close

Вход

Забыли?

вход по аккаунту

?

00207454.2017.1389926

код для вставкиСкачать
International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
α2-adrenoceptor-ir neurons density changes
after single dose of clonidine and yohimbine
administration in the hippocampus of male rat
M. Jahanshahi, E. Nikmahzar, L. Elyasi, F. Babakordi & E. Hooshmand
To cite this article: M. Jahanshahi, E. Nikmahzar, L. Elyasi, F. Babakordi & E. Hooshmand
(2017): α2-adrenoceptor-ir neurons density changes after single dose of clonidine and yohimbine
administration in the hippocampus of male rat, International Journal of Neuroscience, DOI:
10.1080/00207454.2017.1389926
To link to this article: http://dx.doi.org/10.1080/00207454.2017.1389926
Accepted author version posted online: 24
Oct 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ines20
Download by: [Linköping University Library]
Date: 26 October 2017, At: 19:17
Publisher: Taylor & Francis
Journal: International Journal of Neuroscience
DOI: https://doi.org/10.1080/00207454.2017.1389926
Title: α2-adrenoceptor-ir neurons density changes after single dose of clonidine
and yohimbine administration in the hippocampus of male rat
Authors: *Jahanshahi M.1, Nikmahzar E. 2, Elyasi L. 1, Babakordi F. 2 , Hooshmand E. 2
Downloaded by [Linköping University Library] at 19:17 26 October 2017
1
Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of
Medical Sciences, Gorgan, Iran
2
Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
Running title: clonidine, yohimbine and α2-adrenoceptor-ir neurons density
Email addresses:
Mehrdad Jahanshahi: mejahanshahi@yahoo.com
Emsehgol Nikmahzar: nikmahzar@yahoo.com
Leila Elyasi: elyasy_leila@yahoo.com
Fatemeh Babakordi: babakordi_78@yahoo.com
Eisa Hooshmand: eisahooshmand@gmail.com
*Corresponding author: Dr. Mehrdad Jahanshahi
Department of Anatomy, Neuroscience Research Center, Faculty of Medicine, Gorgan University of Medical
Sciences, km 4 Gorgan-Sari Road (Shastcolah), Gorgan, Iran.
E-mail: mejahanshahi@yahoo.com
Tel/Fax: +98 17 32420515
Abstract
Objective: Despite the important role of α2-adrenoceptors in pain modulation processes, the impact
of administration of α2-adrenoceptor agonist and antagonist on density of hippocampal α2-adrenoceptorimmunoreative neurons has not been investigated. Therefore, we aimed to determine
the effect of single doses of clonidine and yohimbine on the density of α2-adrenoceptorimmunoreactive
neurons in rat hippocampus.
Materials and Methods: Adult male Wistar rats received a single dose of clonidine (0.7 mg/kg)
alone or 5 minutes after intraperitoneal (1 mg/kg) and/or intracerebroventricular (5 µg/kg) injection
of yohimbine. After histological processing, neurons with α2-adrenoceptor immunoreactivity were
identified and counted through immunohistochemical analysis of hippocampal regions.
Results: Clonidine slightly increased the number of α2-adrenoceptor-immunoreactive neurons in
Downloaded by [Linköping University Library] at 19:17 26 October 2017
the hippocampal subregions compared with the normal saline group. Intraperitoneal injection of
yohimbine followed by injection of clonidine significantly increased the number of α2-adrenoceptorimmunoreactive neurons in subregions CA1 and CA3. Intracerebroventricular injection of yohimbine after
injection of clonidine significantly reduced the number of α2-adrenoceptor-immunoreactive neurons in all
hippocampal subregions.
Conclusion: The present study demonstrates that intraperitoneal administration of α2-adrenoceptor
agonist clonidine increases the density of α2-adrenoceptor-immunoreactive neurons in rat hippocampus,
while intracerebroventricular injection of yohimbine decreases the density of these
neurons.
Keywords: Clonidine, Yohimbine, α2-Adrenoceptor, Hippocampus
Introduction
In most vertebrates, the central nervous system (CNS) is equipped with various pain modulatory mechanisms
such as opioidergic, noradrenergic and serotonergic systems [1]. Adrenergic receptors are a group of G
protein-coupled receptors that are sensitized by catecholamines [2]. There are two main classes of adrenergic
Downloaded by [Linköping University Library] at 19:17 26 October 2017
receptors (α and β), and each class has a number of subtypes (α1, α2, β1, β2, and β3) [3]. According to
previous studies, α-adrenoceptors are involved in pain processing of peripheral and central pain modulatory
systems [4]. These receptors have a wide distribution in the peripheral nervous system (PNS) and CNS [5],
and could be post- or pre-synaptic [1]. Based on molecular cloning and pharmacological evaluations, α2adrenoceptors are categorized into α2A, α2B, and α2C [6]. Subtypes α2A and α2C are mostly expressed in the
cerebral cortex, hippocampus, nuclei of thalamus and cerebellum. On the other hand, α2C is expressed in the
basal ganglia, while α2B is released selectively in the thalamus [7]. These subtypes can couple with a diverse
range of G-proteins, resulting in distinct effects on the tissues in which they are expressed [8]. Various
subtypes may be involved in activation of different physiological and pharmacological pathways, and could
act as potential targets of recently developed selective agents [9]. Intracellular activity of adenylyl cyclase is
reduced by α2-adrenoceptors, while the activity of ion channels (e.g., Na+/H+ antiporters) is directly altered
by these receptors [10].
α2-adrenoceptor agonists provide dose-dependent sedation, analgesia, and muscle relaxation. Before inducing
general anesthesia, α2-adrenoceptor agonists are commonly applied for sedation in veterinary medicine. They
can also decrease the concentration of agents used for induction and maintenance of anesthesia [11].
Considering the activity of α2-adrenergic agonists in the CNS and PNS, evaluation of their role in pain
modulation could be beneficial [1]. Clonidine is an α2-adrenoceptor agonist that has been used in medicine
for more than four decades [12]. Clonidine-induced analgesia is mediated through α2-adrenoceptors [13].
Several studies have identified the activities of clonidine that could subsequently change the adrenergic
component of pain perception. In addition, clonidine seems to be involved in modification of neurohumoral
response to tissue damage. Therefore, it can be of use for managing pain-related problems, and provide a
solution for inhibition of pain progression to chronic phase [14]. Yohimbine is a relatively selective α2adrenoceptor antagonist that has been commonly used to evaluate the contribution of α2-adrenergic receptors
to drug activities [15].
The hippocampus is an essential part of the limbic system and a major target of neuroscience research [16]. It
is thought that hippocampal formation has an important role in pain information processing, including
anatomical features, behavioral experiments, electrophysiology, functional imaging, and other molecular
research [17]. It has been suggested that humans with chronic or severe pain have smaller hippocampal
volume compared to healthy individuals [18]. The hippocampus of an adult rat includes extensive
noradrenergic neuronal somata, axons and dendrites. In addition, CA1 and dentate gyrus (DG) are involved
in modulation of nociceptive pain [16]. Peripheral neuropathy changes gene expression in the hippocampus,
indicating the role of hippocampus in neuropathic pain and symptoms [19]. Further research should be
performed on hippocampal mechanisms involved in pain development, dissipation and management [20].
Considering the critical role of hippocampus and α2-adrenoceptors in pain modulation, the present study
aimed to determine the effect of single doses of clonidine and yohimbine on density of α2-adrenoceptor-
Downloaded by [Linköping University Library] at 19:17 26 October 2017
immunoreactive (ir) neurons in rat hippocampus.
Materials and Methods
Animals
Adult male Wistar rats (250-300 g) were purchased from Pasteur Institute (Tehran, Iran). The animals were
kept in separate cages at 22±2 ºC on a light-dark cycle (12:12 hours) with ad libitum access to food and
water. The experiments were performed between 8:00 am and 2:00 pm (light hours). The procedures were
performed in accordance with the guidelines of National Institutes of Health for care and use of laboratory
animals (NIH Publications No. 8023, revised 1978). The study was approved by the Ethical Committee of
Golestan University of Medical Sciences, Iran.
Intracerebroventricular (ICV) cannula surgery
The rats were anesthetized following intraperitoneal (IP) injection of ketamine-xylazine mixture. The
animals were placed in a stereotaxic instrument (David Kopf Instruments, USA), in a flat skull position. A
cannula (22-gauge) was implanted in the right lateral ventricle under sterilized conditions, according to the
Paxinos and Watson rat brain atlas [21] (coordinates relative to bregma; anterior/posterior -0.84 mm,
medial/lateral + 1.5 mm, and dorsal/ventral -4 mm). The unilateral guide cannula was anchored to jeweler
screws using dental acrylic. Before the injection of drug into the rats, a stainless steel stylet (27-gauge) was
placed in the cannula to prevent clogging. The rats were given at least one week to recover from the surgery.
ICV injections
The rats were restrained by hand for unilateral injection of drugs. The stainless stylet was detached from the
cannula and replaced with an injection needle (27-gauge), which was attached to a Hamilton microsyringe
(10 μL) with a polyethylene tube. The needle was inserted 1 mm beneath the cannula’s tip. The solutions
were injected (total volume, 5 μL per rat) into the right lateral ventricle within one minute. The needle was
kept in place for one more minute to facilitate diffusion [22].
Experimental design
Animals were randomly divided into five groups, each consisting of eight rats. Control groups 1 and 2
received an IP injection of saline (1 ml/kg) and ICV microinjection of dimethyl sulfoxide (5μl, Merck,
Germany), respectively. In group 3 (clonidine: C, IP), the animals received a single IP dose of clonidine (0.7
Downloaded by [Linköping University Library] at 19:17 26 October 2017
mg/kg), the α2-adrenoceptor agonist. In group 4 (Yohimbine: Y, IP + C, IP), the animals first received a
single dose of yohimbine (1 mg/kg, IP), and then received a single dose of clonidine (0.7 mg/kg, IP) after 5
minutes. In group 5 (Y, ICV + C, IP), the animals received ICV injection of yohimbine (5 μg/kg) 5 minutes
before injection of clonidine (0.7 mg/kg, IP).
Tissue preparation for immunohistochemistry
Forty-eight hours after the last injection, chloroform was used for induction of deep anesthesia. Later, 0.9%
saline and 4% paraformaldehyde (Merck, Germany) were used for transcardial perfusion. Brains were
removed and fixed in 4% paraformaldehyde for seven days. Histological processing was done using an
automated tissue processor (Did Sabz, Iran). Brain tissue was embedded in paraffin wax. Then, 6-μm-thick
serial sagittal sections of each brain were cut on a rotary microtome (Pooyan MK 1110, Iran) from the
hippocampal formation at the coordinates lateral 1.40 mm to 3.90 mm [21]. The brain sections were selected
in a 24 μm interval between every two consecutive sections.
Immunohistochemistry
Rabbit
polyclonal
anti-α2-adrenoceptor
antibody
(1:150,
Abcam
Inc.,
USA)
was
used
for
immunohistochemical staining according to our previous study [22] with slight modifications. First, the brain
sections were incubated at 37 °C for 15 minutes. Then, the sections were deparaffinized with xylene and
hydrated using a graded ethanol series. The brain sections were covered with epitope retrieval solution
(Tashkis Baft Aragene, Iran) at 90 °C for 15 minutes. After placing the slides at room temperature for 20
minutes, the brain sections were washed twice with rinsing buffer (phosphate buffered saline -Tween 20 in
0.1% Triton X100). Endogenous peroxidase was blocked with 0.35% H2O2 in phosphate buffered saline for
10 minutes at room temperature, and washed twice with the rinsing buffer. Avidin/biotin solution was
applied to block the brain sections (Dako, Denmark) at room temperature for 20 minutes, and washed twice
with rinsing buffer. Nonspecific reactivity was blocked by adding bovine serum albumin (1%) at 37 °C for 1
hour. After incubating the primary antibody for 60 minutes at 37 °C, the brain sections were washed twice
with rinsing buffer. Incubation was performed in biotinylated secondary antibody (goat anti-rabbit IgG;
Abcam Inc., USA) for 60 minutes at 37 °C. The brain sections were washed with rinsing buffer after the
secondary antibody incubation. The brain sections were then incubated with streptavidin (HRP, 1:5000;
Abcam Inc., USA) for 60 minutes at room temperature. After washing with rinsing buffer, the brain sections
were stained and counterstained with diaminobenzidine (Dako, Denmark) and Mayer’s hematoxylin solution,
respectively. Ethanol was used to dehydrate the brain sections, and xylene was used to clear them. Each
section was placed on glass slides and coverslipped using Entellan (Merck, Germany).
Downloaded by [Linköping University Library] at 19:17 26 October 2017
Image processing and cell counting
A light microscope (BX51, Olympus, Japan) equipped with a digital camera (DP72, Olympus, Japan) was
used to acquire images from the sagittal brain sections (100× magnification for DG and 40× magnification
for CA1 and CA3). The α2-adrenoceptor-ir neurons were counted in a 30000 μm2 field for the CA1 and CA3
areas and in a 4800 μm2 field for the DG area [22] using ImageJ software. Imaging and counting were
performed blind to treatment.
Statistical analysis
SPSS version 16 (Armonk, NY, USA) was used for data analysis. The data were expressed as mean ±
standard deviation (SD). The data were examined using one-way analysis of variance and post hoc least
significant difference test. The significance level for all statistical analyses was set at 0.05.
Results
Based on the findings, α2-adrenoceptor was expressed in DG granular neurons as well as in CA1 and CA3
pyramidal neurons (Figure 1). The single dose of clonidine slightly increased the number of α2-adrenoceptorir neurons in the CA1, CA3, and DG hippocampal subregions compared to control-saline rats (Figures 2, 3
and 4). In the CA1 and CA3 subregions, injection of clonidine after IP injection of yohimbine significantly
increased the density of α2-adrenoceptor-ir neurons compared to clonidine-treated rats (P < 0.001, Figures 2
and 3). This indicates that the impact of IP injection of yohimbine on the density of α2-adrenoceptor-ir
neurons could be completely antagonized by IP injection of clonidine (Figures 2, 3 and 4). However, there
was no significant difference in the α2-adrenoceptor-ir neuron density in the DG area of rats in the controlsaline, clonidine (IP) and yohimbine (IP) + clonidine (IP) groups (Figure 4).
The density of α2-adrenoceptor-ir neurons in CA1, CA3 and DG subregions of the hippocampus decreased
significantly following the ICV injection of yohimbine prior to clonidine injection (P < 0.001, Figures 2, 3
and 4). However, the IP injection of clonidine after ICV injection of yohimbine could not inhibit the
yohimbine-induced decrease in density of this receptor in all areas of the hippocampus.
Discussion
In this study, we aimed to determine the effect of single doses of clonidine and yohimbine on density of α2adrenoceptor-ir neurons in different subregions of rat hippocampus. According to the results, the single dose
of clonidine slightly increased the number of α2-adrenoceptor-ir neurons in the hippocampus. Clonidine
Downloaded by [Linköping University Library] at 19:17 26 October 2017
treatment after IP injection of yohimbine increased the number of α2-adrenoceptor-ir neurons in CA1 and
CA3 subregions. However, administration of clonidine could not inhibit the effect of ICV injection of
yohimbine on the density of hippocampal α2-adrenoceptor-ir neurons.
It is well known that intrathecal or epidural administration of α2-adrenoceptor agonists such as clonidine
produces antinociception and analgesia, and reduces the need for other agents [23-26]. Study of Yoon et al.
showed that α2A-adrenoceptor activation in trigeminal innervated areas could result in anti-nociceptive
activity of clonidine [27]. In addition, clonidine enhances analgesic effects through simultaneous alteration
of excitatory and inhibitory receptors in afferent neurons after peripheral nerve damage [28, 29]. The number
of α2A-adrenoceptors increases noticeably in the spinal cord of sheep, which is involved in nociceptive
activities [30]. Moreover, α2-adrenoceptor G-protein coupling in the spinal cord is enhanced by spinal nerve
ligation-induced neuropathy, indicating the high potential of clonidine in the management of neuropathic
pain [31]. A previous study on formalin-induced pain in rats showed that clonidine induces analgesia, while
yohimbine inhibits the analgesic effect of clonidine [32]. Although these findings suggest that clonidineinduced analgesia is mediated through α2-adrenoceptors [13, 33], it complicates the interpretation of the
effects of altered α2-adrenoceptor levels on physiological functions. Our findings demonstrated that IP
injection of clonidine after IP injection of yohimbine increases the density of hippocampal α2-adrenoceptor-ir
neurons, an effect not observed after the ICV injection of yohimbine. The exact mechanism by which
clonidine and yohimbine change the hippocampal α2-adrenoceptor-ir neuron density could be the subject of
future studies.
Expression of α2-adrenoceptors and or binding affinity of receptors are changed in different pain models. For
example, Leiphart et al. reported that the expression of spinal α2A- and α2C-adrenoceptors decreases in
chronic constriction injury nerve ligation model of neuropathic pain. They also suggested that this
underexpression might be related to tonic-descending noradrenergic inputs or elimination of inhibitory
interneurons [34]. On contrary, binding of α2-adrenoceptors enhanced in a study where sciatic nerve
transection was performed to present a rat model of neuropathic pain [35]. The discrepancy between these
results could be attributed to varying pathophysiological mechanisms of sciatic nerve transection in
comparison with the neuropathic pain model [34].
It is well documented that α2-adrenoceptor activation is involved in the modulation of antinociceptive
properties. Moreover, α2-adrenoceptors are paired with Gi proteins, and decrease adenylyl cyclase activity,
cAMP production and protein kinase A activity at the same time. This mechanism might be involved in the
antinociceptive activities of clonidine [27]. Wang et al. reported that interference with calcium/calmodulindependent protein kinase II signaling might be the underlying mechanism for noradrenergic suppression of
inflammatory pain [36].
In the present study, we have shown that the density of hippocampal α2-adrenoceptor-ir neurons changes
after single doses of clonidine and yohimbine injection. However, several studies have demonstrated that α2adrenoceptor density is closely associated with neuropathologic disorders including Alzheimer's disease,
Parkinson's disease and diabetes [2, 37]. For instance, in Alzheimer's disease, the density of α2-adrenoceptors
Downloaded by [Linköping University Library] at 19:17 26 October 2017
significantly reduces in the hippocampus, and prefrontal and frontal cortices [38, 39]. Several studies have
shown that α2-adrenoceptors in the CNS are involved in the modulation of memory process. For instance,
Jafari-Sabet et al. found that α2-adrenoceptors of the dorsal hippocampal area may play an important role in
muscimol state-dependent memory [40]. Galeotti et al. also indicated that the activation of the α2Aadrenoceptor is necessary for induction of amnesia by clonidine and guanabenz in the mouse passive
avoidance test. However, the lack of involvement of α2B and α2C subtypes has been observed [41]. It has
been reported that clonidine could ameliorate cognitive deficits and neuronal impairment induced by chronic
cerebral hypoperfusion via upregulation of γ-aminobutyric acid-B receptor 1 and glutamic acid
decarboxylase 67 in hippocampal CA1 area [42]. However, no study has yet investigated the relationship of
α2-adrenoceptor density with memory in the rat brain tissue. A study reported a decrease in the α2adrenoceptors density [43] and sensitivity [44] in Parkinson's disease. Omiya et al. reported that increased
density of α2-adrenoceptors in the spinal cord is related to the enhanced antinociceptive potential in diabetic
mice [37]. Studies on receptor binding of the brain revealed enhanced α2-adrenoceptor binding and increased
expression of receptor mRNA in suicide victims [45, 46], and increased receptor agonist binding in
depressed patients, particularly in the hippocampus, cerebral cortex [47] and the pontine regions [48].
However, recent studies on rat model of depression have reported decreased binding of α2-adrenoceptors [49,
50].
Conclusion
The present study demonstrates that IP injection of clonidine, α2-adrenoceptor agonist, can increase the
density of α2-adrenoceptor-ir neurons in rat hippocampus, while ICV injection of yohimbine decreases the
density of these neurons.
Acknowledgments
we would like to express our gratitude to the Neuroscience Research Center for performing the histological
evaluations. This study has been supported by a grant from the Department of Research and Technology,
Golestan University of Medical Sciences, Iran.
- Dr. Mehrdad Jahanshahi is a professor of Anatomy Department of Medical Anatomy, Golestan University
of Medical Sciences, Gorgan, Iran. He teaches anatomy, histology and neuroanatomy, and his research fields
include neurosciences, Alzheimer disease.
- Nikmahzar E. is a MSc of animal biology and laboratory assistant in Neuroscience Research Center,
Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
Downloaded by [Linköping University Library] at 19:17 26 October 2017
- Dr. Leila Elyasi is an assistant professor of Anatomy Department of Medical Anatomy, Golestan University
of Medical Sciences, Gorgan, Iran. She teaches anatomy and embryology, and her research fields include
neurosciences, Parkinson and Alzheimer disease, and anthropology.
- Houshmand E. is a MSc of medical physiology and researcher in Neuroscience Research Center, Faculty of
Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
- Babakordi F. is a MSc of animal biology and researcher in Neuroscience Research Center, Faculty of
Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
Disclosure of conflict of interest
The authors declare that there is no conflict of interest.
References
[1] Makau CM, Towett PK, Abelson KS, et al. Intrathecal administration of clonidine or yohimbine decreases
the nociceptive behavior caused by formalin injection in the marsh terrapin (Pelomedusa subrufa). Brain
Behav. 2014;4(6):850-7.
2.
Xu Y, Yan J, Zhou P, et al. Neurotransmitter receptors and cognitive dysfunction in Alzheimer's
disease and Parkinson's disease. Prog Neurobiol. 2012;97(1):1-13.
3.
Norozpour Y, Nasehi M, Sabouri-Khanghah V, et al. The effect of CA1 α2 adrenergic receptors on
memory retention deficit induced by total sleep deprivation and the reversal of circadian rhythm in a rat
model. Neurobiol Learn Mem. 2016;133:53-60.
4.
Vučković SM, Tomić MA, Stepanović-Petrović RM, et al. The effects of α2-adrenoceptor agents on
anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain. Pain.
2006;125(1–2):10-9.
5.
Fairbanks CA, Stone LS, Wilcox GL. Pharmacological profiles of alpha 2 adrenergic receptor agonists
identified using genetically altered mice and isobolographic analysis. Pharmacol Ther. 2009;123(2):224-38.
6.
Lemmens S, Brône B, Dooley D, et al. Alpha‐Adrenoceptor Modulation in Central Nervous System
Trauma: Pain, Spasms, and Paralysis–An Unlucky Triad. Med Res Rev. 2015;35(4):653-77.
7.
Scheinin M, Lomasney JW, Hayden-Hixson DM, et al. Distribution of α 2-adrenergic receptor
subtype gene expression in rat brain. Mol Brain Res. 1994;21(1):133-49.
8.
Grenier P. Attenuation of morphine tolerance, reward, and spinal gliosis in neuropathic pain by
ultra-low dose alpha2-adrenergic antagonists. Canada: Queen’s University; 2016.
Downloaded by [Linköping University Library] at 19:17 26 October 2017
9.
Gyires K, Zádori ZS, Török T, et al. α 2-Adrenoceptor subtypes-mediated physiological,
pharmacological actions. Neurochem Int. 2009;55(7):447-53.
10.
Pertovaara A. The noradrenergic pain regulation system: A potential target for pain therapy. Eur J
Pharmacol. 2013;716(1–3):2-7.
11.
Seddighi R. α-2 Adrenoceptor Agonists. In: Egger CM, Love L, Doherty T, editors. Pain Management
in Veterinary Practice. Chichester, UK: John Wiley & Sons, Ltd; 2013. p. 93-103.
12.
Wrzosek A, Woron J, Dobrogowski J, et al. Topical clonidine for neuropathic pain. Cochrane
Database Syst Rev. 2015;8:CD010967.
13.
Bhalla S, Ali I, Andurkar SV, et al. Centhaquin antinociception in mice is mediated by α 2A-and α 2Bbut not α 2C-adrenoceptors. Eur J Pharmacol. 2013;715(1):328-36.
14.
Neil MJ. Clonidine: clinical pharmacology and therapeutic use in pain management. Curr Clin
Pharmacol. 2011;6(4):280-7.
15.
Makau CM, Towett PK, Abelson KSP, et al. Modulation of formalin‐induced pain‐related behaviour
by clonidine and yohimbine in the Speke's hinged tortoise (Kiniskys spekii). J Vet Pharmacol Ther. 2016.
16.
Jin H, Teng Y, Zhang X, et al. Noradrenergic mechanism involved in the nociceptive modulation of
hippocampal CA3 region of normal rats. Neurosci Lett. 2014;574:31-5.
17.
Fasick V, Spengler RN, Samankan S, et al. The hippocampus and TNF: common links between
chronic pain and depression. Neurosci Biobehav Rev. 2015;53:139-59.
18.
Wang JY, Chen R, Chen SP, et al. Electroacupuncture Reduces the Effects of Acute Noxious
Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and
Neuropathic Pain Rats. Neural Plast. 2016;2016:1-11.
19.
Norman GJ, Karelina K, Zhang N, et al. Stress and IL-1β contribute to the development of
depressive-like behavior following peripheral nerve injury. Mol Psychiatry. 2010;15(4):404-14.
20.
Sud R, Spengler RN, Nader ND, et al. Antinociception occurs with a reversal in α2-adrenoceptor
regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory. Eur J
Pharmacol. 2008;588(2–3):217-31.
21.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates.: San Diego: Academic Press; 2007.
22.
Moghadami S, Jahanshahi M, Sepehri H, et al. Gonadectomy reduces the density of androgen
receptor-immunoreactive neurons in male rat’s hippocampus: testosterone replacement compensates it.
Behav Brain Funct. 2016;12(1):5.
23.
Spengler RN, Sud R, Knight PR, et al. Antinociception mediated by α2-adrenergic activation involves
increasing tumor necrosis factor α (TNFα) expression and restoring TNFα and α2-adrenergic inhibition of
norepinephrine release. Neuropharmacology. 2007;52(2):576-89.
24.
Maze M, Fujinaga M. α2Adrenoceptors in Pain Modulation: Which Subtype Should Be Targeted to
Produce Analgesia? Anesthesiology. 2000;92(4):934-6.
Downloaded by [Linköping University Library] at 19:17 26 October 2017
25.
Bischoff P, Schmidt G, Scharein E, et al. Clonidine induced sedation and analgesia. J Neurol.
2004;251(2):219-21.
26.
Yu HP, Hseu SS, Yien HW, et al. Oral clonidine premedication preserves heart rate variability for
patients undergoing larparoscopic cholecystectomy. Acta Anaesthesiol Scand. 2003;47(2):185-90.
27.
Yoon SY, Kang SY, Kim HW, et al. Clonidine Reduces Nociceptive Responses in Mouse Orofacial
Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor
Coordination. Biological and Pharmaceutical Bulletin. 2015;38(9):1320-7.
28.
Romero-Sandoval A, Eisenach JC. Perineural clonidine reduces mechanical hypersensitivity and
cytokine production in established nerve injury. Anesthesiology. 2006;104(2):351-5.
29.
Ma W, Zhang Y, Bantel C, et al. Medium and large injured dorsal root ganglion cells increase TRPV1, accompanied by increased α2C-adrenoceptor co-expression and functional inhibition by clonidine. Pain.
2005;113(3):386-94.
30.
Brandt SA, Livingston A. Receptor changes in the spinal cord of sheep associated with exposure to
chronic pain. Pain. 1990;42(3):323-9.
31.
Bantel C, Eisenach JC, Duflo F, et al. Spinal nerve ligation increases α 2-adrenergic receptor Gprotein coupling in the spinal cord. Brain Res. 2005;1038(1):76-82.
32.
Houshmand E, Jahanshahi M, Attarzadeh-Yazd G. The role of BK potassium channels in analgesia
produced by alpha-2 adrenergic receptors. J Babol Univ Med Sci. 2016;18(2):32-40.
33.
Zhang F, Feng X, Dong R, et al. Effects of clonidine on bilateral pain behaviors and inflammatory
response in rats under the state of neuropathic pain. Neurosci Lett. 2011;505(3):254-9.
34.
Leiphart JW, Dills CV, Levy RM. Decreased spinal alpha2a- and alpha2c-adrenergic receptor subtype
mRNA in a rat model of neuropathic pain. Neurosci Lett. 2003;349(1):5-8.
35.
McMahon SB. Mechanisms of sympathetic pain. Br Med Bull. 1991;47(3):584-600.
36.
Wang XT, Lian X, Xu YM, et al. α 2 noradrenergic receptor suppressed CaMKII signaling in spinal
dorsal horn of mice with inflammatory pain. Eur J Pharmacol. 2014;724:16-23.
37.
Omiya Y, Yuzurihara M, Suzuki Y, et al. Role of α2-adrenoceptors in enhancement of antinociceptive
effect in diabetic mice. Eur J Pharmacol. 2008;592(1–3):62-6.
38.
Kalaria RN, Andorn AC. Adrenergic receptors in aging and Alzheimer's disease: Decreased α 2receptors demonstrated by [3H] p-aminoclonidine binding in prefrontal cortex. Neurobiol Aging.
1991;12(2):131-6.
39.
Pascual J, Grijalba B, García-Sevilla JA, et al. Loss of high-affinity α 2-adrenoceptors in Alzheimer's
disease: an autoradiographic study in frontal cortex and hippocampus. Neurosci Lett. 1992;142(1):36-40.
40.
Jafari-Sabet M, Banafshe HR, Khodadadnejad M-A. Modulation of muscimol state-dependent
memory by α 2-adrenoceptors of the dorsal hippocampal area. Eur J Pharmacol. 2013;710(1):92-9.
Downloaded by [Linköping University Library] at 19:17 26 October 2017
41.
Galeotti N, Bartolini A, Ghelardini C. Alpha-2 agonist-induced memory impairment is mediated by
the alpha-2A-adrenoceptor subtype. Behav Brain Res. 2004;153(2):409-17.
42.
Lu Y, Li C, Zhou M, et al. Clonidine ameliorates cognitive impairment induced by chronic cerebral
hypoperfusion via up-regulation of the GABA B R1 and GAD67 in hippocampal CA1 in rats. Pharmacol
Biochem Behav. 2015;132:96-102.
43.
Cash R, Ruberg M, Raisman R, et al. Adrenergic receptors in Parkinson's disease. Brain Res.
1984;322(2):269-75.
44.
Berlan M, Rascol O, Belin J, et al. [alpha] 2-Adrenergic Sensitivity in Parkinson's Disease. Clin
Neuropharmacol. 1989;12(2):138-44.
45.
Escribá PV, Ozaita A, García-Sevilla JA. Increased mRNA Expression of [alpha] 2A-Adrenoceptors,
Serotonin Receptors and [mu]-Opioid Receptors in the Brains of Suicide Victims.
Neuropsychopharmacology. 2004;29(8):1512-21.
46.
Gonzalez-Maeso J, Rodriguez-Puertas R, Meana J, et al. Neurotransmitter receptor-mediated
activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of
[alpha] 2A-adrenoceptors. Mol Psychiatry. 2002;7(7):755-67.
47.
González AM, Pascual J, Meana JJ, et al. Autoradiographic Demonstration of Increased
α2‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide
Victims. J Neurochem. 1994;63(1):256-65.
48.
Ordway GA, Schenk J, Stockmeier CA, et al. Elevated agonist binding to α 2-adrenoceptors in the
locus coeruleus in major depression. Biological Psychiatry. 2003;53(4):315-23.
49.
Landau AM, Phan JA, Iversen P, et al. Decreased in vivo α2 adrenoceptor binding in the Flinders
Sensitive Line rat model of depression. Neuropharmacology. 2015;91:97-102.
50.
Lillethorup TP, Iversen P, Fontain J, et al. Electroconvulsive shocks decrease α 2-adrenoceptor
binding in the Flinders rat model of depression. Eur Neuropsychopharmacol. 2015;25(3):404-12.
Legends of Figures:
Figure 1: Photomicrographs of α2-adrenoceptor-ir neurons in rat hippocampus after immunohistochemical
staining (brown). A: Control-saline IP group, B: clonidine, IP group, C: yohimbine, IP + clonidine, IP group, D:
Control-DMSO, ICV group E: yohimbine, ICV+ clonidine, IP group. Scale bars=50 μm (for CA1 and CA3 areas)
Downloaded by [Linköping University Library] at 19:17 26 October 2017
and
20
μm
(for
DG
area).
Downloaded by [Linköping University Library] at 19:17 26 October 2017
Figure 2: Density of α2-adrenoceptor-ir neurons in the hippocampal CA1 subregion. Values represent mean
(**P<0.01 and ***P<0.001).
Figure 3: Density of α2-adrenoceptor-ir neurons in the CA3 subregion of rat hippocampus. Values represent
mean (***P<0.001).
Downloaded by [Linköping University Library] at 19:17 26 October 2017
Figure 4: Density of α2-adrenoceptor-ir neurons in the rat hippocampal DG subregion. Values represent
mean (***P<0.001).
Downloaded by [Linköping University Library] at 19:17 26 October 2017
Документ
Категория
Без категории
Просмотров
0
Размер файла
1 496 Кб
Теги
2017, 00207454, 1389926
1/--страниц
Пожаловаться на содержимое документа