The Hypothalamuspituitaryadrenal Hpa Axis

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The stress response mediated through activation of the HPA axis is essential to meet physical and psychological challenges. The HPA axis consists of corticotrophin-releasing factor/hormone (CRF/CRH) and arginine vasopressin (AVP) neurons in the hypothalamus, which stimulate adrenocorticotrophic hormone (ACTH) secretion from corticotrophs in the anterior pituitary through CRF-R1 and V1b receptors, respectively. ACTH, in turn, stimulates adrenal cortical glucocorticoid secretion. Negative feedback from glucocorticoids completes the classic endocrine feedback loop. CRH and AVP neurons are located in the parvocellular hypothalamic PVN. CRH appears to be more involved in acute stress, whereas AVP is more important in chronic stress (36). The HPA axis is under control of the hypothalamic suprachiasmatic nucleus (SCN), which produces the circadian rhythm in cortisol (corticos-terone in rats) secretion. Stress is relayed to the PVN from peripheral nerves via neurons in the brainstem.

A number of data suggest that the orexins influence the HPA axis; a direct interaction on CRH and AVP neurons is likely because:

1. The orexin-2 but not orexin-1 receptor is expressed in the PVN (30). Interestingly Backberg et al. (37) have reported that OXxR immunoreactivity is present in CRH and AVP neurons. The reason for the discrepancy between receptor gene expression and immunoreactivity is unclear.

2. Administration of orexins icv dose-dependently increased plasma ACTH and corticosterone (14,38). This was blocked by pretreatment with the CRH antagonist a-helical CRH (38). The actions of icv orexins on the HPA axis were also blocked by NPY antiserum (39). The stimulation of ACTH by icv orexin-A was observed to peak at 30 min and was maintained over 120 min, returning to baseline at 240 min post injection (40).

3. Orexins administered icv induced Fos mRNA in the PVN (41).

4. Orexin-A increased CRH release from hypothalamic explants. This was blocked by the NPY Y1 receptor antagonist BIBP3226 (27). No effects of orexin-A on AVP release from hypothalamic explants was observed.

5. Orexin-A depolarized and increased spike frequency in magno- and parvocellular PVN neurons in hypothalamic slice preparations (42).

6. The behavior effects of orexin-A such as grooming were reversed by the CRH antagonist a-heli-cal CRF (43).

7. Orexin-A administered icv significantly increased CRH and AVP mRNA in the PVN (40).

The orexins are therefore likely to be involved in the stress response, through direct effects on PVN CRH and AVP neurons, but also indirectly through brainstem and hypothalamic neurons (Fig. 4). It is well known that different stressors activate the stress axis through different mechanisms. Ida et al. (44) have reported that immobilization stress, increased prepro-orexin mRNA levels in 2-mo-old rats, and cold stress increased prepro-orexin mRNA levels in 6-mo-old rats (44). Zhu et al. (45) have reported increased Fos protein in orexin neurons after noxious stimuli, but not after conditioned fear stimuli.

It is possible that the orexins affect the HPA axis by stimulating arousal or influencing cir-cadian input to the HPA axis. Part of the arousal response to orexins may be mediated by activation of the HPA axis. The temporal basis for the orexins to influence plasma corticosterone physiologically has been little studied, but changes in cortisol were not correlated with CSF orexin-A in the squirrel monkey model (46).

Most patients with narcolepsy-cataplexy have a deficiency in orexin neurotransmission (2,47,48). Higuchi et al. (49) studied four male narcoleptics and found that the circadian periodicity of cortisol secretion was normal. The numbers in this study were, however, small, and it is unknown whether the patients were orexin deficient. Kok et al. (50) studied cortisol secretion in seven male orexin-deficient patients. They reported a blunted basal and total ACTH production in narcoleptics, but no difference in basal pulsatile cortisol secretion. The early morning rise in ACTH and cortisol was not different between patients and controls, suggesting an intact circadian control of the HPA axis. Whether these observations, have any practical implications in narcolepsy and other disorders remains to be studied. However, they suggest that the observed effects of the orexins on the HPA axis are not through alterations in circadian control mechanisms.

Difference Between Raas And Hpa Axis

Fig. 4. Control of the hypothalamo-pituitary-adrenal (HPA) axis and the role of the orexins. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) neurons release their hormones into the portal circulation. CRH and AVP then stimulate adrenocorticotropic hormone (ACTH) secretion by pituitary corticotrophs, which, in turn, stimulates adrenocortical glucocorticoid secretion. Glucocorticoids feed back at pituitary and hypothalamic levels to reduce ACTH, and CRH and AVP secretion respectively. Glucocorticoids also act on the hippocampus, which acts on the hypothalamus to reduce CRH and AVP. Other influences include stimulation by noradrenergic (NA), serotoninergic (5HT), and glutamatergic (Glu) inputs. Inhibition occurs via y-aminobutyric (GABA) ergic inputs. A number of neuropeptides may stimulate or inhibit HPA axis activity. The orexins may influence HPA activity directly or indirectly via brainstem (e.g., locus coeruleus [LC] noradrenergic) and hypothalamic (e.g., NPY) circuits, and/or via altering the circadian influences on HPA axis activity. The role of negative feedback onto orexin neurons by glucocorticoids is not completely determined. The immune system can influence the stress axis at multiple junctions.

Fig. 4. Control of the hypothalamo-pituitary-adrenal (HPA) axis and the role of the orexins. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) neurons release their hormones into the portal circulation. CRH and AVP then stimulate adrenocorticotropic hormone (ACTH) secretion by pituitary corticotrophs, which, in turn, stimulates adrenocortical glucocorticoid secretion. Glucocorticoids feed back at pituitary and hypothalamic levels to reduce ACTH, and CRH and AVP secretion respectively. Glucocorticoids also act on the hippocampus, which acts on the hypothalamus to reduce CRH and AVP. Other influences include stimulation by noradrenergic (NA), serotoninergic (5HT), and glutamatergic (Glu) inputs. Inhibition occurs via y-aminobutyric (GABA) ergic inputs. A number of neuropeptides may stimulate or inhibit HPA axis activity. The orexins may influence HPA activity directly or indirectly via brainstem (e.g., locus coeruleus [LC] noradrenergic) and hypothalamic (e.g., NPY) circuits, and/or via altering the circadian influences on HPA axis activity. The role of negative feedback onto orexin neurons by glucocorticoids is not completely determined. The immune system can influence the stress axis at multiple junctions.

Adrenalectomy did not alter orexin immunoreactivity in the hypothalamus (Taheri, unpublished data). Stricker-Krongrad and Beck (51) have, however, reported that with adrenalectomy there is a 50% decrease in lateral hypothalamic prepro-orexin mRNA detected by in situ hybridization. This returned to normal with dexamethasone administration. The reason for the discrepancy between peptide and mRNA levels is unclear.

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