Acupuncture for Pain Management: Molecular Mechanisms of Action.

Acupuncture reduces pain by activating specific areas called acupoints on the patient's body. When these acupoints are fully activated, sensations of soreness, numbness, fullness, or heaviness called De qi or Te qi are felt by clinicians and patients. There are two kinds of acupuncture, manual acupuncture and electroacupuncture (EA). Compared with non-acupoints, acupoints are easily activated on the basis of their special composition of blood vessels, mast cells, and nerve fibers that mediate the acupuncture signals. In the spinal cord, EA can inhibit glial cell activation by down-regulating the chemokine CX3CL1 and increasing the anti-inflammatory cytokine interleukin-10. This inhibits P38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways, which are associated with microglial activation of the C-Jun N-terminal kinase signaling pathway and subsequent astrocyte activation. The inactivation of spinal microglia and astrocytes mediates the immediate and long-term analgesic effects of EA, respectively. A variety of pain-related substances released by glial cells such as the proinflammatory cytokines tumor necrosis factor [Formula: see text], interleukin-1[Formula: see text], interleukin-6, and prostaglandins such as prostaglandins E2 can also be reduced. The descending pain modulation system in the brain, including the anterior cingulated cortex, the periaqueductal gray, and the rostral ventromedial medulla, plays an important role in EA analgesia. Multiple transmitters and modulators, including endogenous opioids, cholecystokinin octapeptide, 5-hydroxytryptamine, glutamate, noradrenalin, dopamine, [Formula: see text]-aminobutyric acid, acetylcholine, and orexin A, are involved in acupuncture analgesia. Finally, the "Acupuncture [Formula: see text]" strategy is introduced to help clinicians achieve better analgesic effects, and a newly reported acupuncture method called acupoint catgut embedding, which injects sutures made of absorbable materials at acupoints to achieve long-term effects, is discussed.

Dynamics of ACTH and Cortisol Secretion and Implications for Disease.

The past decade has seen several critical advances in our understanding of hypothalamic-pituitary-adrenal (HPA) axis regulation. Homeostatic physiological circuits need to integrate multiple internal and external stimuli and provide a dynamic output appropriate for the response parameters of their target tissues. The HPA axis is an example of such a homeostatic system. Recent studies have shown that circadian rhythmicity of the major output of this system-the adrenal glucocorticoid hormones corticosterone in rodent and predominately cortisol in man-comprises varying amplitude pulses that exist due to a subhypothalamic pulse generator. Oscillating endogenous glucocorticoid signals interact with regulatory systems within individual parts of the axis including the adrenal gland itself, where a regulatory network can further modify the pulsatile release of hormone. The HPA axis output is in the form of a dynamic oscillating glucocorticoid signal that needs to be decoded at the cellular level. If the pulsatile signal is abolished by the administration of a long-acting synthetic glucocorticoid, the resulting disruption in physiological regulation has the potential to negatively impact many glucocorticoid-dependent bodily systems. Even subtle alterations to the dynamics of the system, during chronic stress or certain disease states, can potentially result in changes in functional output of multiple cells and tissues throughout the body, altering metabolic processes, behavior, affective state, and cognitive function in susceptible individuals. The recent development of a novel chronotherapy, which can deliver both circadian and ultradian patterns, provides great promise for patients on glucocorticoid treatment.

Models in neuroendocrinology.

The neuroendocrine systems of the hypothalamus are critical for survival and reproduction, and are highly conserved throughout vertebrate evolution. Their roles in controlling body metabolism, growth and body composition, stress, electrolyte balance and reproduction have been intensively studied, and have yielded a rich crop of original and challenging insights into neuronal function, insights that circumscribe a vision of the brain that is quite different from conventional views. Despite the diverse physiological roles of pituitary hormones, most are secreted in a pulsatile pattern, but arising through a variety of mechanisms. An important exception is vasopressin which uses bursting neural activity, but produces a graded secretion response to osmotic pressure, a sustained robust linear response constructed from noisy, nonlinear components. Neuroendocrine systems have many features such as multiple temporal scales and nonlinearity that make their underlying mechanisms hard to understand without mathematical modelling. The models presented here cover the wide range of temporal scales involved in these systems, including models of single cell electrical activity and calcium dynamics, receptor signalling, gene expression, coordinated activity of neuronal networks, whole-organism hormone dynamics and feedback loops, and the menstrual cycle. Many interesting theoretical approaches have been applied to these systems, but important problems remain, at the core the question of what is the true advantage of pulsatility.

Comparison of stress-induced changes in adults and pups: is aldosterone the main adrenocortical stress hormone during the perinatal period in rats?

Positive developmental impact of low stress-induced glucocorticoid levels in early development has been recognized for a long time, while possible involvement of mineralocorticoids in the stress response during the perinatal period has been neglected. The present study aimed at verifying the hypothesis that balance between stress-induced glucocorticoid and mineralocorticoid levels is changing during postnatal development. Hormone responses to two different stressors (insulin-induced hypoglycaemia and immune challenge induced by bacterial lipopolysaccharid) measured in 10-day-old rats were compared to those in adults. In pups corticosterone responses to both stressors were significantly lower than in adults, which corresponded well with the stress hyporesponsive period. Importantly, stress-induced elevations in aldosterone concentration were significantly higher in pups compared both to corticosterone elevations and to those in adulthood with comparable adrenocorticotropin concentrations in the two age groups. Greater importance of mineralocorticoids compared to glucocorticoids in postnatal period is further supported by changes in gene expression and protein levels of gluco- (GR) and mineralocorticoid receptors (MR) and selected enzymes measured by quantitative PCR and immunohystochemistry in the hypothalamus, hippocampus, prefrontal cortex, liver and kidney. Gene expression of 11beta-hydroxysteroid dehydrogenase 2 (11ß-HSD2), an enzyme enabling preferential effects of aldosterone on mineralocorticoid receptors, was higher in 10-day-old pups compared to adult animals. On the contrary, the expression and protein levels of GR, MR and 11ß-HSD1 were decreased. Presented results clearly show higher stress-induced release of aldosterone in pups compared to adults and strongly suggest greater importance of mineralocorticoids compared to glucocorticoids in stress during the postnatal period.

Loss of NSCL-2 in gonadotropin releasing hormone neurons leads to reduction of pro-opiomelanocortin neurons in specific hypothalamic nuclei and causes visceral obesity.

Regulation of sexual reproduction and energy homeostasis are closely interconnected, but only few efforts were made to explore the impact of gonadotropic neurons on metabolic processes. We have used Nscl-2 mutant mice suffering from adult onset of obesity and hypogonadotropic hypogonadism to study effects of gonadotropin releasing hormone (GnRH) neurons on neuronal circuits controlling energy balance. Inactivation of Nscl-2 in GnRH neurons but not in pro-opiomelanocortin (POMC) neurons reduced POMC neurons and increased visceral fat mass, suggesting a critical role of GnRH cells in the regulation of POMC neurons. In contrast, absence of POMC processing in the majority of Nscl-2-deficient POMC neurons had no effect on energy homeostasis. Finally, we investigated the cellular basis of the reduction of GnRH neurons in NSCL-2 mutants using a lineage tracing approach. We found that loss of Nscl-2 results in aberrant migration of GnRH neurons in Nscl-2 mutant mice causing a lineage switch of ectopically located GnRH neurons.

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite.

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.

ACTH: cellular peptide hormone synthesis and secretory pathways.

Adrenocorticotrophic hormone (ACTH) is derived from the prohormone, pro-opiomelanocortin (POMC). This precursor undergoes proteolytic cleavage to yield a number of different peptides which vary depending on the tissue. In the anterior pituitary, POMC is processed to ACTH by the prohormone convertase, PC1 and packaged in secretory granules ready for stimulated secretion. In response to stress, corticotrophin releasing hormone (CRH), stimulates release of ACTH from the pituitary cell which in turn causes release of glucocorticoids from the adrenal gland. In tissues, such as the hypothalamus and skin, ACTH is further processed intracellularly to alpha melanocyte stimulating hormone (alphaMSH) which has distinct roles in these tissues. The prohormone, POMC, is itself released from cells and found in the human circulation at concentrations greater than ACTH. While much is known about the tightly regulated synthesis of POMC, there is still a lot to learn about the mechanisms for differentiating secretion of POMC, and the POMC-derived peptides. Understanding what happens to the POMC released from cells will provide new insights into its function.

Endogenous ACTH, not only alpha-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms.

ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH) are both consecutively processed from proopiomelanocortin (POMC), which is synthesized in hypothalamic arcuate neurons innervating the paraventricular nuclei (PVN). POMC secretion/synthesis is regulated by energy availability. ACTH and alpha-MSH bind with equal affinity to melanocortin-4 receptors and elicit similar effects on signal transduction in-vitro. Endogenous alpha-MSH thus far is believed to be the major physiological agonist and to act in an anorexigenic manner. Until now, it was fully unknown whether endogenous ACTH is also involved in the regulation of appetite and food intake. In this study in rats, we now show that icv ACTH as well as alpha-MSH possess anorexigenic effects in the PVN or areas in close proximity in vivo and that the effect of ACTH is direct and not mediated via alpha-MSH. We investigated the roles of endogenous ACTH and alpha-MSH by PVN application of the respective antibodies under different physiological conditions. In satiated rats with high levels of ACTH and alpha-MSH in the PVN, antibody administration increased food intake and body weight gain; hungry animals were unaffected. Finally, repeated injections of ACTH antibodies into PVN resulted in persistently increased food intake during the light period. These data now provide robust evidence that endogenous ACTH without further processing acts in the PVN or areas in close proximity to reduce food intake under conditions of feeding-induced satiety.

Distinct gender-related sleep pattern in an acute model of TMJ pain.

Since it is recognized that acute inflammation of the temporomandibular joint results in sleep disturbances in male rats, and that the orofacial region may display a site-specific effect of ovarian hormones on nociception, we hypothesized that distinct genders would respond differently when subjected to this inflammatory acute orofacial pain. Sleep was monitored after injection of saline/Freund's adjuvant into the temporomandibular joint in male and female (proestrus and diestrus phases) rats. Progesterone and stress-related hormones were also assessed. In males, Freund's adjuvant induced a significant nociceptive response and sleep disturbances. Behavior and sleep architecture in the females remained unaffected. Our results suggest that females and males present distinct responses to an acute model of orofacial pain.

Hypothesis: Musculin is a hormone secreted by skeletal muscle, the body's largest endocrine organ. Evidence for actions on the endocrine pancreas to restrain the beta-cell mass and to inhibit insulin secretion and on the hypothalamus to co-ordinate the neuroendocrine and appetite responses to exercise.

Recent studies indicate that skeletal muscle may act as an endocrine organ by secreting interleukin-6 (IL-6) into the systemic circulation. From an analysis of the actions of IL-6 and of additional literature, we postulate that skeletal muscle also secretes an unidentified hormone, which we have named Musculin (Latin: musculus = muscle), which acts on the pancreatic beta-cell to restrain the size of the (beta-cell mass and to tonically inhibit insulin secretion and biosynthesis. It is suggested that the amount of Musculin secreted is determined by, and is positively correlated with, the prevailing insulin sensitivity of skeletal muscle, thereby accounting for the hyperinsulinemia that occurs in insulin resistant disorders such as type 2 diabetes mellitus, obesity, and the polycystic ovary syndrome. In addition, it is postulated that Musculin acts on the hypothalamus (arcuate nucleus, dorsomedial hypothalamic nucleus) to co-ordinate the neuroendocrine and appetite responses to exercise. However, the possibilities that Musculin may act on additional central nervous system sites and that an additional hormone(s) may be responsible for these actions are not excluded. It is suggested that a search be made for Musculin, since analogues of such a substance may be of therapeutic benefit in the treatment of the current global diabetes and obesity epidemic.

ACTH reduces the rise in ApoB-48 levels after fat intake.

It has been repeatedly demonstrated that ACTH administration lowers plasma lipid concentrations in man. The present study was designed to test the hypothesis, based on observations of decreased apolipoprotein B (ApoB) synthesis and secretion in vitro, that ACTH administration inhibits the postprandial output of ApoB in man. Therefore, we studied the response to a fat-rich meal supplemented with Vitamin A in eight healthy volunteers, who underwent this test without premedication, after 4 days administration of ACTH, and after 4 days administration of a glucocorticoid (betamethasone). As expected, fasting plasma levels of low-density lipoproteins (LDL)-cholesterol (-25%) and ApoB (-17%) decreased after ACTH, but not after betamethasone administration. Also, the elevation of plasma ApoB-48 in response to fat intake (to twice the basal levels) was markedly reduced after ACTH administration. However, the postprandial rise in plasma triglycerides and retinyl palmitate was unimpaired, suggesting that ACTH administration induced the secretion of fewer but larger chylomicrons. The effect of betamethasone on the postprandial response was similar but less pronounced. This study confirms earlier reports on the lipid-lowering effects of ACTH and supports our theory, based on in vitro studies, that the lipid-lowering effects of ACTH administration in man involves an inhibition of ApoB production.

Pituitary deficiency after brain radiation therapy.

Brain radiotherapy is a frequent and overlooked cause of pituitary deficiency in adults which may alter patients' health and quality of life. Hormonal consequences have been better studied in children. The onset of hormonal deficiencies depends on the dose delivered to the pituitary-hypothalamic region while their incidence and severity depends on dose fractionating and follow-up duration. Somatotrophic function is the first affected, 90% of patients being GH deficient 10 years after radiotherapy. Other anterior pituitary functions are affected later and less frequently. While initial damage occurs in the hypothalamus, accounting for mild hyperprolactinemia in 30-50% of cases, diabetes insipidus is never observed. Direct pituitary deficiency may occur later. Responses to ACTH or GHRH-arginine tests may be normal for several years though an ACTH and/or GH deficiency has been demonstrated by an insulin tolerance test, which is considered as the gold standard. When the cranio-spinal area--including the neck--has been irradiated, primary thyroid deficiency might occur. Repeated cervical ultrasonographic follow-up is mandatory to exclude radiation-induced thyroid cancer. The gonadotrophic function might be altered after small doses of irradiation causing precocious puberty, while at higher doses delayed puberty or true gonadotrophic deficiencies are more often observed. Combined radio- and chemotherapy might result in mixed central and peripheral deficiencies that might be difficult to diagnose. When radiotherapy is performed in adulthood, GH deficiency is less common, although the sequence of hormonal deficiencies is similar to that observed in children. Prospective longitudinal studies are required to determine the time course and sequence of onset of each deficiency, in order to tailor the monitoring of these patients to their specific needs.

Choice of lard, but not total lard calories, damps adrenocorticotropin responses to restraint.

Although rats given the choice of eating high-density calories as concentrated sucrose solutions or lard exhibit reduced responsivity in the hypothalamo-pituitary-adrenal axis, rats fed high-fat diets have normal or augmented responses to stressors. To resolve this apparent discrepancy, we compared in adult male rats the effects of 7-d feeding with lard + chow (choice) to feeding a 50% lard-chow mixture (no-choice) and to chow only. Rats with choice composed diets with 50-60% total calories from lard. Rats were exposed to 30 min of restraint on d 7. In the choice group, there was a robust inhibition of ACTH and corticosterone responses to restraint compared with chow or no-choice groups. Total caloric intake was less with choice than no-choice. Fat depot weights and body weight gain were similar in the high-fat groups. Leptin concentrations were equal but insulin was higher in the choice group. We conclude the following: 1) choice of eating high-density calories strongly damps hypothalamo-pituitary-adrenal responses to stress; without choice, high-density diet is ineffective; and 2) insulin may signal metabolic well-being, and may act through hypothalamic sites to reduce caloric intake but through forebrain sites to damp stress responses.

Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice.

Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.

Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.

Appropriate regulatory control of the hypothalamo-pituitary-adrenocortical stress axis is essential to health and survival. The following review documents the principle extrinsic and intrinsic mechanisms responsible for regulating stress-responsive CRH neurons of the hypothalamic paraventricular nucleus, which summate excitatory and inhibitory inputs into a net secretory signal at the pituitary gland. Regions that directly innervate these neurons are primed to relay sensory information, including visceral afferents, nociceptors and circumventricular organs, thereby promoting 'reactive' corticosteroid responses to emergent homeostatic challenges. Indirect inputs from the limbic-associated structures are capable of activating these same cells in the absence of frank physiological challenges; such 'anticipatory' signals regulate glucocorticoid release under conditions in which physical challenges may be predicted, either by innate programs or conditioned stimuli. Importantly, 'anticipatory' circuits are integrated with neural pathways subserving 'reactive' responses at multiple levels. The resultant hierarchical organization of stress-responsive neurocircuitries is capable of comparing information from multiple limbic sources with internally generated and peripherally sensed information, thereby tuning the relative activity of the adrenal cortex. Imbalances among these limbic pathways and homeostatic sensors are likely to underlie hypothalamo-pituitary-adrenocortical dysfunction associated with numerous disease processes.

Understanding the physiological effects of unrelieved pain.

Pain produces a physiological stress response that includes increased heart and breathing rates to facilitate the increasing demands of oxygen and other nutrients to vital organs. Failure to relieve pain produces a prolonged stress state, which can result in harmful multisystem effects. Good acute pain management is an essential part of holistic nursing care.

Hormonal interactions within the hypothalamus and pituitary with respect to stress and reproduction in sheep.

Endocrine systems may be used as indicators of stress in two ways. The primary role of a hormone may be as part of the homeostatic response to a stimulus (e.g., adrenaline, corticosteroids). The amplitude of hormone response may correlate with the severity of the stimulus and any change indicate that the body is responding. Alternatively, a hormone may have a key role in normal body function (e.g., reproduction) and stress may deleteriously alter the hormone signal prevent normal function. This demonstrates that the stimulus was sufficiently severe that homeostatic mechanisms were unable to maintain normal function. Stress may effect reproduction by reducing both LH pulse amplitude and frequency. The LH surge may also be delayed. Several mechanisms may account for these effects both at the hypothalamus and pituitary. Corticosteroids have a broad, yet fundamental, role in homeostasis and have been used as primary indicators of stress for many years. Excess corticosteroid can be detrimental so the concentration is controlled via the hypothalamus-pituitary-adrenal (HPA) axis by multi-level feedback mechanisms. Under field and experimental conditions, after an initial large response prolonged stimulation leads to a gradually reducing plasma corticosteroid concentrations. This has been interpreted as a reduction in perceived stimulus severity or habituation to the stimulus and the animal deemed "less stressed" and its welfare "better." However, this reduction may be due to the intrinsic control mechanisms designed to prevent prolonged increases in corticosteroid concentrations. The stress signal at higher brain levels may still be present and the animal may still be experiencing the stimulus as aversive. Thus, the welfare interpretation of a corticosteroid concentration may differ during the time course of a stress response. A greater understanding of the mechanisms controlling corticosteroid secretion at each level of the HPA is required to determine what is the correct interpretation at any time point. To address these issues, we have used mathematical modelling to produce representations of possible control mechanisms at each level of the HPA. The starting point was to measure AVP and CRH concentrations in hypophysial portal blood and ACTH and cortisol concentrations in jugular blood in conscious sheep during 2h road transport (a cognitive stimulus). Modelling identified the signal inputs that were most likely to explain the secretion rate of each hormone. Modelling suggested that the reduction in AVP and CRH secretion observed during transport was most likely due to a reduction in stimulus input, with a significant contribution from cortisol negative feedback only on AVP secretion. At the pituitary level, ACTH secretion was stimulated more by AVP than by CRH (ratio 2.3:1) and there was also a stimulatory effect related to cortisol concentration at the time of sampling. However, the responses to both stimuli were curtailed by cortisol negative feedback and an inhibitory effect of prior CRH concentration. These are complex effects, but the modelling does suggest that while "stress" inputs may reduce over time hormone negative feedback is a major factor reducing hormone responses. When interpreting hormone data for animal welfare purposes, it is important not to interpret a reduction in hormone concentration due to intrinsic hormone control mechanisms as a reduction due to a decrease in the stress stimulus.

Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders.

Sleep is an important component of mammalian homeostasis, vital for survival. Sleep disorders are common in the general population and are associated with significant medical, psychologic, and social disturbances. Sleep, in particular deep sleep, has an inhibitory influence on the HPA axis, whereas activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. Insomnia, the most common sleep disorder, is associated with a 24-hour increase of ACTH and cortisol secretion, consistent with a disorder of central nervous system hyperarousal. Sleepiness and fatigue are very prevalent in the general population, and recent studies have demonstrated that the proinflammatory cytokines IL-6 and/or TNF-alpha are elevated in disorders associated with excessive daytime sleepiness, such as sleep apnea, narcolepsy, and idiopathic hypersomnia. Sleep deprivation leads to sleepiness and daytime hypersecretion of IL-6. Combined, these findings suggest that the HPA axis stimulates arousal, while IL-6 and TNF-alpha are possible mediators of excessive daytime sleepiness in humans.

ACTH does not mediate divergent stress responsiveness in rainbow trout.

Two lines of rainbow trout selected for high (HR) and low (LR) responsiveness to a standardised confinement stressor displayed a sustained divergence in plasma cortisol levels during a 3-h period of confinement (max.: HR: 167+/-13 ng ml(-1); LR: 103+/-8 ng ml(-1); P<0.001). However, no significant difference in plasma ACTH levels was evident (max: HR: 153+/-9 pg ml(-1); LR: 142+/-7 pg ml(-1)). Dexamethasone (DEX) was administered to HR and LR fish to block endogenous adrenocorticotropin (ACTH) release. Administration of a weight-adjusted dose of ACTH to the DEX-blocked fish elevated plasma cortisol levels to a significantly greater extent in HR (233+/-24 ng ml(-1)) than LR (122+/-14 ng ml(-1)) fish (P<0.001). Plasma cortisol levels in DEX-blocked HR and LR fish after sham injection were low but also significantly different (HR: 6.7+/-1 ng ml(-1); LR: 2.2+/-0.2 ng ml(-1); P<0.001). These results indicate that modulation of cortisol responsiveness to stressors in HR and LR fish resides, at least in part, downstream of the hypothalamic-pituitary axis.