Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator.

BACKGROUND: Less than 50% of patients experience sufficient pain relief with current drug therapy for neuropathic pain. Minocycline shows promising results in rodent models of neuropathic pain but was not studied in humans with regard to the treatment of neuropathic pain. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, patients with subacute lumbar radicular pain received placebo, amitriptyline 25 mg, or minocycline 100 mg once a day (n = 20 per group) for 14 days. Primary outcome measure was the pain intensity in the leg as measured by a numeric rating scale ranging from 0 to 10 on days 7 and 14. Secondary outcome measures were the reduction of neuropathic pain symptoms in the leg as determined with a neuropathic pain questionnaire, consumption of rescue medication, and adverse events on days 7 and 14. RESULTS: Sixty patients were randomized and included in an intention-to-treat analysis. After 14 days, patients in the minocycline and amitriptyline groups reported a reduction of 1.47 (95% confidence interval, 0.16-2.83; P = 0.035) and 1.41 (95% confidence interval, 0.05-2.78; P = 0.043), respectively, in the numeric rating scale compared to the placebo group. No differences were seen in the neuropathic pain questionnaire values at any time point during treatment between the three groups. The rate of adverse events in the amitriptyline group was 10% versus none in the minocycline and placebo groups. No differences were noted in the consumption of rescue medication. CONCLUSIONS: Although both groups differed from placebo, their effect size was small and therefore not likely to be clinically meaningful.

Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus.

Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal's energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24 h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal's energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.

From frog integument to human skin: dermatological perspectives from frog skin biology.

For over a century, frogs have been studied across various scientific fields, including physiology, embryology, neuroscience, (neuro)endocrinology, ecology, genetics, behavioural science, evolution, drug development, and conservation biology. In some cases, frog skin has proven very successful as a research model, for example aiding in the study of ion transport through tight epithelia, where it has served as a model for the vertebrate distal renal tubule and mammalian epithelia. However, it has rarely been considered in comparative studies involving human skin. Yet, despite certain notable adaptations that have enabled frogs to survive in both aquatic and terrestrial environments, frog skin has many features in common with human skin. Here we present a comprehensive overview of frog (and toad) skin ontogeny, anatomy, cytology, neuroendocrinology and immunology, with special attention to its unique adaptations as well as to its similarities with the mammalian integument, including human skin. We hope to provide a valuable reference point and a source of inspiration for both amphibian investigators and mammalian researchers studying the structural and functional properties of the largest organ of the vertebrate body.

Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model.

BACKGROUND: In animal models of neuropathic pain (NP), promising results have been reported with the administration of minocycline, possibly through inhibition of spinal brain-derived neurotrophic factor (BDNF) expression. No data are available on the effect of amitriptyline and gabapentin on spinal BDNF expression. If the mechanism of action of the latter drugs does not involve brain-derived NP inhibition, further clinical research in BDNF is warranted. METHODS: In this placebo-controlled study, we investigated the effects of amitriptyline (5 mg/kg), gabapentin (50 mg/kg), and minocycline (25 mg/kg) twice a day on NP behavior in a sciatic chronic constriction injury (CCI) rat model. Drug treatment started 7 days after CCI and lasted 14 days. At postoperative day 21, spinal BDNF expression in laminae I and II was quantified using immunocytochemistry. RESULTS: Sciatic CCI resulted in NP behavior throughout the duration of the experiment in the placebo group. When administered for 2 weeks, minocycline (P ≤ 0.001) and amitriptyline (P ≤ 0.05), but not gabapentin, reduced thermal hyperalgesia. None of these drugs reduced mechanical allodynia. As opposed to amitriptyline and gabapentin, 2 weeks of treatment with minocycline reduced brain-derived, neurotrophic factor immunoreactivity (P ≤ 0.05) in the ipsilateral dorsal horn. CONCLUSIONS: Minocycline and amitriptyline both reduce NP behavior in a sciatic CCI rat model, but only minocycline reduces spinal BDNF, indicating different modes of action of these 2 drugs. The observed actions of minocycline closely fit the clinical needs for the treatment of NP.

Pituitary melanotrope cells of Xenopus laevis are of neural ridge origin and do not require induction by the infundibulum.

Classical studies in amphibians have concluded that the endocrine pituitary and pars intermedia are derived from epithelial buccal epidermis and do not require the infundibulum for their induction. These studies also assumed that the pituitary is not subsequently determined by infundibular induction. Our extirpation, auto-transplantation and immunohistochemical studies with Xenopus laevis were initiated to investigate early presumptive pituitary development. These studies were conducted especially with reference to the pars intermedia melanotrope cell's induction, and its production and release of α-melanophore stimulating hormone (α-MSH) from the precursor protein proopiomelanocortin (POMC). Auto-transplantation studies demonstrated that the pituitary POMC-producing cells are determined at a stage prior to pituitary-infundibular contact. The results of experiments involving the extirpation of the presumptive infundibulum also indicated that the infundibulum is not essential for the differentiation of POMC-producing cells. We also demonstrated that early pituitary development involves adherence to the prechiasmatic area of the diencephalon with the pituitary placode growing in a posterior direction toward the infundibulum where contact occurs at Xenopus stage 39/40. Overall, our studies provide a model for early tissue relations among presumptive pituitary, suprachiasmatic nucleus, pars tuberalis and infundibulum during neurulation and later neural tube stages of development. It is hypothesized that the overlying chiasmatic area suppresses pituitary differentiation.

Leptin and the hypothalamo-pituitary-adrenal stress axis.

Leptin is a 16-kDa protein mainly produced and secreted by white adipose tissue and informing various brain centers via leptin receptor long and short forms about the amount of fat stored in the body. In this way leptin exerts a plethora of regulatory functions especially related to energy intake and metabolism, one of which is controlling the activity of the hypothalamo-pituitary-adrenal (HPA) stress axis. First, this review deals with the basic properties of leptin's structure and signaling at the organ, cell and molecule level, from lower vertebrates to humans but with emphasis on rodents because these have been investigated in most detail. Then, attention is given to the various interactions of adipose leptin with the HPA-axis, at the levels of the hypothalamus (especially the paraventricular nucleus), the anterior lobe of the pituitary gland (action on corticotropes) and the adrenal gland, where it releases corticosteroids needed for adequate stress adaptation. Also, possible local production and autocrine and paracrine actions of leptin at the hypothalamic and pituitary levels of the HPA-axis are being considered. Finally, a schematic model is presented showing the ways peripherally and centrally produced leptin may modulate, via the HPA-axis, stress adaptation in conjunction with the control of energy homeostasis.

The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release α-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background.

Sex-dependent and differential responses to acute restraint stress of corticotropin-releasing factor-producing neurons in the rat paraventricular nucleus, central amygdala, and bed nucleus of the stria terminalis.

Male and female rodents respond differently to acute stress. We tested our hypothesis that this sex difference is based on differences in stress sensitivity of forebrain areas, by determining possible effects of a single acute psychogenic stressor (1-hr restraint stress) on neuronal gene expression (c-Fos and FosB immunoreactivities), storage of corticotropin-releasing factor (CRF) immunoreactivity, and CRF production (CRF mRNA in situ hybridization) as well as the expression of genes associated with epigenetic processes (quantitative RT-PCR) in the rat paraventricular nucleus (PVN), the oval and fusiform subdivisions of the bed nucleus of the stria terminalis (BSTov and BSTfu, respectively), and the central amygdala (CeA), in both males and females. Compared with females, male rats responded to the stressor with a stronger rise in corticosterone titer and a stronger increase in neuronal contents of c-Fos, CRF mRNA, and CREB-binding protein mRNA in the PVN. In the BSTov, females but not males showed an increase in c-Fos, whereas the CRF mRNA content was increased in males only. In the BSTfu, males and females showed similar stress-induced increases in c-Fos and FosB, whereas in the CeA, both sexes revealed similar increases in c-Fos and in CRF mRNA. We conclude that male and female rats differ in their reactivity to acute stress with respect to possibly epigenetically mediated (particularly in the PVN) neuronal gene expression and neuropeptide dynamics (PVN and BSTov) and that this difference may contribute to the sex dependence of the animal's physiological and behavioral responses to an acute stressor.

Gene expression profiling of pituitary melanotrope cells during their physiological activation.

The pituitary melanotrope cells of the amphibian Xenopus laevis are responsible for the production of the pigment-dispersing peptide α-melanophore-stimulating hormone, which allows the animal to adapt its skin color to its environment. During adaptation to a dark background the melanotrope cells undergo remarkable changes characterized by dramatic increases in cell size and secretory activity. In this study we performed microarray mRNA expression profiling to identify genes important to melanotrope activation and growth. We show a strong increase in the expression of the immediate early gene (IEG) c-Fos and of the brain-derived neurotrophic factor gene (BDNF). Furthermore, we demonstrate the involvement of another IEG in the adaptation process, Nur77, and conclude from in vitro experiments that the expression of both c-Fos and Nur77 are partially regulated by the adenylyl cyclase system and calcium ions. In addition, we found a steady up-regulation of Ras-like product during the adaptation process, possibly evoked by BDNF/TrkB signaling. Finally, the gene encoding the 105-kDa heat shock protein HSPh1 was transiently up-regulated in the course of black-background adaptation and a gene product homologous to ferritin (ferritin-like product) was >100-fold up-regulated in fully black-adapted animals. We suggest that these latter two genes are induced in response to cellular stress and that they may be involved in changing the mode of mRNA translation required to meet the increased demand for de novo protein synthesis. Together, our results show that microarray analysis is a valuable approach to identify the genes responsible for generating coordinated responses in physiologically activated cells.

Sex-specific differences in the dynamics of cocaine- and amphetamine-regulated transcript and nesfatin-1 expressions in the midbrain of depressed suicide victims vs. controls.

An intriguing novel pathophysiological insight into mood disorders is the notion that one's metabolic status influences mood. In rodents, cocaine- and amphetamine-regulated transcript (CART) and nesfatin-1/NUCB2 have not only been implicated in metabolism, but in the pathobiology of anxiety and depressive-like behaviour, however they have not previously been investigated in depressed subjects. Both peptides are highly expressed in centrally projecting neurons in the Edinger-Westphal nucleus (EWcp) in the midbrain. The EWcp has been implicated in stress adaptation and stress-related mood disorders like major depressive disorder in a sex-specific manner. This is intriguing, given the fact that females have higher prevalence of mood disorders. Here, we hypothesized that the expression of CART and nesfatin-1 in EWcp would exhibit a sex-specific difference between depressed suicide victims vs. controls. We found that CART and nesfatin/NUCB2 colocalized in the human EWcp, and that CART mRNA content was much higher in both male (×3.8) and female (×5.9) drug-free suicide victims than in controls (persons who died without any diagnosed neurodegenerative or psychiatric disorder). Similarly, NUCB2 mRNA content was also higher (×1.8) in male suicides, whereas in female suicide victims, these contents were ×2.7 lower compared to controls. These observations are the first to show changes in the dynamics of CART and nesfatin/NUCB2 expressions in the midbrain of drug-free depressed suicide victims vs. controls. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Peptidergic Edinger-Westphal neurons and the energy-dependent stress response.

The continuously changing environment demands for adequate stress responses to maintain the internal dynamic equilibrium of body and mind. A successful stress response requires energy, in an amount matching the severity of the stressor and the type of response ('fight, flight or freeze'). The stress response is generated by the central nervous system, which needs to be informed about both the threatening stressor and the availability of energy. In this review, evidence is considered for a role of the midbrain Edinger-Westphal centrally projecting neuron population (EWcp; synonym: non-preganglionic Edinger-Westphal nucleus) in the energy-dependent stress adaptation response. It deals with studies on the neurochemical organization of the EWcp with particular reference to the neuropeptides urocortin-1 and cocaine- and amphetamine-regulated transcript peptide, on the EWcp responses to different types of stressor (e.g., acute and chronic) and a changed energy state (e.g., fasting and leptin change), and on the sex-specificity of these responses. Finally, a model is presented for the way the EWcp might contribute to the coordination of the energy-dependent stress adaptation response.

Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat.

BACKGROUND: Although the higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive. METHODS: Male and female rats were exposed to chronic variable mild stress (CVMS) after which immediate early gene products, corticotropin-releasing factor (CRF) mRNA and peptide, various epigenetic-associated enzymes and DNA methylation of the Crf gene were determined in the hypothalamic paraventricular nucleus (PVN), oval (BSTov) and fusiform (BSTfu) parts of the bed nucleus of the stria terminalis, and central amygdala (CeA). RESULTS: CVMS induced site-specific changes in Crf gene methylation in all brain centers studied in female rats and in the male BST and CeA, whereas the histone acetyltransferase, CREB-binding protein was increased in the female BST and the histone-deacetylase-5 decreased in the male CeA. These changes were accompanied by an increased amount of c-Fos in the PVN, BSTfu and CeA in males, and of FosB in the PVN of both sexes and in the male BSTov and BSTfu. In the PVN, CVMS increased CRF mRNA in males and CRF peptide decreased in females. CONCLUSIONS: The data confirm our hypothesis that chronic stress affects gene expression and CRF transcriptional, translational and secretory activities in the PVN, BSTov, BSTfu and CeA, in a brain center-specific and sex-specific manner. Brain region-specific and sex-specific changes in epigenetic activity and neuronal activation may play, too, an important role in the sex specificity of the stress response and the susceptibility to depression.

The gray area between synapse structure and function-Gray's synapse types I and II revisited.

On the basis of ultrastructural parameters, the concept was formulated that asymmetric Type I and symmetric Type II synapses are excitatory and inhibitory, respectively. This "functional Gray synapses concept" received strong support from the demonstration of the excitatory neurotransmitter glutamate in Type I synapses and of the inhibitory neurotransmitter γ-aminobutyric acid in Type II synapses, and is still frequently used in modern literature. However, morphological and functional evidence has accumulated that the concept is less tenable. Typical features of synapses like shape and size of presynaptic vesicles and synaptic cleft and presence of a postsynaptic density (PsD) do not always fit the postulated (excitatory/inhibitory) function of Gray's synapses. Furthermore, synapse function depends on postsynaptic receptors and associated signal transduction mechanisms rather than on presynaptic morphology and neurotransmitter type. Moreover, the notion that many synapses are difficult to classify as either asymmetric or symmetric has cast doubt on the assumption that the presence of a PsD is a sign of excitatory synaptic transmission. In view of the morphological similarities of the PsD in asymmetric synapses with membrane junctional structures such as the zonula adherens and the desmosome, asymmetric synapses may play a role as links between the postsynaptic and presynaptic membrane, thus ensuring long-term maintenance of interneuronal communication. Symmetric synapses, on the other hand, might be sites of transient communication as takes place during development, learning, memory formation, and pathogenesis of brain disorders. Confirmation of this idea might help to return the functional Gray synapse concept its central place in neuroscience.

Acute ether stress differentially affects corticotropin-releasing factor and urocortin 1 in the Brattleboro rat.

Arginine-vasopressin (AVP), corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1) play a role in the stress response. The CRF-producing paraventricular nucleus of the hypothalamus (PVN), oval bed nucleus of the stria terminalis (BSTov) and central amygdala (CeA), and the Ucn1-expressing non-preganglionic Edinger-Westphal nucleus (npEW) all possess AVP receptors. We hypothesized that AVP is involved in the response of these four brain centers to acute physiological (ether) stress. To test this hypothesis, we studied AVP-deficient Brattleboro (BB) rats using quantitative immunocytochemistry. First, we showed that non-stressed wild-type (WT) and BB rats did not differ from each other in Fos contents, indicating similar (immediate early) gene expression activity, but that in BB rats CRF contents were lower in the PVN and higher in the CeA. Second, we found that stress induced Fos response in the PVN, CeA and npEW with strengths different for each center, but similar for BB and WT rats. Finally, no effects of stress on CRF and Ucn1 contents were seen in the WT rat brain, but in BB rats stress increased CRF contents in the PVN, and the CeA revealed more CRF in stressed BB than in WT rats. On the basis of these results we propose that during acute stress AVP interacts with, especially, the PVN and the CeA, to change their rates of biosynthesis and/or release of CRF.

ERK-regulated double cortin-like kinase (DCLK)-short phosphorylation and nuclear translocation stimulate POMC gene expression in endocrine melanotrope cells.

We tested whether double cortin-like kinase-short (DCLK-short), a microtubule-associated Ser/Thr kinase predominantly expressed in the brain, is downstream of the ERK signaling pathway and is involved in proopiomelanocortin gene (POMC) expression in endocrine pituitary melanotrope cells of Xenopus laevis. Melanotropes form a well-established model to study physiological aspects of neuroendocrine plasticity. The amphibian X. laevis adapts its skin color to the background light intensity by the release of α-MSH from the melanotrope cell. In frogs on a white background, melanotropes are inactive but they are activated during adaptation to a black background. Our results show that melanotrope activation is associated with an increase in DCLK-short mRNA and with phosphorylation of DCLK-short at serine at position 30 (Ser-30). Upon cell activation phosphorylated Ser-30-DCLK-short was translocated from the cytoplasm into the nucleus, and the ERK blocker U0126 inhibited this process. The mutation of Ser-30 to alanine also inhibited the translocation and reduced POMC expression, whereas overexpression stimulated POMC expression. This is the first demonstration of DCLK-short in a native endocrine cell. We conclude that DCLK-short is physiologically regulated at both the level of its gene expression and protein phosphorylation and that the kinase is effectively regulating POMC gene expression upon its ERK-mediated phosphorylation.

Together or alone?: foraging strategies in Caenorhabditis elegans.

A central goal in Life Sciences is to understand how genes encode behaviour and how environmental factors influence the expression of the genes concerned. To reach this goal a combined ecological, molecular biological and physiological approach is required in combination with a suitable model organism. Such an approach allows the elucidation of all parts of the complicated chain of events that lead from induction of gene expression to behaviour, i.e. from environmental stimulus, sensory organs and extracellular and intracellular neuronal signal processing to activation of effector organs. A particularly good model species with which to take this approach is the nematode Caenorhabditis elegans, as it has been described in great detail at the genomic, cellular and behavioural levels. Different strains of C. elegans display prominent behavioural variation in foraging behaviour. Some strains will form social feeding groups when subjected to certain environmental stimuli, while others do not. This variation is due to the existence of just two isoforms of the gene npr-1, namely 215F and 215V. Here, we describe these behavioural variations at the molecular and cellular levels to attempt to determine the environmental inputs that cause aggregation of these small nematodes. As many different stimuli affect aggregation either positively or negatively, aggregation behaviour seems to be displayed when it improves survival chances. However, not much is known about the ecological context in which C. elegans lives. Investigation of the habitats of different strains of C. elegans would help us to understand why and how a specific foraging strategy enhances survival. The relatively well-understood molecular pathways that direct its social feeding behaviour make C. elegans a highly suitable model organism to test ecological and behavioural hypotheses about the mechanisms that differentiate between aggregation and solitary behaviours.

Leptin signaling modulates the activity of urocortin 1 neurons in the mouse nonpreganglionic Edinger-Westphal nucleus.

A recent study systematically characterized the distribution of the long form of the leptin receptor (LepRb) in the mouse brain and showed substantial LepRb mRNA expression in the nonpreganglionic Edinger-Westphal nucleus (npEW) in the rostroventral part of the midbrain. This nucleus hosts the majority of urocortin 1 (Ucn1) neurons in the rodent brain, and because Ucn1 is a potent satiety hormone and electrical lesioning of the npEW strongly decreases food intake, we have hypothesized a role of npEW-Ucn1 neurons in leptin-controlled food intake. Here, we show by immunohistochemistry that npEW-Ucn1 neurons in the mouse contain LepRb and respond to leptin administration with induction of the Janus kinase 2-signal transducer and activator of transcription 3 pathway, both in vivo and in vitro. Furthermore, systemic leptin administration increases the Ucn1 content of the npEW significantly, whereas in mice that lack LepRb (db/db mice), the npEW contains considerably reduced amount of Ucn1. Finally, we reveal by patch clamping of midbrain Ucn1 neurons that leptin administration reduces the electrical firing activity of the Ucn1 neurons. In conclusion, we provide ample evidence for leptin actions that go beyond leptin's well-known targets in the hypothalamus and propose that leptin can directly influence the activity of the midbrain Ucn1 neurons.

Analysis of the melanotrope cell neuroendocrine interface in two amphibian species, Rana ridibunda and Xenopus laevis: a celebration of 35 years of collaborative research.

This review gives an overview of the functioning of the hypothalamo-hypophyseal neuroendocrine interface in the pituitary neurointermediate lobe, as it relates to melanotrope cell function in two amphibian species, Rana ridibunda and Xenopus laevis. It primarily but not exclusively concerns the work of two collaborating laboratories, the Laboratory for Molecular and Cellular Neuroendocrinology (University of Rouen, France) and the Department of Cellular Animal Physiology (Radboud University Nijmegen, The Netherlands). In the course of this review it will become apparent that Rana and Xenopus have, for the most part, developed the same or similar strategies to regulate the release of α-melanophore-stimulating hormone (α-MSH). The review concludes by highlighting the molecular and cellular mechanisms utilized by thyrotropin-releasing hormone (TRH) to activate Rana melanotrope cells and the function of autocrine brain-derived neurotrophic factor (BDNF) in the regulation of Xenopus melanotrope cell function.

Brain-derived neurotrophic factor stimulates growth of pituitary melanotrope cells in an autocrine way.

Brain-derived neurotrophic factor (BDNF) is expressed in the mammalian pituitary gland, in both the anterior and intermediate lobes, where its functional significance is unknown. Melanotrope cells in the intermediate pituitary lobe of the amphibian Xenopus laevis also produce BDNF, which co-exists in secretory granules with α-melanophore-stimulating hormone (α-MSH), a peptide that causes pigment dispersion in dermal melanophores during adaptation of the toad to a dark background. Xenopus melanotropes are highly plastic, undergoing very strong growth to support the high biosynthesis and release of α-MSH in black-adapted animals. In this study we have tested our hypothesis that this enhanced growth of the melanotrope is maintained by autocrine release of BDNF. Furthermore, since the extracellular-regulated kinase (ERK) pathway is a major component of BDNF signaling in neuronal plasticity, we investigated its involvement in melanotrope cell growth. For these purposes melanotropes were treated for 3 days in vitro, with either an anti-BDNF serum or a recombinant tropomyosin-receptor kinase B (TrkB) receptor fragment to eliminate released BDNF, or with the ERK inhibitor U0126. We also applied a novel inhibitor of the TrkB receptor, cyclotraxin-B, to test this receptor's involvement in melanotrope cell growth regulation. All treatments markedly reduced melanotrope cell growth. Therefore, we conclude that autocrine release of BDNF and subsequent TrkB-dependent ERK-mediated signaling is important for melanotrope cell growth during its physiologically induced activation.

Plasticity of melanotrope cell regulations in Xenopus laevis.

This review focuses on the plasticity of the regulation of a particular neuroendocrine transducer cell, the melanotrope cell in the pituitary pars intermedia of the amphibian Xenopus laevis. This cell type is a suitable model to study the relationship between various external regulatory inputs and the secretion of an adaptive endocrine message, in this case the release of α-melanophore-stimulating hormone, which activates skin melanophores to darken when the animal is placed on a dark background. Information about the environmental conditions is processed by various brain centres, in the hypothalamus and elsewhere, that eventually control the activity of the melanotrope cell regarding hormone production and secretion. The review discusses the roles of these hypothalamic and extrahypothalamic nuclei, their neurochemical messengers acting on the melanotrope, and the external stimuli they mediate to control melanotrope cell functioning.