Elsevier

Neuropharmacology

Volume 53, Issue 1, July 2007, Pages 101-112
Neuropharmacology

Highly activated c-fos expression in specific brain regions (ependyma, circumventricular organs, choroid plexus) of histidine decarboxylase deficient mice in response to formalin-induced acute pain

https://doi.org/10.1016/j.neuropharm.2007.04.001Get rights and content

Abstract

Activation of different brain regions for acute pain-related stress induced by a single subcutaneous injection of 4% formalin was investigated in histidine decarboxylase-deficient mice. Besides pain- and stress-related brain areas and the tuberomamillary neurons, strong Fos activation and c-fos mRNA expression were found in distinct brain regions and cell types, which have not been activated in wild type control mice. These structures include the circumventricular organs (organum vasculosum of the lamina terminalis, subfornical organ, area postrema), some of the ependymal cells along the wall of the ventricles, tanycytes in the third ventricle's ependyma and the median eminence, as well as in the epithelial cells of the choroid plexus in the lateral, third and fourth ventricles. All of these areas and cell types are known as compartments of the brain-blood-cerebrospinal fluid interface. The present observations provide strong evidence that an acute stressor, formalin-evoked painful stimulus elicits rapid alterations in the activity of neuroglial elements of histidine decarboxylase-deficient mice that are directly involved in the communication between the brain and the cerebrospinal fluid space.

Introduction

In the central nervous system, histamine is synthesized by tuberomamillary neurons, transported by their axons and stored in nerve terminals (Schwartz et al., 1991, Brown et al., 2001). These neurons contain specific enzymes for histamine synthesis (histidine decarboxylase, HDC) and metabolism (histamine N-methyl transferase). Histamine stimulates adenylate cyclase-cAMP activity in the brain through mainly G-protein-coupled H2 histamine receptor subtypes (Hill, 1990, Schwartz et al., 1991). Histamine receptors (H1, H2 receptor subtypes and H3/H4 inhibitory autoreceptors) have widespread expressions in the brain. They are present not only in neuronal cells but also in astrocytes, ependymal cells, endothelial cells of cerebral vessels, and the neuroepithelium during development (Schwartz et al., 1991, Kinnunen et al., 1998, Brown et al., 2001, Karlstedt et al., 2001). A second histamine pool in the brain is represented by the mast cells that are scattered through the entire tissue. Cerebral endothelium may represent a third physiological histamine pool in the brain (Edvinsson et al., 1993).

Histamine in the brain is involved in a great variety of regulatory mechanisms, like thermal regulation, cerebral circulation, cardiovascular regulation, drinking and feeding behavior, motor activity, analgesia, sleep and wakefulness, antinociception and neuroendocrine regulations (Schwartz et al., 1991, Onodera et al., 1994, Brown et al., 2001). Histamine controls cerebral blood flow, endothelial permeability, blood–brain barrier functions (Edvinsson et al., 1993, Joo et al., 1994, Deli and Ábrahám, 2004) and brain-cerebrospinal fluid interface (Schwartz et al., 1991, Karlstedt et al., 2001).

Histamine in the brain plays a role in central regulations responding to stressful stimuli; it functions as an inhibitory bioprotective system against various noxious and unfavourable stimuli (Yanai and Watanabe, 2004). However, contradictory results have been reported regarding the effects and the possible mechanism of action of stress-induced antinociception on brain histamine in rats and mice (Schwartz et al., 1991, Brown et al., 2001). Therefore, in the present study, c-fos activation was investigated in brain areas of mice following formalin-induced acute pain. The transcription of c-fos gene is induced rapidly and transiently: c-fos mRNA is expressed few minutes after the stimulus. Under experimental conditions, the immunohistochemical demonstration of c-fos or Fos is an excellent morphological tool to visualize acutely activated neuronal, ependymal and glial cells following proper stimuli (Morgan and Curran, 1989, Herdegen and Leah, 1998, Pacak and Palkovits, 2001).

Histamine deficient mice (HDC-KO) have been generated by targeted mutation of the gene of HDC, responsible for the synthesis of histamine in mammals (Ohtsu et al., 2001). When kept on histamine-free diet HDC-KO mice have no histamine in their tissues, therefore, they provide a new model to investigate the effects of histamine. Results of experiments with HDC-KO animals confirmed the classical functions of histamine. The allergic and peripheral inflammatory reactions are reduced. In the gastrointestinal tract gastric acid secretion is decreased and hypergastrinemia is developed. Unexpected new roles for histamine have also been elucidated. HDC-KO animals show higher bone density, decreased reproductive activity, hyperleptinemia and visceral adiposity. Changes in neuronal functions include hypoactivity, increased anxiety, altered memory functions and sleep pattern, and somnolency (Watanabe and Falus, 2004).

Reportedly, histamine KO mice are less sensitive to nociceptive stimuli (Yanai and Watanabe, 2004). Therefore, we investigated the action of formalin-induced acute pain on HDC-KO mice. Surprisingly, very strong c-fos activation was found in specific areas and cell types of the ependyma, the circumventricular organs and in the choroid plexus of histamine deficient mice after formalin injections indicating a possible, until unrecognized role of histamine in the brain-cerebrospinal fluid interaction.

Section snippets

Animals

Eight to 12 week old wild type (HDC+/+) and HDC deficient (HDC−/−) mice (n = 29), bred and maintained separately, and kept on a histamine-deficient diet were used. The animals were fasted for 24 h before each experiment during which only tap water ad libitum was provided. The study was conducted in accordance with the guidelines set by the European Communities Council Directive (86/609 EEC) and Hungarian Government directive 243/98 and approved by the Institutional Animal Care and Use Committee of

Results

Based on common histological stainings like luxol fast blue/cresyl violet, haematoxylin-eosin or Nissl, no visible differences in the general cytology of brain structures were observed in HDC+/+ versus HDC−/− mice. In contrast, signs of hyperplasia of ependymal cells of different part of the ventricle system were seen in HDC−/− mice. Hypertrophized, double-layered ependyma occurred especially in the mid-hypothalamic portion of the third ventricle, in the ventral parts of the cerebral aqueduct

Discussion

Histamine has been recognized as a neurotransmitter in the brain with multiple neuromodulatory roles. It functions in a great variety of central regulatory mechanisms, and it acts on the blood–brain barrier (Brown et al., 2001). However, we do not know the action of histamine on the activity of tanycytes and circumventricular organs indicating a possible role of histamine or histamine receptors on the modulation of brain-CSF interface.

The blood–brain barrier is present throughout the central

Acknowledgements

The authors thank Judit Helfferich for skilful technical assistance. The skilful secretarial assistance of Magdolna Kasztner is gratefully acknowledged. This work was supported by grants from the Hungarian Science Research Foundation, OTKA T 049861 (M.P.), T043169 (ZE.T.) and T31887 (A.F.) (E.B.), and from the Hungarian Ministry of Health ETT 589/2006 (M.D.).

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