Neurotrophins and the primate central nervous system: a minireview

The central nervous system (CNS) of primates is more complex than the CNS of other mammals. Details of the development and aging of the primate CNS have recently been revealed by various neurobiological techniques. It has become clear that the primate CNS has unique characteristics, for example, the capacity for the overproduction and elimination of fibers and synapses. Some differences have also been found in the distribution of and changes with development in levels of various neuroactive substances. Recent discoveries of a variety of neurotrophins in the mammalian CNS have led to research on the neurobiology of these molecules in the primate CNS. The distribution of and changes with development in levels of nerve growth factor (NGF) in the primate CNS are closely correlated with the cholinergic system of the basal forebrain. The administration of NGF into the monkey brain prevents the degeneration of the cholinergic neurons of the basal forebrain after axotomy, a result that suggests that neurotrophins might be very valuable agents for the future treatment of neurological diseases, such as Alzheimer's and Parkinson's diseases.     

Cocaine and the nervous system

Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

Clinical patterns of neuronal migrational disorders and parental consanguinity

The primary metabolite of morphine, morphine-6-beta-glucuronide (M-6-G), is reported to contribute to the effects of morphine. The authors investigated the effects of M-6-G on the central nervous system (CNS) after short-term intravenous (i.v.) administration by employing both electroencephalograph (EEG) power spectra analyses and clinical signs as indicators of opioid effects. Three dosages of M-6-G, one dosage of morphine (bolus 10 mg/70 kg and 3.5 mg/70 kg/hour for 4 hours), a combination of morphine and M-6-G, and placebo were administered to 20 healthy volunteers as i.v. bolus plus i.v. infusion for 4 hours. M-6-G was dosed to produce steady state plasma concentrations that were either identical, 2 times, or 3 times higher than the M-6-G plasma concentrations observed after administration of morphine. The EEG background activity and clinical effects were recorded 3.5 hours after the infusion started. M-6-G failed to produce effects on any of the investigated EEG or clinical parameters at the doses tested. In contrast, morphine produced a significant increase in the alpha 1 and delta power of the EEG. In addition, morphine increased the subjects' ratings of tiredness, sickness, vertigo, and drowsiness, and decreased their level of performance in a tracking task. It was concluded that after short-term i.v. administration, M-6-G does not affect the CNS at the doses tested. Therefore, its contribution to clinical effects of morphine after short-term administration is questionable. The missing CNS effects were probably caused by the slow brain permeability of M-6-G, which in short-term treatment might not attain effective CNS concentrations.     

Treatment of malignant gliomas: a new approach

The etiology of seizures associated with cocaine use is unclear. Because cocaine seizures are relatively uncommon, they should be diagnosed by exclusion and a neurological workup to rule out central nervous system (CNS) catastrophe should be made. This report describes the clinical findings, treatment, and blood cocaine and metabolite concentrations in a patient who, on two separate occasions, had seizures associated with crack cocaine ingestion. Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously. His workup for CNS bleeding, infection, and trauma was negative. Cocaine concentrations on the first incident peaked at 2.48 mg/L and on the second incident peaked at 3.9 mg/L. Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation. Blood cocaine and metabolite analysis revealed extremely high concentrations. Other than the incident of seizures and transient cardiovascular aberrations, these high concentrations were tolerated by the patient without further sequelae. A review of cocaine-induced seizures and treatment is included.     

Regional differences in cerebral noradrenaline turnover in mice withdrawn from repeated morphine treatment and tolerance to the effects of acute morphine

The effects of morphine withdrawal and challenge doses (10 or 30 mg/kg) on the alpha-methyl-p-tyrosine (alpha MT)-induced noradrenaline (NA) depletion as well as on the free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG) concentration were studied in various brain areas of NMRI mice. Morphine was given subcutaneously 3 times daily for 5 days followed by 1 or 3 days' withdrawal. In morphine withdrawn mice the alpha MT-induced NA depletion and the free MOPEG concentrations were differentially altered. At 1-day withdrawal the alpha MT-induced NA depletion was retarded and the NA concentration was elevated in the forebrain area indicating reduced release of NA. Simultaneously, however, the free MOPEG concentration was significantly elevated in the forebrain area and in the lower brain stem suggesting enhanced NA turnover. No withdrawal-induced changes were found in the hypothalamic NA turnover. Acute morphine elevated the free MOPEG concentration and accelerated the alpha MT-induced NA depletion in all brain areas of control mice but not in mice withdrawn for 1 day from repeated morphine treatment. At 3 days' withdrawal, however, the 30 mg/kg morphine dose slightly accelerated the NA depletion in the forebrain area. These results show that morphine withdrawal differentially alters the alpha MT-induced NA depletion and the free MOPEG concentration in various mouse brain areas. These effects are relatively modest suggesting that in mice the noradrenergic mechanisms play a minor role in morphine withdrawal syndrome. However, in all brain areas of the morphine-withdrawn mice tolerance was found towards the NA turnover and release accelerating effect of acute morphine.     

Extinction of tolerance to the analgesic effect of morphine: Intracerebroventricular administration and effects of stress.

Previous research demonstrated that tolerance to the analgesic effect of morphine in rats is attenuated by administrations of a placebo in the context of drug-associated cues. Such apparent extinction of tolerance has been interpreted as support for a Pavlovian conditioning model of tolerance. Recently, it has been suggested that these findings are attributable to stress, induced during placebo sessions and augmenting the analgesic effect of morphine (rather than to Pavlovian extinction). Our results indicate that placebo sessions actually attenuate tolerance by extinguishing the association between predrug cues and the systemic effects of the drug. In addition, the results indicate that conditioning contributes to analgesic tolerance when morphine is administered intracerebroventricularly, which suggests that conditional alterations within the central nervous system mediate such tolerance. This contrasts with alternative suggestions that conditional alterations in drug distribution or metabolism mediate the effects of conditioning manipulations on tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain macrophages stimulate neurite growth and regeneration by secreting thrombospondin

The presence of macrophages in the developing or lesioned central nervous system (CNS) led us to study the influence of these cells on neuronal growth. Macrophages were isolated from embryonic rat brain and we observed that factors released in vitro by these cells stimulate neurite growth and regeneration of cultured CNS neurons. This effect was inhibited by antibodies directed against thrombospondin, an extracellular matrix protein that we found to be synthesized and released by brain macrophages. Immunodetection of thrombospondin in the adult rat brain lesioned by kainic acid confirmed the production of this protein by brain macrophages and indicated an early intraparenchymal accumulation of thrombospondin following injury. These results suggest that brain macrophages contribute actively to neurite growth or regeneration during the development or in pathological contexts.     

Effect of 6-hydroxydopamine and 5,6-dihydroxytryptamine on the response of the coaxially stimulated guinea-pig ileum to morphine

Studies were conducted to determine the role of norepinephrine and 5-hydroxytryptamine in the action of morphine in the coaxially stimulated guinea-pig ileum. 6-hydroxydopamine produced supersensitivity to norepinephrine and decreased the levels of norepinephrine in the ileum. 6-Hydroxydopamine did not interfere with the acute effects of morphine but did interfere with the degree of tolerance developed to morphine, which is in contrast to reported results of the effect of 6-hydroxydopamine on the analgesic response to morphine. No evidence was found that 5,6-dihydroxytryptamine altered the acute or chronic response of the ileum to morphine. Again this is in contrast to results for the analgesic receptor where 5,6-dihydroxytryptamine has been reported to inhibit the development of tolerance to morphine. Thus, the role of the biogenic amines in the action of morphine in the ileum appears to differ from their reported role in the action of morphine in the central nervous system.     

Oxygen toxicity induces apoptosis in neuronal cells

1. A high oxygen atmosphere induced apoptosis in cultured neuronal cells including PC12 cells and rat embryonic cortical, hippocampal, and basal forebrain neurons associated with DNA fragmentation and nuclear condensation. 2. The sensitivity of CNS neurons to a high-oxygen atmosphere was the following order; cortex > basal forebrain > hippocampus. 3. Cycloheximide and actinomycin-D inhibited the apoptosis, indicating that it depends on new macromolecular synthesis. In contrast, cultured postnatal CNS neurons were resistant to oxidative stress. 4. Neurotrophic factors such as nerve growth factor (NGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) blocked the apoptosis induced by a high-oxygen atmosphere.     

Delayed rupture of the spleen and streptokinase therapy

The morphine distribution in human tissues was studied by immunohistochemical method. Four cases of opiate associated death were examined. Morphine was demonstrated not only in some neuronal cytoplasma of cerebral cortex, hippocampus, basal ganglia thalamus, brainstem, and cerebellum, but also found in some nervous fibers and some capillary walls in the central nervous system. Besides, it was also found in the capsule and mesenchyma of heart, liver, spleen, lung, kidney, adrenal gland, pancreas, thymus, thyroidea and testis. Morphine was not seen in the parenchyma of these organs. It was suggested that the postmortem redistribution was not in the central nervous system, but in other organs. We considered that immunohistochemical staining of morphine is useful in the diagnosis of death from opiate addiction.     

Medial preoptic area oxytocin and female sexual receptivity.

Intracerebroventricular (icv) administration of the nonapeptide oxytocin (OXT) increases sexual receptivity in female rats. The medial preoptic area (MPOA) appeared to be the most sensitive brain area to the facilitative effects of OXT. Bilateral infusions of 100 ng of OXT into the MPOA significantly elevated lordosis quotients in overiectomized (OVX), estrogen-treated rats. This dose of OXT was ineffective when infused icv or into the ventromedial hypothalamus, mesencephalic central gray, or ventral tegmental area. A 500-ng dose of OXT significantly elevated lordosis responding when infused icv, corresponding with our previous findings. Mounting by males significantly increased immunoreactive levels of OXT and decreased the number of OXT immunostaining cells in the MPOA of sexually receptive rats pretreated with estrogen and progesterone. The MPOA is a primary site of the OXT facilitation of sexual receptivity where OXT may be released during mating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

XCE, a new member of the endothelin-converting enzyme and neutral endopeptidase family, is preferentially expressed in the CNS

In the present study, we have isolated a cDNA encoding a novel member of the family of zinc metallopeptidases that includes neutral endopeptidase and endothelin-converting enzyme. The predicted amino-acid sequence of this enzyme, termed XCE, consists of 775 amino-acids with a single putative membrane-spanning region, an N-terminal cytoplasmic domain of 59 residues, and a large luminal domain that contains a characteristic zinc-binding motif. Western blot analysis of cells stably expressing this new metallopeptidase revealed a glycosylated protein of approximately 95 kDa. XCE mRNA was found to be predominantly expressed in the central nervous system, sympathetic ganglia and in uterine subepithelial cells. In the rat and human CNS, a very specific pattern of neuronal labelling (in presumptive cholinergic interneurons of basal ganglia, basal forebrain neurons, as well as brainstem and spinal cord motoneurons) was detected by in situ hybridization histochemistry. The enzyme substrate, as yet unidentified, might be found among the numerous neuropeptide transmitters which are colocalized with acetylcholine in these neurons.     

The effects of cholinergic compounds on the development of morphine tolerance, dependence and increased naloxone potency in mice

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Furthermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependence on, morphine in mice.     

Increased creatine kinase brain isoenzyme concentration in cerebrospinal fluid with meningitis

CPK-BB (CK-BB) isoenzyme is an intracellular enzyme released in various neurologic conditions, including central nervous system (CNS) infections. Activity of CK-BB in cerebrospinal fluid (CSF) was determined in 80 children by electrophoresis and densitometry. The possible correlation between CNS infection and CK concentrations was assessed. Significantly elevated concentrations of CK activity (P < 0.01) in the CSF were found in children with bacterial meningitis as compared with children with either aseptic meningitis or normal CSF findings. The data suggest the possibility of utilizing CSF CK activity to differentiate between bacterial and viral meningitis in situations where a routine CSF examination is inconclusive.     

Possible role of nitric oxide in the antinociceptive action of intraventricular bradykinin in mice

The i.c.v. administration of bradykinin (4, 8 and 16 micrograms) induced antinociception in mice which was resistant to naloxone; furthermore, the induction of tolerance to morphine by a single s.c. injection (100 mg/kg, 24 h before test doses of the peptide) did not affect antinociception. Since bradykinin is known to increase nitric oxide (NO) in peripheral tissues, we studied the possibility that its antinociceptive action may be related to NO effects in the central nervous system. Bradykinin effects were antagonized by previous treatment with NG-nitro-L-arginine or concomitant i.c.v. administration of bradykinin and methylene blue. The immediate precursor of NO, L-arginine, which by itself produces analgesia, also reduced bradykinin effects; moreover, tolerance to L-arginine significantly decreased the response to the peptide. These results suggest that NO is involved in antinociception induced by i.c.v. administration of bradykinin.     

Alcoholic effect on male sexual function

Though an adequate volume of ethanol relieves nervousness and enhances sexual desire, acute administration of a great deal of ethanol suppresses central nervous system and causes sensory torpor and penile erectile dysfunction. Long term and excessive intake of ethanol causes central and/or peripheral neuropathy and sexual dysfunction; atrophy of testicles, low serum level of testosterone, impaired spermatogenesis and penile erectile dysfunction. It also invades various organs in digestive tract, cardiovascular system, central and peripheral nervous system and causes functional disorders in these organs. Successful treatment of patients with penile erectile dysfunction should be performed with treatment of these underlying and associated disease.     

Ontogeny of vesicular monoamine transporter mRNAs VMAT1 and VMAT2. I. The developing rat central nervous system

We used in situ hybridization histochemistry to study the expression of the mRNA of the two vesicular monoamine transporters (VMAT1 and VMAT2) during embryonic and postnatal development of the central nervous system (CNS) in the rat. In the adult rat, VMAT2 mRNA is present exclusively in monoaminergic cell groups of the CNS and VMAT1 mRNA was reported to be present in the adrenal medulla and certain intestinal epithelial cells. In contrast to the above, the expression of VMAT1 mRNA has previously never been detected in the central nervous system. This study shows the first evidence that both transporter molecules are expressed in CNS during ontogenesis. We here demonstrate four main expression patterns detected during development: 1. VMAT2 mRNA expression in monoaminergic neurons of the brainstem beginning as early as embryonic day E13. 2. Expression of VMAT2 mRNA in all major sensory relay nuclei of central nervous system. 3. Co-expression of VMAT1 and VMAT2 mRNA in most limbic structures, basal ganglia, as well as in some hypothalamic nuclei. 4. Exclusive expression of VMAT1 mRNA in the neocortical subventricular zone, in the amygdala at early (E15-18) and late (P1-P28) timepoints, the granular cell layer of cerebellum, and in several brainstem motor nuclei. Based on their distribution during development we suggest that monoamines, released in a controlled fashion, might affect wiring of sensory and also motor circuits. VMAT1 mRNA expression may reflect a specific effect of monoamines in glial differentiation and cerebellar granule cell migration and/or differentiation.     

Corticosterone increases severity of acute withdrawal from ethanol, pentobarbital, and diazepam in mice

It has been suggested that withdrawal from several subclasses of central nervous system (CNS) depressants involves common underlying mechanisms. For example, mice genetically selected for severe ethanol withdrawal convulsions (Withdrawal Seizure Prone or WSP) have also been found to express severe withdrawal following treatment with barbiturates and benzodiazepines. Corticosteroids appear to modulate severity of withdrawal from CNS depressants. Therefore, it was hypothesized that corticosterone would enhance withdrawal convulsions following acute ethanol, pentobarbital, and diazepam in WSP mice. Corticosterone (20 mg/kg) administered following each of these drugs significantly increased severity of handling-induced convulsions during withdrawal. Corticosterone did not affect pre-withdrawal convulsion scores or handling-induced convulsions of drug-naive mice. These results suggest that withdrawal convulsions following acute ethanol, pentobarbital, and diazepam are sensitive to modulation by corticosterone and they support the hypothesis that stress may increase drug withdrawal severity.     

Lack of tolerance in peripheral opioid analgesia in mice

We recently developed a sensitive peripheral analgesic test in mice. Bradykinin, a representative pain-producing substance, when given subcutaneously through a polyethylene tube into the plantar of the limb connected to a transducer, induced a flexor reflex response, in a dose dependent manner. When morphine, a mu-opioid receptor agonist, was added to the plantar through another polyethylene tube, bradykinin-induced responses were completely abolished in a naloxone-reversible manner. These peripheral analgesic effects were also observed with DAMGO, another mu-opioid receptor agonist, and U-69,593, a kappa-opioid receptor agonist, but not DSLET, a delta-opioid receptor agonist. When morphine was given subcutaneously to the back, a potent analgesia in the tail pinch test was observed. Repeated administrations of morphine once per day for 5 days showed a marked tolerance or reduction in morphine analgesia on the 6th day, while there was no significant reduction in the peripheral analgesia of morphine. These findings suggest that tolerance to morphine analgesia is mediated through synaptic plasticity in the central nervous system, but not through a receptor desensitization at the level of the single cell.