Antimigraine drug, zolmitriptan, inhibits high-voltage activated calcium currents in a population of acutely dissociated rat trigeminal sensory neurons

Morikawa Tomoko, Matsuzawa Yoshiyasu, Makita Koshi, Katayama, Katayama Yoshifumi

Description

Triptans, 5-HT 1B/ID agonists, act on peripheral and/or central terminals of trigeminal ganglion neurons (TGNs) and inhibit the release of neurotransmitters to second-order neurons, which is considered as one of key mechanisms for pain relief by triptans as antimigraine drugs. Although high-voltage activated (HVA) Ca 2+ channels contribute to the release of neurotransmitters from TGNs, electrical actions of triptans on the HVA Ca 2+ channels are not yet documented. Results In the present study, actions of zolmitriptan, one of triptans, were examined on the HVA Ca 2+ channels in acutely dissociated rat TGNs, by using whole-cell patch recording of Ba 2+ currents (I Ba ) passing through Ca 2+ channels. Zolmitriptan (0.1–100 μM) reduced the size of I Ba in a concentration-dependent manner. This zolmitriptan-induced inhibitory action was blocked by GR127935, a 5-HT 1B/1D antagonist, and by overnight pretreatment with pertussis toxin (PTX). P/Q-type Ca 2+ channel blockers inhibited the inhibitory action of zolmitriptan on I Ba , compared to N- and L-type blockers, and R-type blocker did, compared to L-type blocker, respectively (p < 0.05). All of the present results indicated that zolmitriptan inhibited HVA P/Q- and possibly R-type channels by activating the 5-HT 1B/1D receptor linked to G i/o pathway. Conclusion It is concluded that this zolmitriptan inhibition of HVA Ca 2+ channels may explain the reduction in the release of neurotransmitters including CGRP, possibly leading to antimigraine effects of zolmitriptan.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2006
• Nombre de lectures: 4
• Langue: English

Extrait

BioMed CentralMolecular Pain
Open AccessResearch
Antimigraine drug, zolmitriptan, inhibits high-voltage activated
calcium currents in a population of acutely dissociated rat
trigeminal sensory neurons
1,2 1,2 1Tomoko Morikawa* , Yoshiyasu Matsuzawa , Koshi Makita and
2Yoshifumi Katayama
1 2Address: Department of Anesthesiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan and Department of
Autonomic Physiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
Email: Tomoko Morikawa* - [e-mail]; Yoshiyasu Matsuzawa - [e-mail];
Koshi Makita - [e-mail]; Yoshifumi Katayama - [e-mail]
* Corresponding author
Published: 20 March 2006 Received: 19 November 2005
Accepted: 20 March 2006
Molecular Pain2006, 2:10 doi:10.1186/1744-8069-2-10
This article is available from: http://www.molecularpain.com/content/2/1/10
© 2006Morikawa et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: Triptans, 5-HT agonists, act on peripheral and/or central terminals of trigeminal1B/ID
ganglion neurons (TGNs) and inhibit the release of neurotransmitters to second-order neurons,
which is considered as one of key mechanisms for pain relief by triptans as antimigraine drugs.
2+ Although high-voltage activated (HVA) Ca channels contribute to the release of
2+ neurotransmitters from TGNs, electrical actions of triptans on the HVA Ca channels are not yet
documented.
Results: In the present study, actions of zolmitriptan, one of triptans, were examined on the HVA
2+ 2+ Ca channels in acutely dissociated rat TGNs, by using whole-cell patch recording of Ba currents
2+ (I ) passing through Ca channels. Zolmitriptan (0.1–100 μM) reduced the size of I in aBa Ba
concentration-dependent manner. This zolmitriptan-induced inhibitory action was blocked by
GR127935, a 5-HT antagonist, and by overnight pretreatment with pertussis toxin (PTX). P/1B/1D
2+ Q-type Ca channel blockers inhibited the inhibitory action of zolmitriptan on I , compared to N-Ba
and L-type blockers, and R-type blocker did, compared to L-type blocker, respectively (p < 0.05).
All of the present results indicated that zolmitriptan inhibited HVA P/Q- and possibly R-type
channels by activating the 5-HT receptor linked to G pathway.1B/1D i/o
2+ Conclusion: It is concluded that this zolmitriptan inhibition of HVA Ca channels may explain the
reduction in the release of neurotransmitters including CGRP, possibly leading to antimigraine
effects of zolmitriptan.
shown that trigeminal ganglion stimulation leads to theBackground
It is known that the pain associated with migraine is release of CGRP in humans and cats, which is antagonized
relieved by triptans, 5HT agonists, including by sumatriptan administration [1]. Subsequently, several1B/1D
sumatriptan, zolmitriptan, naratriptan and so on. Indeed, lines of histochemical and electrophysiological studies
they are in clinical use for treatment of migraine. It is demonstrate the involvement of 5HT agonist in neu-1B/1D
Page 1 of 9
(page number not for citation purposes)n=3
n=8
n=12
n=6
n=6
n=4
n=3
Molecular Pain 2006, 2:10 http://www.molecularpain.com/content/2/1/10
a.
control zolmitriptan (10μ M)
IBa
10mV
500pAvoltage
-60mVcommand
20ms
b.
zolmitriptan application
1
0.1mM (n=4)
0.8 1mM (n=6)
10mM (n=12)0.6
100mM (n=3)0.4
0.2
0
-20 0 20 40 60 80 100 120 140 160 180 200
time(s)
c.
**
*1
0.8
0.6
0.4
0.2
0
0 0.1 1 5 10 40 100
zolmitriptan concentration (mM)
Inhibition of HVAFigure 1 I by zolmitriptanBa
Inhibition of HVA I by zolmitriptan. (a) Typical illustration of I elicited in response to command pulses from -60 mV to Ba Ba
10 mV for 40 ms. I was inhibited by 2 min application of 10 μM zolmitriptan. (b) The average time course of I inhibition by Ba Ba
zolmitriptan at four different concentrations. Superfusing application of zolmitriptan started at t = 0 and lasted for 120 s during
the period indicated by horizontal bar. Mean value of the relative amplitude of I compared to the control I at t = 0 was plot-Ba Ba
ted on ordinate (I ratio) against time on abscissa. The number of neurons examined is indicated for the respective concentra-Ba
tions. S.E.M. value was not indicated. (c) Concentration-inhibition relationship for zolmitriptan. Bar graph shows the relative
amplitude of I at two minutes after application of zolmitriptan compared to the control. (*p < 0.05 **p < 0.01).Ba
Page 2 of 9
(page number not for citation purposes)
IBa ratio
IBa ration=4
n=6
n=12
Molecular Pain 2006, 2:10 http://www.molecularpain.com/content/2/1/10
a.
*
*
1
0.8
0.6
0.4
0.2
0
GR127935(-) GR127935 0.1(M GR127935 0.3(M
GR127935
zolmitriptan (10mM)
120 s
I (control) I (test)Ba Ba
b.
1000pA
20msec
control GR127935 0.3mM GR127935 0.3mM
+zolmitriptan 10mM
Figure 2GR127935 modulation on zolmitriptan-sensitive IBa
GR127935 modulation on zolmitriptan-sensitive I . (a) GR127935, 5HT antagonist, depressed the inhibition of IBa 1B/1D Ba
by zolmitriptan (10 μM). Bar graph shows that the zolmitriptan-induced inhibition of I was significantly reduced by pretreat-Ba
ment with 0.3 μM of the antagonist GR127935 (*p < 0.05). I ratio is the value that I (test) was divided by I (control). Inset Ba Ba Ba
shows the time course of GR127935 and zolmitriptan application. I (control) and I (test) were recorded as shown in the Ba Ba
chart. (b) Typical illustration of I in control (left), in the presence of 0.3 μM GR127935 (center), and 10 μM zolmitriptan Ba
added on 0.3 μM GR127935 (right).
Page 3 of 9
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I ratio
BaMolecular Pain 2006, 2:10 http://www.molecularpain.com/content/2/1/10
rotransmitter release from trigeminal ganglion neurons Concentration-dependent action of zolmitriptan on IBa
(TGNs). First, 5HT and/or receptors are localized in Zolmitriptan was applied to TGNs by superfusion for two1B 1D
receptors are dem- was inhibited in the pres-trigeminal vascular systems [2]. 5HT minutes. As shown in Fig. 1a, I1B Ba
onstrated on dural arteries [2] and 5HT receptors on ence of zolmitriptan at 10 μM. Inhibitory actions of zol-1D
trigeminal sensory neurons including peripheral and cen- mitriptan on I were examined at concentrations betweenBa
tral projections [2-4]. Second, small and medium- sized 0.1 and 100 μM (Fig. 1b, the number of cells indicated).
TGNs possess 5HT receptors, colocalized with CGRP Zolmitriptan at lower concentrations slowly started1B/1D
and Substance P [5]. Third, naratriptan inhibits neuronal depressing the I at 10 to 20 s from the onset of applica-Ba
activity in TGNs [6]. Fourth, synaptic transmission from tion. This depressing action slowly increased but could
TGNs to central trigeminovascular neurons is blocked by not reach its maximum in 2 min at concentrations lower
activation of presynaptic 5HT receptors on central ter- than 10 μM. On the other hand, at 100 μM, the I was1B/1D Ba
minals of meningeal nociceptors [7]. All of these studies very rapidly inhibited within 10 s and completely abol-
suggest that triptans might act on 5HT receptors of ished within one min of the drug application.1B/1D
TGNs and inhibit the release of neurotransmitters such as
CGRP, reducing central and/or peripheral neuronal excit- As noticed from Fig. 1b, this inhibitory effect of zol-
ability. mitriptan on I lasted after the end of the drug applica-Ba
tion and afterwards became more marked, attaining to its
2+ An activation of high-voltage activated (HVA) Ca chan- peak. Then, it should be noted that the inhibitory action
nels is known to trigger the release of neurotransmitters of zolmitriptan on I could be hardly washed out. There-Ba
and to control numerous neuronal functions such as neu- fore, the inhibitory effect of the drug was compared by
2+ ronal excitability. HVA Ca channels are divided into four using the I ratio (see Method and figure legend) at 2 minBa
subtypes; that is N-, P/Q-, L-, and R-type channels. All of after the onset of the application. The I ratios were 0.96Ba
2+ four subtypes of HVA Ca channels are demonstrated to ± 0.06 (0.1 μM, n = 4), 0.81 ± 0.08 (1 μM, n = 6), 0.75 ±
be expressed in TGNs [8]. Recent findings indicate that the 0.07 (5 μM, n = 6), 0.71 ± 0.06 (10 μM, n = 12), 0.40 ±
2+ blockade of HVA Ca channels prevents CGRP release 0.12 (40 μM, n = 8), and 0.00 ± 0.00 (100 μM, n = 3), and
2+ and prevents dural vessel dilation, and so HVA Ca block- compared with the I ratio of control group without zol-Ba
ade might minimize neurological inflammation [9]. mitriptan (0.97 ± 0.03, n = 3), as summarised in Fig. 1c,
Although it is shown that N- and P/Q-currents are inhib- showing the concentration-inhibition relationship for the
ited via G protein-coupled mechanisms by