Book of abstracts - British Neuroscience Association

60.03
Characterization of the effect of selective cyclooxygenase-2
inhibition in experimental cerebral hypoperfusion in rats
Farkas E, Institoris A, Sule Z, Bari F
Department of Anatomy, School of Medicine, University of Szeged,
Szeged, Hungary, Department of Physiology, School of Medicine,
University of Szeged, Szeged, Hungary, Pharmacy, University of
Bradford, Bradford, United Kingdom,
An experimental model to create cerebral hypoperfusion as it occurs in
aging and Alzheimer’s disease is the permanent, bilateral occlusion of
the common carotid arteries of rats (2VO). Ishemic brain injury
involves the upregulation of the cyclooxygenase-2 (COX-2) having
deleterious effects on the ischemic site. We have set out to identify the
role of COX-2 in the 2VO-induced hippocampus damage.
2VO was imposed on male Wistar rats (n=24), while controls were
sham-operated (SHAM, n=31). After surgery, the animals received
either the selective COX-2 inhibitor NS-398 (3 x 10 mg/kg daily, i.p.),
or vehicle. Animals were sacrificed 3 days (n=29) or 2 weeks after the
onset of 2VO (n=26). In the later group, the memory capacity was
assessed in the Morris water maze 1 week after 2VO initiation.
Hippocampal slices were stained with cresyl violet to examine
neuronal damage. The density of MAP-2-positive dendrites, the
proliferation of GFAP-labeled astrocytes and the level of OX-42-
labeled microglial activation were determined immunocytochemically.
2VO induced memory impairment, dendritic degeneration, astrocytic
proliferation and microglial activation. The neurodegenerative
processes were more pronounced at 2 weeks as compared with 3
days after 2VO onset. NS-398 improved spatial learning but also
augmented granule cell damage in the dentate gyrus. COX-2 inhibition
was ineffective on dendritic degeneration, astrocytic proliferation and
microglial activation.
The data demonstrate that COX-2 inhibition leads to paradoxical
effects on the hypoperfused hippocampus. Since COX-2 gives rise to
a number of prostanoids with various physiological roles, the inhibition
of their combined actions may result in complex effects.
60.04
Stimulation or lesioning of the dopaminergic A11 cell group affects
neuronal firing in the trigeminal nucleus caudalis
Charbit A, Holland P, Goadsby P
Headache Group, UCL Institute of Neurology, Queen Square, London,
WC1N 3BG
Introduction: The A11 nucleus, located in the posterior hypothalamus,
provides the only known source of descending dopaminergic innervation for
the spinal grey matter. The study aimed to investigate the effect of A11
stimulation and lesioning on trigeminovascular nociceptive transmission in
the rat.
Methods: Male Sprague-Dawley rats were anaesthetised with propofol (20-
25mg/kg-1/hr-1). Extracellular recordings were made in the trigeminal
nucleus caudalis (TNC), in response to electrical stimulation of the middle
meningeal artery (MMA, 8-16v, 0.2-1ms, 0.5-0.8Hz). Receptive fields were
characterised by mechanical noxious and innocuous stimulation of the
ipsilateral ophthalmic dermatome. After recording baseline firing evoked by
MMA stimulation (20 sweeps) and receptive field nociceptive or innocuous
stimulation (2s), the A11 was either stimulated (5-50μA, 0.5ms, 5-100Hz; n
= 14) or lesioned (200-1000μA, 0.5ms, 20-50Hz for 2-3 minutes; n = 8) and
the effect on TNC firing determined.
Results: Stimulation of the A11 significantly inhibited MMA (F4.4,48.5 =
2.59; P < 0.05) and noxious pinch (F9.0,108.0 = 4.58; P < 0.001) evoked
firing of neurons from the TNC. This inhibition was reversed by the D2
receptor antagonist, eticlopride (3 mg/kg i.v; n = 5) (MMA: F1.3,3.8 = 1.65;
P = 0.284; Noxious pinch: F1.3,2.6 = 2.12; P = 0.266). Lesioning of the A11
significantly facilitated evoked firing of neurons from the TNC (MMA:
F2.3,13.6 = 3.62; P < 0.05; Noxious Pinch: F3.0,14.9 = 4.60; P < 0.05;
Innocuous bush: F4.0,23.8 = 2.43; P < 0.05).
Conclusion: Neurons in the A11 may through a dopaminergic mechanism
modulate trigeminovascular nociceptive traffic.
60.05
Activation of GluR5 kainate receptors inhibits neurogenic dural
vasodilation in trigeminovascular nociception animal model
Andreou A, Holland P R, Goadsby P J
Headache Group, Institute of Neurology London, UK and University of
California, San Francisco, San Francisco CA USA
Objectives: To investigate the possible involvement of pre-juctional
kainate receptors which carry the glutamate receptor subunit 5
(GluR5) in a model of neurogenic dural vasodilation (NDV).
Methods: Rats were anaesthetised with pentobarbitone (60 mg/kg)
and cannulated for measurement of blood pressure, experimental drug
administration and maintenance of anaesthesia. Techniques were
carried out under a project licence issued by the Home Office under
the UK Animals (Scientific Procedures) Act, 1986. The effects of the
specific GluR5 antagonist (S)-1-(2-Amino-2-carboxyethyl)-3-(2-
carboxybenzyl)pyrimidine-2,4-dione (UBP302; 50 mg/kg) and the
specific GluR5 agonist (S)-(-)-5 Iodowillardiine (IWA; 10 mg/kg) were
investigated on neurogenic and CGRP induced dural vasodilation,
using intravital microscopy.
Results: Administration of IWA was able to inhibit MMA dilation
caused by electrical stimulation (F3,12 = 10.6; P < 0.001). This effect
was blocked by pre-treatment with UBP 302 (F2,11 = 0.59; P = 0.59).
Administration of the GluR5 antagonist UBP 302 alone had no
significant effect on NDV. CGRP (1 mg/kg) induced dural vasodilation,
was not inhibited by the GluR5 agonist IWA (F2,9 = 3.2; P = 0.08).
Conclusions: The current study demonstrates that activation of the
GluR5 kainate receptors with the selective agonist IWA is able to
inhibit neurogenic dural vasodilation. This effect is likely to result from
inhibition of pre-junctional release of CGRP from trigeminal neurons.
60.06
Pre- and post-synaptic involvement of GluR5 kainate receptors in
trigeminovascular nociceptive processing
A Andreou, Holland P R, Goadsby P J
Headache Group, Institute of Neurology London, UK and University of
California, San Francisco, San Francisco CA USA
Objectives: To investigate the possible involvement of kainate receptors
carrying the glutamate receptor subunit GluR5 in trigeminovascular
nociceptive processing in the trigeminocervical complex (TCC).
Methods: Rats were anaesthetised with pentobarbitone (60 mg/kg) and
cannulated for blood pressure measurement and anaesthesia maintenance
(UK Animals (Scientific Procedures) Act, 1986). Wide-dynamic-range
neurons (n = 30), responding to electrical stimulation of the middle
meningeal artery (MMA) and microiontophorised L-glutamate, (2S,4R)-4-
Methylglutamic acid (SYM2081; kainate receptor agonist), (S)-(-)-5
Iodowillardiine (IWA; specific GluR5 receptor agonist ) or the α-amino-3-
hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor agonist (S)-(-)-5-
Fluorowillardiine (FWA), were studied. The effect of (S)-1-(2-amino-2-
carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione (UBP302), a
specific GluR5 receptor, antagonist was also studied..
Results: Application of UBP302 significantly inhibited cell firing responses
to IWA (P < 0.05) and at higher currents the responses to L-glutamate and
SYM2081. Cells responding to IWA, demonstrated a significant facilitation
of the MMA activation during UBP302 application at higher doses (P <
0.001), while non-noxious and noxious (corneal) receptive fields (RF) were
inhibited at lower doses. In cells tested for the presence of FWA responses,
non-noxious responses were significantly reduced (P < 0.001) by UBP302,
while 50% of the cells displayed significant inhibition of the MMA (P <
0.001) and noxious RF responses (P < 0.005).
Conclusions: The data provides evidence for the presence of GluR5
carrying kainate receptors on second order neurons, particularly in
superficial laminae of the TCC. The significant facilitation observed with
MMA stimulation responses at high doses of UBP302, suggests the
possible involvement of pre-synaptic GluR5 kainate receptors in
trigeminovascular nociceptive processing.
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