Physiological Pathways Regulating the Activity of Magnocellular Neurosecretory Cells

Opioid drugs and endogenous opioid peptides exert profound effects on body temperature. The particular effect seen is dependent on species, ambient temperature, degree of restraint imposed on the subject, route of drug administration, and a number of other factors. A major determinant is the opioid receptor type with which the agonist forms a complex. Evidence is accumulating that opioid ligands and opioid receptors play a functional role in thermoregulation, even though the opioid system may not be tonically active. Although further studies are needed to fully define the role and the mechanisms involved, as well as the generality of the role in a variety of species, a reasonable working hypothesis is that mu receptors in the rat and the mouse are involved in responses that result in heat gain, while K receptor activation results in opposite responses. To a large extent, the mu receptors in the rat appear to be located primarily in the brain, while the K receptors are outside the brain and perhaps even outside of the central nervous system. At present there is no evidence of involvement of delta receptors in thermoregulation. A fuller understanding of the opioid system and its role in thermoregulation will have broad clinical implications, as well as provide insights into interactions among the several neurotransmitter systems involved in thermoregulatory control of body temperature.

The opioid system and temperature regulation.

From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants.

In this study, we investigated the effects of acute morphine administration, chronic intermittent escalating-dose morphine administration and spontaneous withdrawal from chronic morphine on mRNA levels of mu opioid receptor (MOP-r), and the opioid peptides pro-opiomelanocortin (POMC) and preprodynorphin (ppDyn) in several key brain regions of the rat, associated with drug reward and motivated behaviors: lateral hypothalamus (lat.hyp), nucleus accumbens (NAc) core, amygdala, and caudate-putamen (CPu). There was no effect on MOP-r mRNA levels in these brain regions 30 min after either a single injection of morphine (10 mg/kg, i.p.) or chronic intermittent escalating-dose morphine (from 7.5 mg/kg per day on day 1 up to 120 mg/kg per day on day 10). Activation of the stress-responsive hypothalamic-pituitary-adrenal axis by 12 h withdrawal from chronic morphine was confirmed; both POMC mRNA levels in the anterior pituitary and plasma adrenocorticotropic hormone levels were significantly elevated. Under this withdrawal-related stress condition, there was an increase in MOP-r mRNA levels in the lat.hyp, NAc core, and CPu. Recent studies have demonstrated a novel role for the lat.hyp orexin (or hypocretin) activation in both drug-related positive rewarding, and withdrawal effects. Around 50% of lat.hyp orexin neurons express MOP-r. Therefore, we also examined the levels of lat.hyp orexin mRNA, and found them increased in morphine withdrawal, whereas there was no change in levels of the lat.hyp ppDyn mRNA, a gene coexpressed with the lat.hyp orexin. Our results show that there is an increase in MOP-r gene expression in a region-specific manner during morphine withdrawal, and support the hypothesis that increased lat.hyp orexin activity plays a role in morphine-withdrawal-related behaviors.

/pdf/mu-opioid-receptor-and-orexin-hypocretin-mrna-levels-in-the-ydf8b7dmtc.pdf

Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.

A review of the pharmacology of selegiline.

The influence of the L-type calcium channel antagonist nimodipine on both the activity of noradrenergic neurons projecting to the hypothalamus and the pituitary-adrenal response during morphine tolerance and withdrawal was analysed. Tissue concentration of hypothalamic noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxy-phenylethylen-glycol (MHPG) were determined by high-pressure liquid chromatography. Plasma corticosterone concentration (a marker of pituitary-adrenal activity) was measured by radioimmunoassay. Rats rendered tolerant to morphine decreased hypothalamic MHPG concentration, and reduced hypothalamic NA turnover. Chronic infusion of nimodipine concurrently with morphine prevented the decrease in NA turnover during tolerance. After naloxone administration to tolerant rats we found a striking parallelism between an increased activity of the hypothalamic-pituitary-adrenal axis and an enhanced activity of noradrenergic neurons projecting to the hypothalamus. However, hypothalamic NA turnover and MHPG concentration, both elevated during withdrawal, returned to control levels in rats infused chronically with nimodipine, concomitantly with a reduction of the secretion of corticosterone. Taken together, these data indicate that increased noradrenergic neuronal activity in the hypothalamic nerve terminals is associated with the neuroendocrine morphine withdrawal syndrome and suggest that an up-regulated calcium system might contribute to the activation of these neurons.

Neurochemical activity of noradrenergic neurons and pituitary-adrenal response after naloxone-induced withdrawal: the role of calcium channels.

Simultaneous changes in hypothalamic catecholamine levels and plasma corticosterone concentration in the rat after acute morphine and during tolerance.

It has been demonstrated previously that chronic treatment with opioid antagonists enhances the potency of opioid agonists (supersensitivity) and produces an increase in brain opioid binding sites (up-regulation). The objective of the present study was to examine whether chronic blockade of mu-opioid receptors with naloxone would produce functional supersensitivity to the action of selective mu- and/or kappa-opioid agonists, within the hypothalamus-pituitary-adrenocortical axis. Naloxone (0.5 mg/kg/hr) was infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days. The increase in plasma corticosterone produced by 30 mg/kg i.p. of morphine in control rats was shown to be significantly higher in naloxone-pretreated rats, 24 hr after pump removal. Furthermore, in naloxone-pretreated rats, 10 mg/kg i.p. of morphine significantly increased corticosterone levels 24 hr after naloxone was withdrawn, whereas in control rats the concentration of corticosterone increased first after the 30-mg/kg dose. No supersensitivity could be detected to the stimulating action on corticosterone release of U-50,488H (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidynyl)cyclohexyl]ben zeneacetamide methane sulfonate; 1 or 15 mg/kg i.p.), 1 day after cessation of naloxone treatment. These data suggest that chronic blockade of the mu receptor with naloxone may induce a functional supersensitivity to the effects of mu- but not to those of kappa-agonists on the hypothalamus-pituitary-adrenocortical axis.

Chronic naloxone treatment induces supersensitivity to a mu but not to a kappa agonist at the hypothalamus-pituitary-adrenocortical axis level.

The present study was conducted to evaluate the influence of chronic kappa receptor blockade on the neuroendocrine effects of the selective kappa 1 opioid agonist U-50,488H, on the hypothalamo-pituitary-adrenocortical (HPA) axis. Male Sprague-Dawley rats were chronically treated with naloxone (3 mg kg-1 day-1 for 7 days) or distilled water by s.c. implantation of osmotic minipumps and the response of the HPA axis to U-50,488H or saline was assessed before and 24 h after pump removal. Chronic infusion of naloxone reduced body weight gain and blocked the increase in corticosterone secretion induced by U-50,488H, indicating occupation of kappa opioid receptors. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 5 or 15 mg/kg were observed 1 day after cessation of naloxone treatment compared with those in corresponding control rats. The enhanced responsiveness of the HPA axis to U-50,488H (15 mg/kg) was antagonized by norbinaltorphimine (5 mg/kg), suggesting a role for kappa receptors in mediating supersensitivity to the kappa agonist. The findings of the present study demonstrated that chronic blockade of the kappa receptor results in augmentation of kappa agonist-induced stimulation of the HPA axis activity (functional supersensitivity).

Chronic kappa opioid receptor antagonism produces supersensitivity to U-50,488H at the hypothalamo-pituitary-adrenocortical (HPA) axis level.

1 1 Hypothalamic noradrenaline (NA), dopamine (DA) and plasma cortiocosterone concentrations were determined after acute morphine administration to both naive and morphine-tolerant rats and during naloxone-induced withdrawal 2 2 Acutely administered morphine (30 mg/kg) significantly increased the plasma level of corticosterone and reduced the NA and DA content in the hypothalamus Naloxone (1 mg/kg), administered before morphine, blocked the effect of the opiate on both plasma corticosterone and hypothalamic NA concentration 3 3 In chronically morphine-treated rats, a challenge dose of morphine (30 mg/kg) neither modified the plasma corticosterone level nor the NA concentration, while DA content was significantly enhanced 4 4 After naloxone-induced withdrawal, the hypothalamic content of NA was significantly reduced, simultaneously with an increase in plasma corticosterone, while DA content remained unchanged 5 5 These results suggest that the hypothalamic noradrenergic neurons are mainly implicated in the effect of acute morphine on the hypothalamus-pituitary-adrenocortical (HPA) axis and in the tolerance development to this effect The results also suggest that a hyperactivity of noradrenergic pathways in the hypothalamus would be one of the physiologically relevant mechanisms mediating the neuroendocrine opiate withdrawal at the HPA level

Modulation by catecholamine of hypothalamus-pituitary-adrenocortical (HPA) axis activity in morphine-tolerance and withdrawal

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