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Notes: The mechanism by which chronic stress affects the course of inflammatory diseases is still not well understood. We have evaluated the effect of two types of nonhabituating stress on a major component of the inflammatory response, synovial plasma extravasation, induced by perfusion of the potent inflammatory mediator, bradykinin and evaluated the underlying neuroendocrine mechanism in the rat. Chronic intermittent noise or ether stress induced profound inhibition of bradykinin-induced plasma extravasation, which is associated with increased adjuvant-arthritis severity. This inhibition, however, took 24 h to fully develop after the last exposure to stress and persisted for at least 48 h. The inhibition could be reversed by an additional exposure to the stressor, just prior to measuring the inflammatory response, suggesting that the delay is due to stress-induced release of a factor that acutely masks the inhibition of the inflammatory response. This novel, unexpected feature of the effect of nonhabituating stress on inflammation may help explain variability in effects of stress in patients with inflammatory disease. The effect of nonhabituating stress on inflammation was dependent on the sympathoadrenal axis with no detectable contribution by the hypothalamic–pituitary–adrenal axis.

Notes: Hypothalamic anorexigenic [corticotropin-releasing factor (CRF) and proopiomelanocortin] peptides decrease and the orexigen, neuropeptide Y, increases with diabetic hyperphagia. However, when diabetic rats are allowed to eat lard (saturated fat) as well as chow, both caloric intake and hypothalamic peptides normalize. These neuropeptide responses to lard require an intact hepatic vagus [la Fleur et al. (2003)Diabetes, 52, 2321–2330]. Here, we delineate temporal interactions after lard consumption ± hepatic vagotomy (HV) between feeding and brain neuropeptide expression in insulin-dependent diabetic rats. CRF-mRNA was reduced in the paraventricular nuclei (PVN) by 6 h after presentation of lard, before caloric intake increased in HV-diabetic rats, and did not increase at 30 or 36 h, as it did in shamHV-diabetic rats eating lard. CRF-mRNA was increased in the bed nuclei of the stria terminalis of HV-diabetic rats compared with shamHV-diabetic rats only when caloric intake was high at 30 or 36 h. At 36 h, shamHV-diabetic rats eating chow had increased CRF-mRNA in the central amygdala but diabetic rats eating lard had decreased CRF-mRNA, whereas HV-diabetic rats eating chow or lard had normal CRF-mRNA in the central amygdala. We conclude that eating lard restores peptide expression to normal in the hypothalamus of diabetic rats, and because decreased CRF-mRNA in the PVN precedes the increase in caloric intake in HV-diabetic rats eating lard, that the loss of a hepatic vagal signal to PVN may be responsible for increased intake; moreover, CRF-mRNA in limbic structures is also sensitive to both HV and lard ingestion in diabetic rats.

Notes: The lack of ovulation and the inhibition of reproductive functions observed in many species during lactation is closely related to the intensity of the suckling stimulus. However, the mechanisms by which suckling inhibits hypothalamic GnRH and pituitary LH secretion in rats are still unclear. Since we recently demonstrated that suckling is a persistent stimulus to the adrenococortical system of the rat, we tested the hypothesis that suckling-induced activation of central CRF release may mediate the associated inhibition of GnRH secretion. Lactating females were ovariectomized (OVX) on day 2 of lactation, and equipped with icv guide cannula on day 2 and indwelling jugular catheters on day 5 before testing on day 7. Lactating females were separated from their pups for 24 h prior to the suckling test with the following pretreatments: 1) icv injection with artificial CSF (aCSF) or a specific CRF antagonist, alpha-helical CRF (9–41), (25μg/rat, CRF-AX) 15 min prior to pup reunion or 2) iv injection of normal sheep serum (NSS) or CRF antiserum (CRF-AB) 4 h prior to pup reunion. Plasma ACTH, LH and PRL concentrations were determined prior to and at various intervals after pup reunion. After 3 h of suckling, LH and PRL responses to a bolus injection of GnRH (10 ng/rat) were measured; a bolus injection of Angiotensin II (All, 5 μg/rat) was administered after 4 h to test for ACTH responses. Non-lactating females injected with GnRH and All were used as controls.In animals treated icv with aCSF or iv with NSS, the suckling stimulus resulted in increased ACTH and PRL secretion with a decrease in LH release. Iv CRF-AB abolished the increase in ACTH, but did not affect the increase in PRL nor the decrease in LH secretion. In contrast, and in support of our hypothesis, icv CRF-AX abolished the suckling-induced decline in LH secretion without altering the increase in PRL and ACTH secretion. Finally, we did not observe lactation-related changes in LH (or PRL) responses to a bolus GnRH injection or in ACTH responses to All stimulation.Our results suggest that: 1) central CRF release is involved in the decrease in LH secretion which occurs following suckling in lactating females, and 2) the changes in LH secretion during suckling are not mediated by an effect of CRF at the median eminence or by acute changes in pituitary responsiveness to GnRH.

Notes: Neuropeptide Y (NPY) is a powerful stimulus to food intake in the rat. Exogenous NPY given into the third ventricle or into the paraventricular nucleus (PVN) of the hypothalamus stimulates both food consumption as well as the hypothalamus-pituitary-adrenal (HPA) axis. Presumably NPY activates the adrenocortical system through direct stimulation of CRF containing cells in the PVN. Food intake is also a major regulator of adrenocortical activation. Rhythms in HPA axis activity follow rhythms in food consumption, and rats that have been food deprived overnight have inhibited HPA axis responses to restraint stress and corticosteroid feedback the following morning. To investigate the interaction of NPY with both feeding and HPA axis activation three sets of experiments were performed: Animals fed ad lib were injected icv with NPY (2.5 μg) and allowed access to food or not post injection; animals were fasted overnight prior to NPY injection; finally, dose response experiments were performed to examine the relative sensitivities of feeding and HPA axis activation to exogenous NPY. Ad lib fed animals allowed access to food after NPY injection had slightly greater ACTH responses to NPY while glucocorticoid and insulin responses were not significantly different from ad lib fed animals not allowed access to food post injection. Animals allowed to eat post injection had significantly decreased food consumption the night following injection, however, total 24 h food consumption was not different between these animals and those given food 8 h post NPY injection. In overnight fasted animals NPY injections produced ACTH responses of equal magnitude to those in ad lib fed animals. Insulin responses to NPY were significantly elevated compared to CSF controls in overnight fasted animals. Dose response studies revealed that the adrenocortical system responds to icv NPY with at least as great sensitivity as feeding systems. NPY is discussed as a potential integrator of feeding and responsiveness in the HPA axis.

Notes: To determine a role of norepinephrine (NE) in stress-induced HPA function, young male rats were treated with diethyldithiocarbamide (DDC) which inhibits dopamine-β-hydroxylase, the enzyme that synthesizes NE from dopamine (DA). DDC injected 5 h prior to ether stress stimulated ACTH and corticosterone (B) during this time, and there was no further HPA response to ether. To control for elevated B feedback in DDC effects on HPA responses to ether, rats were adrenalectomized (Adx) and replaced with no (0% B), moderate (40% B) and high (80% B) levels of steroid 5 d prior to DDC or saline with ether stress 5 h later; Sham-Adx rats were included. In Adx rats increasing B inhibited thymus weight, median eminence CRF content, pituitary and plasma ACTH. In saline-treated rats, ether 5 h later caused increased CRF content and plasma ACTH in Sham-Adx and Adx, 0%B, increased ACTH in Adx, 40%B, and no response in Adx, 80% B. B treatment did not alter catecholamine content, and DDC treatment reduced NE content in the paraventricular nuclei by 50–60% in all groups. 5 h after DDC, pituitary ACTH was decreased in all rats with B and plasma ACTH was increased in sham-Adx and Adx, 40%B; thus DDC caused significant, prolonged stress which should facilitate subsequent HPA responses to acute stress. There was no HPA response to ether in Sham-Adx, Adx, 0% or 40% B groups, but there was a marked ACTH response to ether in the Adx, 80%B group treated with DDC. We conclude that: 1) the HPA response to ether stress is probably mediated by catecholamines; 2) DDC does not stimulate responses in the HPA axis in the absence of B; and, 3) facilitation of HPA responses to acute stress depends on increased steady-state B signals. Facilitated responses are probably not mediated by catecholamines. The consequence of facilitation is that under conditions of chronic stress and elevated B concentrations, as in depression or anorexia nervosa in man, or adjuvent-induced arthritis in rats, the HPA axis is continually responsive to new stimuli.