5-HT-induced depression of the spinal
monosynaptic reflex potential utilizes different types of 5-HT receptors depending on Mg 2+
availability
Shripad B. Deshpande, Amar N. Maurya, Jitendra N. Singh1
Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India
1Present address: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab, India
Correspondence:Shripad B. Deshpande, e-mail: desh48@yahoo.com
Abstract:
Receptor subtypes involved in the 5-hydroxytryptamine (5-HT)-induced depression of synaptic transmission in neonatal rat spinal cordsin vitro were evaluated in the absence or presence of Mg2+in the medium. Stimulation of a dorsal root evoked monosynaptic reflex potential (MSP) and polysynaptic reflex potential (PSP) in the segmental ventral root in Mg2+-free medium where the voltage-dependent blockade of NMDA receptors is absent. The 5-HT (0.3–50 µM) in the Mg2+-free medium depressed the MSP and PSP in a concentration-dependent manner. At 30 µM of 5-HT, the depression was 57% and 95% for MSP and PSP, respectively, and no further depression was seen at 50 µM. The 5-HT-induced depression of the reflexes in the Mg2+-free medium was blocked by on- dansetron (5-HT3receptor antagonist), but not by spiperone (5-HT2A/2Cantagonist). In the Mg2+-free medium, phenylbiguanide (5-HT3agonist) also depressed the MSP and PSP in a concentration-dependent manner and was blocked by ondansetron. Addition of Mg2+(1.3 mM) to the medium abolished the PSP and decreased the MSP by 30%. In the presence of Mg2+, 5-HT (1–50 µM) also de- pressed the MSP in a concentration-dependent manner. At 10 µM of 5-HT, there was approximately 20% depression and at 50 µM the depression was 100%. The 5-HT-induced depression of MSP in the Mg2+-containing medium was antagonized by spiperone (p < 0.05, two-way ANOVA), but not by ondansetron. The results indicate that the 5-HT-induced depression of MSP involves 5-HT3 receptors in the Mg2+-free medium and 5-HT2A/2Cin the presence of Mg2+when NMDA receptors are in the closed state.
Key words:
NMDA receptors, 5-HT!receptors, phenylbiguanide, ondansetron, spinal cord, synaptic transmission
Introduction
The 5-hydroxytryptamine (5-HT)-containing nerve terminals are localized in and around the ventral horn [3, 17, 31]. These neurons originate from the raphe nuclei and reach the spinal cord through the descend-
ing bulbospinal tracts [27]. Electrophysiologically, 5-HT possesses diverse actions in the spinal cord [5, 13, 15, 18]. The postsynaptic actions include slow de- polarization or hyperpolarization of motoneurons [18, 31]. The depolarizing action of 5-HT on spinal moto- neuronsin vitro is associated with the depression of the segmental monosynaptic reflex potential (MSP)
Pharmacological Reports 2009, 61, 261267 ISSN 1734-1140
Copyright © 2009 by Institute of Pharmacology Polish Academy of Sciences
of the MSP by 5-HT is thus shown to be mediated through the involvement of the 5-HT1 and 5-HT2 types of receptors, but not by the 5-HT3receptors [8, 9, 12, 23, 30, 34]. However, all of these experiments were performed in a Mg2+-containing medium. In our earlier report, the involvement of the 5-HT3receptors in the depression of the MSP induced by ische- mia/aglycemia or by thePtychodiscus brevis toxin has been shown [10, 26]. These experiments, on the other hand, were performed in a Mg2+-free medium. It is known that in a Mg2+-containing medium, the NMDA receptors are blocked in a voltage dependent manner while in a Mg2+-free medium, the NMDA receptors remain in open state [2, 6, 22, 24, 28]. Thus, the involvement of 5-HT3 receptors in earlier reports of 5-HT-induced depression of the MSP is not consistent in different states of NMDA receptors. As such, this study was undertaken to evaluate the type of 5-HT re- ceptors involved in depressing spinal reflexes in the absence or presence of Mg2+in the medium.
Materials and Methods
Animals, anesthesia and dissection
The method for preparation and recording spinal re- flexes from the neonatal rat spinal cord in vitro has been described elsewhere [11, 25]. Briefly, rat pups ranging from 4 to 8 days in age (Charles-Foster strain) of either sex were anesthetized with diethyl ether. The spinal column was quickly removed and placed in a Sylgard-plated Petri dish containing physiological solution bubbled with 100% O2. The spinal cord was then removed carefully, hemisected sagitally and transferred into a small Plexiglas bath (volume < 1 ml) superfused with oxygenated physiological solution (3–5 ml/min) maintained at 25 ± 0.5°C. All experi- ments were performed according to the guidelines of the Institute of Medical Sciences, Banaras Hindu Uni- versity, Varanasi, India for conducting animal experi- ments. Care was taken to restrict the number of ani- mals used to the minimum possible.
borosilicate glass capillary tubes. These tubes were filled with physiological solution and the cut ends of the corresponding dorsal and ventral roots (between L3-L5 segments) were gently sucked into them.
Stimulation of a dorsal root with rectangular pulses of 0.5 ms duration and supramaximal voltage (40–60 V) at 0.1 Hz evoked reflex potentials (monosynaptic, MSP; and polysynaptic, PSP) at the corresponding ventral root. These potentials were amplified (Har- vard AC/DC preamplifier), monitored on an oscillo- scope, digitized and stored in a personal computer us- ing an A/D card (PCL-208 from Dynalog India Ltd., Mumbai).
Experimental protocol
The experiments were performed in three different groups. In all groups, the recordings were made after 1–3 h stabilization. The averaged signals of five con- secutive reflexes in the absence or presence of various agonists/antagonists were recorded.
In the first group, all experiments were conducted in a Mg2+-free medium. After taking the initial recording, the cord was exposed to a concentration of 5-HT for 10 min and the response was recorded. The cord was then washed with normal physiological so- lution for 30 min. Subsequently, the cord was exposed to the next concentrations of 5-HT for 10 min while washing between the concentrations as before. The response after washing served as a control (initial) for the next concentration. In a separate set of experi- ments, after recording the initial response, the spinal cord was exposed to the antagonist (spiperone or on- dansetron/vehicle) for 30 min, and, subsequently, the concentration response of 5-HT was repeated in the antagonist containing medium.
In the second group of experiments, the cord was exposed to cumulative concentrations of phenylbigua- nide (0.01–10 µM) for 30 min in the Mg2+-free me- dium in the absence or presence of ondansetron. At the end of the experiment, the cord was washed with normal physiological solution for 30 min.
In the third group, all experiments were conducted in the Mg2+-containing medium (1.3 mM). The con- centration response of 5-HT was determined in the absence or presence of antagonists as mentioned be- fore.
Drugs and Solutions
The Mg2+-free physiological solution had the following composition (in mM): NaCl, 124.0; KCl, 5.0; KH2PO4, 1.2; CaCl2, 2.5; NaHCO3, 4.5; and glucose, 11.0. The solution was then bubbled with 100% O2, and the pH of the solution was determined to be 7.3. MgSO4·7H2O was added to this medium to make the final concen- tration equal to 1.3 mM. Phenylbiguanide (PBG), 5-HT and spiperone were obtained from Sigma Chemicals, St. Louis, MO, USA. Ondansetron was obtained from Cipla, India. The stock solution of spiperone was prepared in absolute ethanol while other solutions were prepared in distilled water. All stock solutions were stored in a freezer and thawed just before use.
Data analysis and statistics
The area of the reflex response was calculated using Unkelscope software (MIT, USA) following place- ment of the cursors between two isoelectric points (Fig. 1). In the case of the MSP, the first cursor was placed at the beginning of the potential response and the second cursor was placed at the down stroke of the potential where it becomes isoelectric to the first cur- sor. In the case of the PSP, the first cursor was placed at the beginning of the potential response and the sec- ond cursor was placed either at the end of the re- sponse, as mentioned for the MSP, or at the point when it changes towards positivity. The responses were then normalized to their initial values. Data are presented as the mean ± SEM, and were statistically analyzed using a one-way or two-way ANOVA. Mul- tiple comparisons were made by using the Student- Newman-Keuls test, and the Student’s t-test was also performed. A p < 0.05 was considered statistically significant.
Results
The depression of the MSP and PSP began instantane- ously as 5-HT started reaching the perfusion chamber and was maximal within 10 min. The recordings were therefore made after exposing the cord to each con- centration of 5-HT for 10 min. The 5-HT-induced de- pression of reflexes could be reversed completely by
washing with normal physiological solution for 30 min and no desensitization was observed on re- peated exposures. Hence, the cords were exposed to various concentrations of 5-HT while washing be- tween the concentrations.
Responses in Mg2+-free medium
5-HT depressed the spinal reflexes in Mg2+-free medium
Superfusion of 5-HT (0.3–50 µM) produced a con- centration-dependent depression of the MSP and PSP in the Mg2+-free medium (n = 6). The threshold con- centration of 5-HT was 1 µM, at which the MSP and PSP were depressed by 23% and 17%, respectively.
At 30 µM of 5-HT, the depression was 57% for the MSP and 95% for the PSP (Fig. 1; p < 0.05; one-way ANOVA followed by Student-Newman-Keuls test for multiple comparisons). However, no further decrease was observed even when the concentration was in- creased to 50 µM (Fig. 1).
Spiperone failed to block 5-HT-induced depression
Superfusion of spiperone (0.1 µM) alone for 30 min did not alter the magnitude of the MSP and PSP. In the presence of spiperone, the 5-HT-induced depression of the MSP and PSP was similar to that with 5-HT alone at all concentrations (Fig. 1). Further, ethanol, when used in a concentration of spiperone (0.001%
v/v), did not alter either the magnitude of reflexes or the 5-HT-induced depression of reflexes at various concentrations.
Ondansetron blocked 5-HT-induced depression of reflexes
In the Mg2+-free medium, ondansetron (0.1 µM) by itself did not alter the MSP (97 ± 5.3% of initial) and the PSP (101 ± 7.8% of initial). However, in the pres- ence of ondansetron, the 5-HT-induced depression of the MSP and PSP was blocked completely (Fig. 1;
p < 0.05; two-way ANOVA).
5-HT-induced depression of spinal reflex potentials
Shripad B. Deshpande et al.
PBG-induced depression of reflexes was blocked by ondansetron
PBG depressed the MSP in a concentration-dependent manner in the Mg2+-free medium. At 10 µM PBG, the depression of the MSP and PSP was 40% and 75%, respectively. Ondansetron (0.1 µM) blocked the PBG-induced depression of the MSP/PSP at various concentrations (Fig. 2; p < 0.05; two-way ANOVA
followed by Student-Newman-Keuls test for multiple comparisons).
Responses in Mg2+-containing medium
5-HT also depressed the MSP in Mg2+-containing medium
Addition of Mg2+(1.3 mM) to the medium abolished the PSP completely and decreased the magnitude of the MSP by about 30% as shown elsewhere [10, 25].
5-HT (1–50 µM) produced a concentration-dependent decrease in the MSP (Fig. 3; p < 0.05; one-way ANOVA followed by Student-Newman-Keuls test for multiple comparisons). The threshold concentration of 5-HT was 3 µM as it depressed the MSP by 8%
(p < 0.05; Student’st-test for paired observations). At 10 and 30 µM, the depression of the MSP was 20%
and 75%, respectively. The maximum depression (> 95%) of MSP was observed at 50 µM 5-HT.
two-way ANOVA)
Fig. 1. Concentration-response of 5-HT to the monosynaptic reflex potential (MSP) and polysynaptic reflex potential (PSP) in the pres- ence or absence of antagonists in the Mg2+-free medium. The upper panel shows the actual potentials in the absence (none) and in the presence of ondansetron (0.1 µM; Ond). The area under the poten- tials was computed by placing the cursors on the graphs between ar- rows a and b for the MSP area and arrows c and d for the PSP area. The vertical scale bar is 1 mV, and the horizontal scale bar is 10msec for all the graphs. Note the blockade of depression in the presence of ondansetron. The mean ± SEM values were obtained from 56 different preparations and are presented in the lower graphs. The 5-HT-induced depression of the MSP and PSP was blocked by ondansetron (0.1 µM; p < 0.05; two-way ANOVA), but not by spiperone (spip; 0.1 µM)
Spiperone antagonized the 5-HT-induced response
In spiperone (0.1 µM) containing medium, the con- centration-response of 5-HT was shifted to the right.
In the presence of spiperone, 5-HT at 10 µM did not alter the magnitude of the MSP and at 50 µM the de- pression was 70% (Fig. 3; p < 0.05; two-way ANOVA as compared to the 5-HT alone response). Further- more, ethanol (solvent used for dissolving spiperone) had no effect on the 5-HT-induced concentration- response relationship to the MSP.
Lack of the effect of ondansetron on 5-HT-induced depression of the MSP
Ondansetron (0.1 µM) by itself did not alter the mag- nitude of the MSP. Further, ondansetron in the Mg2+-containing medium did not block the 5-HT- induced depression of the MSP (Fig. 3; p < 0.01;
two-way ANOVA). In the presence of ondansetron, 10 µM of 5-HT depressed the MSP by 20% and 30 µM by 78%.
Discussion
The presented results indicate that the 5-HT-induced depression of the MSP involves 5-HT3 receptors in the Mg2+-free medium, but 5-HT2Areceptors in the presence of Mg2+. The presence of Mg2+in the me- dium blocks NMDA receptors in a voltage-dependent manner [2, 6, 22, 24]. Thus, 5-HT-induced depression of the spinal MSP involves a different type of 5-HT receptor depending upon the status of the NMDA re- ceptor activity.
In the spinal cord, 5-HT is involved in a number of actions such as depolarization or hyperpolarization of the motoneurons/primary afferents, excitatory/inhibi- tory postsynaptic potentials, locomotor pattern gen- eration, and nociceptive transmission [4, 5, 15, 16, 18, 31]. The receptors involved in mediating these re- sponses in the spinal cord vary greatly with different responses [15, 18, 19, 30, 31]. In the present study, our observations revealed that the depression of the spinal reflexes involves the 5-HT2A/2Creceptors (an- tagonized by spiperone) when Mg2+is present in the medium. The depolarization or hyperpolarization of the presynaptic and postsynaptic sites may lead to the depression of the synaptic transmission as suggested elsewhere [18]. The 5-HT1Areceptor involvement in the depression of the monosynaptic reflex is also re- ported [12, 14, 18]. Furthermore, in earlier reports, 5-HT2A/2Creceptor involvement is shown to occur in 5-HT-induced depression of the monosynaptic reflex [12, 14, 19, 23, 30, 34]. The present findings are in agreement with the involvement of 5-HT2A/2Crecep- tors in mediating this response. Moreover, in the pres- ent results, 5-HT3receptor antagonist failed to block the 5-HT-induced depression of the MSP in the Mg2+-containing medium. Such lack of effect of the
5-HT-induced depression of spinal reflex potentials
Shripad B. Deshpande et al.
Fig. 3. Concentration-response of 5-HT on monosynaptic reflex potential (MSP) in Mg2+(1.3 mM) medium in the absence (none) or presence of antagonists. The upper panel shows the actual poten- tials in the absence (none) or presence of spiperone (0.1 µM; Spip).
Vertical calibration = 1 mV and horizontal calibration = 10msec for both panels. Note the antagonism of the response in the presence of spiperone. The mean ± SEM values were obtained from 56 different preparations. The 5-HT response in the presence of ondansetron (0.1 µM) was not different from its absence (p > 0.1; two-way ANOVA)
volvement of the 5-HT3receptor for the depression of the MSP, but not for the 5-HT2A/2Creceptor. Further- more, the 5-HT3receptor agonist, PBG, also depressed the MSP and was blocked by ondansetron (Fig. 2).
This observation confirms 5-HT3 receptor involve- ment in the depression of the spinal reflex potentials.
Furthermore, in another study, non-involvement of the 5-HT1 and 5-HT2 receptors was reported in the Mg2+-free medium, but a 5-HT3 receptor antagonist or agonist was not tested [7]. Thus, our study provides evidence for the involvement of the 5-HT3receptor in the Mg2+-free medium.
The 5-HT3 receptor is a pentameric ligand-gated ion channel, promoting the entry of cations (Na+and Ca2+) to produce depolarization [20, 21]. In this study, the results indicate that 5-HT depressed the MSP irre- spective of the NMDA receptor state. Furthermore, the depression in the Mg2+-free medium (when NMDA receptors are not closed) is exclusively medi- ated through 5-HT3 receptors. Thus, it is likely that the presence of Mg2+in the medium alters the 5-HT3 receptor activity, while allowing the 5-HT2receptors to become active. In the absence of Mg2+, the 5-HT3 receptors regain their activity. Additionally, as Mg2+
blocks the NMDA receptors, it is possible that Mg2+
may also modulate the 5-HT3 receptors’ activity in a similar way.
The 5-HT1 and 5-HT3 receptors are highly ex- pressed in the dorsal horn and particularly in the su- perficial lamina, whereas their presence in the ventral and lateral areas of spinal cord is low [18]. The 5-HT2 receptors on the other hand show different patterns of distribution with a low presence in the dorsal horn and a higher presence in the ventral and lateral areas of the spinal cord [18]. The small amplitude depolarization of some dorsal neurons by the 5-HT3 receptors has been shown previously [1, 18]. Moreover, 5-HT3 receptors inhibit the release of the transmitter from the primary afferents resulting from depolarization.
As such, the involvement of interneurons in the de- pression has been also proposed [18]. Thus, it is pos- sible that in the presence of Mg2+, the primary affer- ent depolarization diminishes and the sensitivity of 5-HT2A/2Cincreases.
In conclusion, Mg2+ modulates 5-HT-induced de- pression of spinal reflex potentials and involves dif- ferent sets of the 5-HT receptors. The absence of
are required to identify the interrelationship between the NMDA receptor activity and the 5-HT receptor functioning.
Acknowledgments:
JNS and ANM wish to thank the Indian Council of Medical Research, New Delhi, India for financial support.
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Received:
June 20, 2008; in revised form: February 18, 2009.
5-HT-induced depression of spinal reflex potentials
Shripad B. Deshpande et al.
