Olanzapine for the treatment of fibromyalgia symptoms.

Fibromyalgia is a chronic condition that is diagnosed primarily by the presence of generalized pain along with tenderness on palpation of certain body regions. Unfortunately, the pharmacological treatment of fibromyalgia remains problematic. Two patients are described who highlight the use of the atypical neuroleptic olanzapine for the control of symptoms related to fibromyalgia. Prior to the use of olanzapine, both patients had received a multitude of treatments, none of which greatly improved their ability to function in daily activities. With olanzapine, both patients reported a significant decrease in pain and marked improvement in daily functioning. In one case, the pain returned during a period of time when olanzapine was discontinued, an effect that was reversed when olanzapine was reintroduced. The paucity of serious side effects (i.e., extrapyramidal signs) with the atypical neuroleptic olanzapine strongly favors further exploration and use of this drug for the treatment of fibromyalgia symptoms.

Eating behavior and plasma beta-endorphin in bulimia.

To study the possible role of plasma beta-endorphin in bulimia, we measured plasma beta-endorphin immunoreactivity in 34 female patients with normal-weight bulimia and 34 normal female controls matched for weight as percent of ideal. Plasma beta-endorphin immunoreactivity in bulimics (mean 59.6 pg/ml; SEM 5.6) was significantly lower (p less than 0.05) than in controls (mean 79.5 pg/ml; SEM 8.5). Within the bulimic group, plasma beta-endorphin immunoreactivity correlated inversely with severity of bulimic symptomatology as measured by the Eating Attitudes Test Bulimia Subscale (p less than 0.05). Endorphin level did not correlate with severity of depression or with percent ideal body weight. Abnormalities in opioid metabolism may be implicated in eating disorders and account for the addictive properties of these disorders.

Effect of temperature on naloxone treatment in canine hemorrhagic shock.

The effects of temperature on naloxone treatment in canine hemorrhagic shock were examined in 24 dogs hemorrhaged to a mean arterial blood pressure of 35 mm Hg (ambient temperature, 21 degrees C). After two hours of hypotension, the blood reservoir was clamped with no return of shed blood. Dogs were divided into three groups: Control (n = 8) received normal saline (0.5 cc/kg/hr); naloxone-cold (n = 8) and -warm (n = 8) received naloxone (2 mg/kg bolus and 2 mg/kg/hr constant infusion). Body temperature was maintained in four dogs with a warming blanket, and four dogs received no external warming. Rectal temperature fell to 34.2 +/- 0.9 degrees C in naloxone-cold animals; naloxone-warm animals were maintained at 38.6 +/- 0.1 degrees C by external warming. Control dogs rapidly deteriorated after reservoir clamping (survival, 18.6 +/- 5 min). Naloxone infusion significantly increased survival regardless of body temperature (cold, 125 +/- 21 min; warm, 199 +/- 13 min). Naloxone transiently increased mean arterial pressure and dP/dt in the colder dogs, while coronary perfusion, myocardial oxygen metabolism, and plasma beta-endorphin levels were unchanged. In the warmer dogs, naloxone significantly improved hemodynamic function and myocardial perfusion as indicated by the increased mean arterial pressure, cardiac output, stroke volume, dP/dt, and coronary blood flow. Furthermore, naloxone reduced plasma beta-endorphin levels and corrected the metabolic derangements of shock in this group. Our data indicate hypothermia significantly diminished the beneficial effects of naloxone treatment in canine hemorrhagic shock.

Endorphin-related peptides in rat cerebrospinal fluid.

Cerebrospinal fluid (CSF) samples were taken from rats implanted with chronic cisternal cannulae and assayed for methionine-enkephalin, beta-endorphin and corticotropin (ACTH). Immobilization stress had little apparent effect on immunoreactive levels of the peptides in the CSF. Gel chromatographic analysis of the beta-endorphin- and ACTH-immunoreactive profiles in rat CSF revealed several peaks. beta-Endorphin-immunoreactive peaks were present at the expected positions of pro-opiocortin, beta-lipotropin and beta-endorphin. ACTH-immunoreactive peaks eluted at positions corresponding to pro-opiocortin, the 20-23K ACTH biosynthetic intermediate, 14K ACTH, and 4.5K ACTH. These results suggest that rat CSF contains peptides of the pro-opiocortin family similar to those previously described in rat pituitary.

Acupuncture relief of chronic pain syndrome correlates with increased plasma met-enkephalin concentrations.

In twenty patients with chronic pain syndrome, acupuncture treatment resulted in significant improvement of both pain and psychiatric symptoms and higher plasma concentrations of metenkephalin. Plasma beta-endorphin concentrations were unchanged. The degree of symptom relief was correlated with the increase in plasma met-enkephalin.

Beta-endorphin and the endocrine pancreas. Studies in healthy and diabetic human beings.

Beta-endorphin is present in the endocrine pancreas, suggesting that endorphins may have a role in islet-cell function. To evaluate this possibility, we infused synthetic human beta-endorphin intravenously in healthy volunteers and in insulin-dependent diabetic patients. In both groups, beta-endorphin increased plasma glucagon concentrations, and this rise was accompanied by a significant increase in plasma glucose concentrations. In nondiabetic subjects, beta-endorphin also increased plasma insulin concentrations. The threshold dose of beta-endorphin for producing increased plasma concentrations of glucose and glucagon was 0.005 mg--a dose that acutely increased plasma concentrations of beta-endorphin by approximately 40-fold. Glucose, glucagon, and insulin responses to beta-endorphin could not be blocked by intravenous naloxone. These studies suggest that endorphins may be involved in gluco-regulation, that their hyperglycemic action is mediated at least in part by glucagon, and that the effect of beta-endorphin on islet-cell function is relatively resistant to naloxone.

A simple method for obtaining chronic cerebrospinal fluid samples from awake rats.

A simple technique is described for taking repeated cerebrospinal fluid (CSF) samples from the cisterna magna of unanesthetized rats. The technique has the advantages that inexpensive, readily available materials are used, the cannulas remain patent for extended periods of time, and large volumes of CSF can be obtained.

Electrophysiological and biochemical responses of noradrenergic neurons to a non-amphetamine CNS stimulant.

Amfonelic acid (AFA), a potent non-amphetamine CNS stimulant, has been shown previously to have marked effects on dopamine (DA) metabolism and DA neuronal activity, but no effect on norepinephrine (NE) metabolism. AFA is known to inhibit the NE neuronal uptake mechanism. Other NE uptake inhibitors, such as desipramine (DMI), have been shown to decrease the firing rate of NE-containing locus coeruleus (LC) neurons. The purpose of the present study was to compare the actions of AFA and DMI electrophysiologically on LC neurons, and biochemically on NE metabolism in whg rate, with DMI being more potent. Brain NE metabolism was not influenced by either AFA or DMI at doses considerably higher than those which were effective in reducing NE neuronal impulse flow. Thus, NE uptake inhibition coupled with a decrease in impulse flow results in no net change in NE metabolite formation. The effects of AFA on LC unit activity do not seem to be due to its marked effects on brain DA, since DA receptor blockade with haloperidol had little effect on LC unit responsiveness to AFA (or amphetamine). Whereas AFA has dramatic effects on DA metabolism via enhanced release per impulse, the drug has minimal effects on NE metabolism, and this specificity of action may be related to differences in NE and DA transmitter storage mechanisms. It is concluded that the effects of AFA on NE neuronal firing rate are likely due to the drug's DMI-like action and not to enhanced NE release per impulse.

Differences in norepinephrine and dopamine neurotransmitter storage systems.

Low doses of d-amphetamine (d-AMP) produced a 50% or greater decrease in the firing rates of both dopamine (DA) neurons (substantia nigra zone compacta) and norepinephrine (NE) neurons (locus coeruleus). However, pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT) blocked the d-AMP-induced reduction in DA neuron firing rate, but had no effect on the d-AMP-induced reduction in NE cell firing rate. Similarly, alpha-MT administered subsequent to d-AMP readily reversed the d-AMP-induced decrease in the firing rates of DA cells, but caused no significant reversal in NE cell firing rates. These electrophysiological findings, in conjunction with biochemical and behavioral data, support the hypothesis that there is a difference in the DA and NE neurotransmitter storage mechanism. In the DA neuron, there appears to be a slow transfer between stored and readily-releasable (newly synthesized) amine pools so that, following synthesis inhibition, there is little DA available for release. However, in the NE neuron, there is a more rapid mobilization of stored amine to readily releasable sites, such that d-AMP continues to cause the release of NE even though synthesis of transmitter is blocked.

Dopaminergic neuronal responses to a non-amphetamine CNS stimulant.

The present study compares the effects of d-amphetamine (d-AMP) and the potent non-amphetamine CNS stimulant, amfonelic acid (AFA), on the firing rate of single midbrain dopaminergic (DA) neurons and on neostriatal DA metabolism (dihydroxyphenylacetic acid--DOPAC). The results indicate that AFA, like d-AMP, reduces the firing rate of DA neurons, although unlike d-AMP, AFA does not cause a decrease in neostriatal DOPAC content and, in fact, enhances that produced by haloperidol (HALO). The AFA-induced decrease in firing rate, like d-AMP, is reversed by the DA receptor blocker HALO, but again unlike d-AMP, the decrease in firing rate is not prevented by catecholamine synthesis inhibition with alpha-methyl-para-tyrosine. Thus, both amphetamine and amfonelic acid have identical electrophysiological effects on DA neurons but act by different mechanisms.

Anatomic and pharmacologic differences between two types of aversive midbrain stimulation.

Chronic stimulating electrodes were implanted into two separate midbrain sites in rats. One site was the dorsal central gray area (DCG), where electrical stimulation produced frantic, escape-seeking behavior which grossly appeared fear-like and/or pain-like. The other site was in the ventral reticular formation (VRF), where stimulation produced a stereotyped circling response. Stimulation at both sites was aversive in that these animals would bar press for escape in a decremental bar-pressing paradigm. In this paradigm, each bar press decremented the current by five per cent of the initial current level. Following the acquisition of stable baseline decremental bar-pressing performance, animals were given injections of either the serotonin-depleting drug, para-chlorophenylalanine (PCPA), or the catecholamine-depleting drug, alpha-methyl-para-tyrosine (AMPT). Control animals received normal saline. Compared to saline control animals, PCPA-injected DCG-stimulated animals showed a marked increase in decremental bar pressing, whereas VRF-stimulated animals showed no change. AMPT-injected VRF-stimulated animals showed a marked decrease in decremental bar pressing, but the DCG-stimulated animals were not affected. These results suggest that escape behavior from electrical stimulation of midbrain sites is mediated by more than one neural system.

Serotonergic reduction of dorsal central gray area stimulation-produced aversion.

Stimulating electrodes were implanted into the dorsal central gray area (DCG) of rats. The animals were trained to bar press to decrement the aversive DCG stimulation current. Rats treated with 5-hydroxytryptophan (5-HTP), 75 mg/kg or 150 mg/kg, showed a dose-dependent reduction in decremental bar pressing. In a second study, animals received either chlorimipramine, 15 mg/kg, protriptyline, 15 mg/kg, or 5-HTP, 150 mg/kg. Chlorimipramine, a strong blocker of serotonin reuptake, and 5-HTP produced significant reductions in decremental bar pressing. Protriptyline, a weak serotonin reuptake blocker, produced no significant effect. These results suggest that serotonin reduces aversive neural mechanisms associated with the dorsal central gray area.

Opiate effects on aversive midbrain stimulation in rats.

Morphine blocked decremental bar pressing of rats to escape electrical stimulation of aversive midbrain sites. These sites included the dorsal central gray area (DCG), the ventral reticular formation (VRF) and the lateral tegmentum (LT). Naloxone, which had no effect alone, blocked the morphine effects of all three aversive sites.

Monoaminergic mechanisms in aversive brain stimulation.

In these experiments we have examined the role of brain monoamines in the fearlike aversive responses produced by the electrical stimulation of the dorsal midbrain tegmentum (DMT). Chronic bipolar stimulating electrodes were bilaterally implanted into the DMT of 77 rats. Electrical stimulation via 34 of these electrodes produced fearlike, escape seeking responses. These animals were then trained for stable stimulus escape using a decremental bar pressing paradigm. In this paradigm, each bar press reduced the stimulation current by a predetermined fraction (5 percent) of the initial current level. Perceived aversive strength of the initial stimulus current was thereby represented by an increasing function of the number of bar presses to escape. Administration of the catecholamine depleting drug alpha-methyl-para-tyrosine yielded no change in bar pressing relative to saline-injected controls. However, the serotonin depleting drub para-chlorophenylalanine produced a marked increase in decremental bar pressing compared to saline-injected controls. These results suggest that fearlike responses to DMT stimulation may be dependent upon brain serotonin levels and relatively insensitive to levels of brain catecholamines.