act as a strong inducer of uterine OT gene expression in vivo, and this effect is potentiated 7-fold by concomitant progesterone (P) administration. We have also cloned the rat OT receptor (OTR) gene and developed a polymerase chain reaction (PCR)-based assay to measure OTR mRNA. Whereas OTR mRNA is strongly induced by E, P does not potentiate but slightly attenuates the E-induced rise. However, E-induced OT binding is completely reversed by concomitant P administration, suggesting an additional post-transcriptional effect of P. The mechanisms of E-induction of the uterine OT gene remain unclear, inasmuch as the OTR gene promoter does not contain a classical estrogen response element (ERE). Moreover, transfection analysis of a 3.1 kb OTR gene promoter fragment linked to a luciferase reporter gene indicates that promoter activity is induced 5-fold by calcium ionophore A23187 but not by E.

Animals↗
PubMed1994

Uterine oxytocin gene expression. I. Induction during pseudopregnancy and the estrous cycle.

We have recently demonstrated that the gene encoding the hypothalamic peptide oxytocin (OT) is highly expressed in the rat endometrial epithelium during the last 4 days of pregnancy. Here, we show that uterine OT gene expression is also induced during the proestrous phase of the estrous cycle and after induction of pseudopregnancy. In mature female rats, OT mRNA levels increased more than 10-fold between diestrus and proestrus and remained elevated at estrus. The levels attained at estrus corresponded to about 1/20th of the levels present at term. In immature rats rendered pseudopregnant by treatment with pregnant mare serum and hCG, uterine OT mRNA levels rose steadily and reached a maximum on day 14 of pseudopregnancy, corresponding to about 1/8th of the levels observed on day 21 of normal pregnancy. Oil-induced decidualization of the left uterine horn prolonged pseudopregnancy and maintained OT mRNA levels in both uterine horns until day 19 of pseudopregnancy. These changes were tissue specific, as hypothalamic OT mRNA levels remained essentially unaffected. The present findings demonstrate that either spontaneous or induced changes in endogenous steroid levels are capable of eliciting important changes in uterine, but not hypothalamic, OT gene expression.

Animals↗
PubMed1992

Interactions between vasotocin and other corticotropic factors on the frog adrenal gland.

The adrenocortical cells of the amphibian interrenal (adrenal) gland are controlled by multiple factors including neuropeptides and classical neurotransmitters. In particular, it has recently been shown that vasotocin (AVT), the amphibian counterpart of vasopressin, is a potent stimulator of frog corticosteroidogenesis. In the present study, we have investigated the possible interactions between AVT and other regulatory factors on frog interrenal tissue. When AVT (10(-9) M) and serotonin (10(-6) M) were infused together, a strict addition of the individual effects was observed. Similar results were obtained with concomitant infusion of AVT and vasoactive intestinal peptide or AVT and ACTH. In contrast, when AVT (10(-9) M) and acetylcholine (5 x 10(-5) M) were added together, the increase in corticosteroid secretion was less than additive. Dopamine induced a significant reduction of AVT-evoked stimulation of corticosterone production. These results indicate that regulatory peptides or classical neurotransmitters which participate in the control of adrenal steroidogenesis may interact on their target cell to modulate the activity of their congeners.

Acetylcholine↗
PubMed1992

Pharmacological characterization of vasotocin stimulation of phosphoinositide turnover in frog adrenal gland.

In a previous report we demonstrated the presence of a vasotocin (AVT)-like peptide in chromaffin cells of the amphibian adrenal gland and showed that synthetic AVT is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells. In the present study we evaluated the relative potency of various AVT analogs and investigated the mechanism of action of AVT on frog interrenal (adrenal) tissue. Several AVT agonists, including hydrin 2, oxytocin (OXT), arginine vasopressin (AVP), Lys-conopressin G, and mesotocin (MT), were able to mimic the stimulatory effect of AVT on steroid secretion, but AVT was by far the most potent stimulator of steroidogenesis. In the series of analogs studied, the order of potency was: AVT greater than hydrin 2 greater than OXT greater than AVP greater than Lys-conopressin G greater than MT greater than [deamino-Cys1,D-Arg8]AVP greater than [d(CH2)5,Tyr(OMe)2] AVP. The effect of AVT (5 x 10(-10) M) was totally blocked by both the antidiuretic V2 antagonist [d(CH2)5,D-Phe2,Ile4,Ala9-NH2]AVP (10(-6) M) and the oxytocinergic antagonist [d(CH2)5,Tyr(OMe)2,Orn8]AVT (10(-6) M); the V2 antagonist was approximately twice as potent as the OXT antagonist. In contrast, the V1 antagonist 1-(1-mercapto-4-phenylcyclohexaneacetic acid)-AVP (10(-6) M) did not affect the response of the interrenal tissue to AVT. Indomethacin (5 microM), a cyclooxygenase inhibitor, induced a dramatic decrease in the spontaneous secretion of corticosteroids, but did not impair the stimulatory effect of AVT (5 x 10(-9) M) on corticosterone and aldosterone secretion. In addition, AVT did not stimulate the production of prostaglandin E2, suggesting that prostaglandins are not involved in the mechanism of action of AVT. Concurrently, AVT did not modify cAMP production by frog adrenal slices. In contrast, AVT induced both an increase in inositolphosphate production and a reduction of membrane phospholipid content. We conclude that in the frog adrenal gland, the stimulatory effect of AVT on steroid secretion is mediated through activation of receptors related to the mammalian V2 and/or OXT receptors, which are positively coupled to phosphoinositide-specific phospholipase C.

Adrenal Cortex Hormones↗
PubMed1992

Effect of vasotocin on cytosolic free calcium concentrations in frog adrenocortical cells in primary culture.

In a previous report we have shown that vasotocin (AVT), the amphibian counterpart of vasopressin, is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells. We have also observed that the stimulatory effect of AVT on corticosteroid secretion is mediated through activation of receptors positively coupled to phospholipase-C. In the present study we examined the effect of AVT on cytosolic Ca2+ concentrations ([Ca2+]i). Since the interrenal (adrenal) gland of the frog is composed of a mixed population of chromaffin and adrenocortical cells, cytochemical identification of cultured cells was performed by immunofluorescence, using antibodies to AVT or 11 beta-hydroxylase as markers of chromaffin cells or steroid-producing cells, respectively. Cultured interrenal cells were loaded with the fluorescent Ca2+ indicator indo-1, and variations in [Ca2+]i were studied using dual emission wavelength microfluorimetry. Exposure of adrenocortical cells to AVT induced elevation of [Ca2+]i. Prolonged infusion of AVT caused an immediate increase in [Ca2+]i, followed by a sustained response of adrenocortical cells. Repeated pulses of AVT resulted in a gradual decline in the [Ca2+]i increase, suggesting the existence of a desensitization phenomenon. The effect of AVT on calcium mobilization was totally blocked when the cells were incubated in the presence of the V2 antagonist [d(CH2)5,D-Phe2,Ile4,Ala9-NH2]AVP. In calcium-free medium, the AVT-evoked increase in [Ca2+]i was suppressed. In contrast, when Ca2+ was replaced by Mn2+ in the incubation medium, the early response of the cells (transient peak of [Ca2+]i) was preserved, while the plateau phase disappeared. Incubation of the cells with the dihydropyridine Ca2+ channel blocker nifedipine did not affect the AVT-induced [Ca2+]i rise. These results indicate that AVT exerts a dual action on [Ca2+]i in frog adrenocortical cells. The initial rise of [Ca2+]i can be ascribed to immediate mobilization of intracellular Ca2+ stores, probably mediated by inositol trisphosphategated channels, whereas the sustained increase in [Ca2+]i results from nifedipine-insensitive plasma membrane Ca2+ channels.

Adrenal Cortex↗
PubMed1991

Self-inhibition of steroid secretion by amphibian adrenocortical cells is not mediated through glucocorticoid receptors.

To investigate a possible direct action of glucocorticoids on adrenal steroidogenesis, the effect of corticosterone on the conversion of pregnenolone into various metabolites by frog adrenal tissue was examined. Frog interrenal slices were incubated with [3H]pregnenolone (1 mCi/ml) and the various labelled metabolites analysed by reverse-phase high-performance liquid chromatography. With the methanol gradient used, five identified steroids were resolved: progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and aldosterone. Corticosterone (10 micrograms/ml) induced a 45-80% decrease in all steroids synthesized from [3H]pregnenolone. In contrast, the glucocorticoid agonist dexamethasone did not reduce the rate of conversion of pregnenolone into its metabolites. In addition, the inhibitory effect of corticosterone was not reversed by the specific glucocorticoid antagonist RU 43044. These results show that corticosterone exerts a direct inhibitory effect on adrenal steroid secretion. In addition, our data indicate that the ultra-short regulation induced by corticosterone is not mediated through glucocorticoid receptors.

Adrenal Cortex↗
PubMed1989

Mechanism of action of serotonin on frog adrenal cortex.

The mechanism of action of serotonin (5-HT) on frog adrenal cortex has been investigated in vitro using the perifusion system technique. The direct effect of 5-HT on corticosteroid secreting cells was demonstrated, using enzymatically dispersed adrenocortical cells. Melatonin and 5-HTP appeared to be less potent than 5-HT to enhance corticosteroid secretion. In contrast Trp and 5-HIAA were totally devoid of effect on steroid secretion. To investigate the type of receptor involved in the stimulatory effect of 5-HT on adrenocortical cells, adrenal slices were stimulated with 5-HT in absence or presence of various antagonists. We observed that classical antagonists of 5-HT1, 5-HT2 and 5-HT3 type receptors failed to block 5-HT-induced corticosteroid secretion in our model. These results show that 5-HT exerts a direct effect on corticosteroid-secreting cells. Our data also indicates that the type of receptor involved in the action of 5-HT in frog adrenal cortex differs from mammalian 5-HT receptors.

5-Hydroxytryptophan↗
PubMed1989

Identification of vasotocin-like immunoreactivity in chromaffin cells of the frog adrenal gland: effect of vasotocin on corticosteroid secretion.

The presence of neurohypophyseal nonapeptides in the adrenal gland of nonmammalian vertebrates and the possible action of these regulatory peptides on corticosteroid secretion have never been investigated. We have applied the indirect immunofluorescence technique to examine whether vasotocin (AVT) and/or mesotocin (MT) are located in frog adrenal (interrenal) tissue. Using antisera against AVT and tyrosine hydroxylase, we found that all chromaffin cells contain an AVT-like peptide. Labeling of consecutive sections with phenylethanolamine-N-methyltransferase or AVT antibodies showed that both noradrenaline- and adrenaline-storing cells contain AVT-like immunoreactivity. In contrast no labeling of frog adrenal slices was observed using a MT antiserum. At the ultrastructural level, the immunogold technique revealed that the AVT-immunoreactive peptide is sequestered in chromaffin granules with varying electron densities. Filtration of frog adrenal tissue extracts on Sep-Pak C-18 cartridges showed that the elution profile of the AVT-like peptide was similar to that of synthetic AVT. The apparent concentration of AVT in the adrenal was 2.7 ng/g tissue. Since chromaffin cells represent approximately one third of all interrenal cells, the actual concentration of AVT in chromaffin tissue was about 8 ng/g tissue. The role of AVT in the regulation of frog adrenal steroidogenesis was studied in vitro using perifused frog interrenal slices. Graded doses of AVT (10(-10)-10(-7) M) induced a dose-dependent stimulation of both corticosterone and aldosterone secretion. The other neurohypophyseal peptides (vasopressin, oxytocin, and MT) were also able to enhance corticosteroid secretion, but AVT was by far the most potent stimulator of steroidogenesis. Prolonged administration (4 h) of AVT induced a rapid increase in corticosterone and aldosterone output, followed by a gradual decline of corticosteroid secretion. These results show that an AVT-like peptide is stored in chromaffin granules of frog adrenal gland. Our data also indicate that synthetic AVT is a potent stimulator of corticosteroid secretion by frog interrenal cells. Since in amphibians adrenocortical and chromaffin cells are intimately intermingled, these results suggest that AVT produced by chromaffin cells may regulate corticosteroid release locally, through a cell to cell mode of communication.

Adrenal Cortex↗