Department of Anatomy and Neurosciences, Marine Biomedical Institute, The University of Texas Medical Branch, Galveston, Texas 77555-1069
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ABSTRACT |
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Lin, Qing, Jing Wu, Yuan Bo Peng, Minglei Cui, and William D. Willis. Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate. Our recent work has suggested that the nitric oxide/guanosine 3',5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.
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INTRODUCTION |
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A number of studies suggest that increased spinal
levels of guanosine 3',5'-cyclic monophosphate (cGMP) contribute to the development of hyperalgesia and allodynia. An increased level of
immunoreactive cGMP within the lumbar spinal enlargement was seen
during hyperalgesia following intraplantar injection of carregeenan (Garry et al. 1994b). Also, intrathecal injection of
8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a
membrane-permeable analogue of cGMP, produced hyperalgesia
(Garry et al. 1994a
; Garry and Davis
1997
). We have recently shown that spinothalamic tract (STT)
neurons can be sensitized when 8-bromo-cGMP is administered into the
dorsal horn of the spinal cord (Lin et al. 1997
).
As discussed in our preceding papers (Lin et al.
1999a,b
), nitric oxide (NO) is well established as an
intercellular regulator, and most of its effects appear to be mediated
via cGMP (Schmidt et al. 1993
). A soluble form of
guanylate cyclase is a key enzyme linking NO with cGMP (Schmidt
et al. 1993
; Southam and Garthwaite 1991
;
Waldman and Murad 1987
). In our experiments (Lin
et al. 1999a
), we found that an elevation of NO within the
dorsal horn results in sensitization of STT cells to cutaneous
mechanical stimuli. This action is accompanied by an attenuation of
spinal inhibition of STT cells produced by activation of a descending inhibitory pathway from the periaqueductal gray (PAG) and of spinal glycine and GABA receptors (Lin et al. 1999b
). NO is
released within the spinal cord when STT cells are sensitized by
intradermal injection of capsaicin (Lin et al. 1999a
).
We have also recently demonstrated that sensitization of STT neurons
produced by intraspinal administration of 8-bromo-cGMP is accompanied
by a reduction in PAG-induced inhibition of responses to peripheral
mechanical stimuli (Lin et al. 1997
). All these changes
were seen consistently in deep wide dynamic range (WDR) STT cells.
These data indicate strongly that the NO/cGMP cascade participates in
the induction of central sensitization in the deep layers of the spinal
cord dorsal horn in part by affecting spinal inhibition.
The present study asked whether an elevation in the cGMP level in the dorsal horn could also reduce the inhibition of primate STT neurons that is produced by the activation of spinal glycinergic and GABAergic receptors. cGMP levels within the spinal cord were elevated by 8-bromo-cGMP delivered by microdialysis or iontophoresis. Inhibitory responses of STT cells to glycine and GABA agonists were tested using iontophoretic application of the inhibitory amino acids (IAAs). As predicted, 8-bromo-cGMP was found to reduce the inhibition produced by IAAs. The linkage between the effects of NO and cGMP production was then tested by administration of 3-morpholinosydnonimine (SIN-1), a NO donor, into the dorsal horn while releasing IAAs iontophoretically onto STT neurons. The reduction in inhibition by SIN-1 was antagonized by microdialysis of a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).
A preliminary report of these findings has been made (Lin et al.
1996c).
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METHODS |
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Data were collected from 19 adult male monkeys (Macaca
fascicularis, 1.9-2.5 kg). Animal preparation and maintenance
were the same as described in detail in our two preceding papers
(Lin et al. 1999a,b
). Experimental approaches used in
this study, such as placement of microdialysis fibers for drug
administration and use of multibarrel electrodes for both extracellular
recordings of STT neurons and drug delivery, have also been described
(Lin et al. 1999b
).
Drug administration
8-bromo-cGMP (from RBI) was administered in two ways.
8-bromo-cGMP was dissolved in artificial cerebrospinal fluid (ACSF) or
normal saline to a concentration of 10 mM and infused into the spinal
dorsal horn by microdialysis. The dose used in this study was
comparable with that used in in vitro studies (Ito and Karachot
1992; Shibuki and Okada 1991
) and has been shown
to change the responses of STT cells to peripheral stimuli (Lin
et al. 1997
). 8-bromo-cGMP was also applied by iontophoresis.
The concentration in the drug barrel was 15 mM (pH 7.2). IAA agonists,
including glycine, GABA, and muscimol, were administered by
iontophoresis in the same way as in our previous studies (Lin et
al. 1994
, 1996b
,d
). Briefly, effects of glycine,
GABA, and muscimol on STT cells were tested by sequential iontophoretic
release of these agents onto STT cells. Observations were made on the
effects of glycine and GABA agonists on noxious stimulation-evoked
activity by applying a sustained Pinch stimulus to the skin during drug
administration. All agents were delivered iontophoretically using three
5- to 10-s-long graded current pulses. ODQ (Tocris) was delivered into the spinal cord at a concentration of 1 mM by microdialysis as previously described (Lin et al. 1997
). ODQ has been
reported to inhibit potently and selectively the NO-stimulated
guanylate cyclase activity without affecting NO synthase (NOS) activity (Garthwaite et al. 1995
).
Experimental design
The responses of STT cells to cutaneous mechanical stimuli,
which included Brush, Press, and Pinch stimuli, were recorded to
classify STT cells according to their response patterns (Chung et al. 1986). The procedure for applying mechanical stimuli to the skin of the receptive field was identical to that in several studies by our group (Dougherty et al. 1992a
;
Dougherty and Willis 1991a
,b
; Lin et al.
1996a
,b
, 1997
) and was described in detail in
our preceding paper (Lin et al. 1999a
). Recordings of
responses to cutaneous mechanical stimuli were recorded to determine
whether 8-bromo-cGMP sensitized STT cells.
The effects of microdialysis of 8-bromo-cGMP on IAA-elicited inhibition
of STT cells were examined on one group of STT neurons. In this group,
some cells were also used to test the effects of 8-bromo-cGMP on PAG
inhibition (see Lin et al. 1997). After baseline inhibitions produced
by iontophoretic application of IAA agonists were recorded,
8-bromo-cGMP was infused into the dorsal horn for 30-60 min, and the
cell's responses to iontophoretic release of glycine and GABA agonists
were retested. The drug was then washed out with ACSF or normal saline
for 30-60 min before the inhibitory responses were again tested.
In another group of STT cells, observations were made of the effects of iontophoretic application of 8-bromo-cGMP on inhibition of STT cells elicited by glycine and GABA agonists. After control responses were recorded, 8-bromo-cGMP was iontophoresed continuously (70-100 nA) during a period when a glycine or GABA agonist was delivered iontophoretically by three graded current pulses.
In some STT cells separate from the above two groups of cells, the effects of ODQ in reducing the IAA receptor-mediated inhibition of STT cells induced by iontophoresis of SIN-1 were tested. SIN-1 was iontophoresed continuously (70-100 nA) during a period when a glycine or GABA agonist was delivered iontophoretically by three graded current pulses while recording from the same cell. The effect of the first SIN-1 ejection was observed without ODQ infusion. After inhibition induced by IAAs was shown to recover, ODQ was infused into the dorsal horn for 30-60 min. The effect of the second SIN-1 ejection on IAA receptor-mediated inhibition was then tested during ODQ infusion.
Data were processed in the same way as in our two preceding papers
(Lin et al. 1999a,b
). The stored digital record of unit activity was retrieved and analyzed off-line. Frequency histograms were
generated for all sensory- and drug-evoked events. The inhibitory effects of iontophoretic application of glycine and GABA agonists on
Pinch-evoked activity were evaluated by calculating the total percentage of inhibition of evoked activity induced by three graded current pulses. A repeated measures ANOVA tested responses in each
group. If significance was obtained, post hoc testing with paired
t-tests assessed differences from the baseline levels. A
value of P < 0.05 was considered significant. All
values are given as the means ± SE.
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RESULTS |
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Recordings were made from a total of 31 STT neurons, including 28 WDR and 3 HT cells, in 19 animals. Cell depths ranged from 944 to 2,040 µm below the spinal cord dorsal surface, and thus the STT neurons
were presumed to be in laminae I-V (see Lin et al. 1999a). Fourteen
neurons (12 WDR cells and 2 HT cells) were tested with 8-bromo-cGMP
administered by microdialysis. The responses of these cells to
mechanical stimuli were presented in a paper on the effects of
8-bromo-cGMP (Lin et al. 1997
). Thirteen neurons (12 WDR
cells and 1 HT cell) were tested with 8-bromo-cGMP applied iontophoretically. The remaining four deep WDR cells were used to
observe changes in the attenuation of IAA receptor-mediated inhibition
produced by SIN-1 administration when guanylate cyclase was blocked.
These STT cells were not reported in our previous work.
Effects of intraspinal administration of 8-bromo-cGMP by microdialysis on the inhibition of STT neurons produced by iontophoretic release of glycine and GABA agonists
We have reported recently that the responses of deep WDR STT cells
to both weak and strong cutaneous mechanical stimuli were sensitized by
spinally administered 8-bromo-cGMP and that the responses of
superficial WDR cells and HT cells to cutaneous mechanical stimuli were
reduced by the same dose of 8-bromo-cGMP (Lin et al.
1997). In the present study, we found that the inhibition of
responses of deep WDR STT cells to mechanical noxious stimuli produced
by glycine and GABA agonists was profoundly reduced when the spinal
cord was perfused with 8-bromo-cGMP. The tests were made on deep WDR
cells, in which responses to mechanical stimuli are enhanced by
infusion of 8-bromo-cGMP within the spinal cord by microdialysis.
Figure 1 is an example showing the
changes in inhibition of a deep WDR STT cell (1,496 µm below the
surface of the spinal cord) produced by glycine and GABA agonists
during infusion of 8-bromo-cGMP at a concentration of 10 mM. The
responses of this cell to both weak and strong mechanical stimuli were
sensitized by 8-bromo-cGMP (Fig. 1A). An attenuation of
IAA-induced inhibition occurred during 8-bromo-cGMP infusion (2nd
row of Fig. 1B) and long outlasted the drug infusion
period (3rd row of Fig. 1B). This long-lasting
change was consistent with the change in the responses to mechanical
stimuli (Fig. 1A). Similar results were obtained for most
deep WDR cells tested. Blockade of glycine-induced inhibition was found
in all seven cells and of GABA- and muscimol-induced inhibition in six
of seven cells. Statistical analysis showed that all of these changes
were significantly different from the baseline levels (Fig.
2A).
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However, in most superficial WDR cells and HT cells, in which responses to mechanical stimuli were reduced by intraspinal infusion of 8-bromo-cGMP, inhibition of Pinch-evoked activity of these cells produced by iontophoretic release of glycine and GABA agonists was not significantly changed when the spinal cord was perfused with 8-bromo-cGMP. A total of five superficial WDR cells and two HT cells were tested with 8-bromo-cGMP, and an attenuation of IAA-induced inhibition was only found in one cell. In some of these cells (4 for glycine-, 2 for GABA- and muscimol-induced inhibition), the inhibition was found to be potentiated during 8-bromo-cGMP administration.
Effects of iontophoretic administration of 8-bromo-cGMP onto STT cells on the inhibition of STT neurons produced by iontophoretic release of glycine and GABA agonists
In a total of 13 STT neurons, the effect of 8-bromo-cGMP applied by iontophoresis (70-100 nA) was tested on the inhibition of these cells produced by glycine and GABA agonists. 8-bromo-cGMP administered by iontophoresis also reduced the inhibition of Pinch-evoked activity produced by iontophoretic release of glycine and GABA agonists, and this effect was seen mainly in the deep WDR STT cells tested. However, 8-bromo-cGMP applied by iontophoresis did not produce an effect as long-lasting or as potent as that produced by 8-bromo-cGMP applied by microdialysis.
Figure 3 shows that the inhibition of the Pinch-evoked response of a deep WDR cell (1,404 µm) produced by IAAs was reduced during continuous iontophoresis of 8-bromo-cGMP (100 nA). In a total of 8 deep WDR cells (1,374-1,700 µm), the effects of 8-bromo-cGMP on glycine-induced inhibition were examined, and an attenuation of inhibition was seen in seven of eight cells. Tests for the effects of 8-bromo-cGMP on GABA- and muscimol-induced inhibition were completed on seven cells, and attenuation of inhibition was obtained in six of seven cells. All of these changes were significantly different from the baseline levels (Fig. 2B).
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In the remaining five neurons, which included four superficial cells (944-1,276 µm) and one HT cell (1,600 µm), the effects of iontophoresis of 8-bromo-cGMP on GABA-induced inhibition were tested in all five cells, but a reduction in inhibition was seen in only one cell. Tests for the effects of iontophoresis of 8-bromo-cGMP on glycine- and muscimol-induced inhibition were completed in four cells. Reduction in inhibition produced by glycine was seen only in one cell, and no attenuation of the muscimol-induced inhibition was obtained. No statistically significant change in this group was observed during 8-bromo-cGMP application.
Figure 4 summarizes the effects of spinal administration of 8-bromo-cGMP by microdialysis and by iontophoresis on the IAA-induced inhibition of different types of STT neurons. The percentage of inhibition of the evoked activity before drug administration is plotted on the abscissa, and the percentage of inhibition during drug administration is plotted on the ordinate. Points would fall on or be near the diagonal line in each graph if predrug inhibition equaled or was similar to the inhibition during drug administration. Points that are below or above the diagonal line reflect a decreased or increased inhibition, respectively. 8-bromo-cGMP-induced attenuation of inhibition of Pinch-evoked activity produced by the three IAA agonists was mostly seen on deep WDR STT cells. In contrast, in most WDR cells distributed in superficial layers or HT cells, 8-bromo-cGMP did not obviously affect the IAA-induced inhibition. In some cells, the inhibition was enhanced slightly.
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Effects of guanylate cyclase inhibitor on the reduction in IAA-induced inhibition produced by NO release
NO release within the spinal cord has been shown to attenuate the
IAA-induced inhibition of deep WDR STT cells in our preceding paper
(Lin et al. 1999b). Here we examined whether blockade of guanylate cyclase interfered with this effect of NO release.
Observations were made on four deep WDR STT neurons. Figure
5 consists of rate histograms for a
representative STT cell that show the effects of iontophoretic release
of SIN-1 on IAA-induced inhibition without and with intraspinal
infusion of a guanylate cyclase inhibitor, ODQ. The top row
shows the baseline recordings of inhibition of PINCH-evoked activity
elicited by iontophoretic release of glycine and GABA agonists. A
nearly complete blockade of inhibition produced by all three IAA
agonists was seen while SIN-1 was being released by iontophoresis
(2nd row). The inhibition recovered or was even increased
around 30 min after terminating SIN-1 ejection (3rd row).
ODQ was then infused into the dorsal horn for 30 min. IAA-induced inhibition showed no obvious change during ODQ application (4th row). A second ejection of SIN-1 by iontophoresis was made while testing the IAA-induced inhibition during ODQ infusion. The inhibition of Pinch-evoked activity was nearly unchanged, in contrast to its
elimination during the initial ejection of SIN-1 (bottom row vs. 2nd row).
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The grouped data (Fig. 6) show results similar to those obtained from this individual cell. There was no significant change in IAA-induced inhibition when the spinal cord was preteated with ODQ (open bar vs. hatched bar in the right set of each group of bars), and ODQ prevented the blockade of inhibition induced by NO release by SIN-1 administration.
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DISCUSSION |
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The current study provides further evidence for our hypothesis
that activation of the NO/cGMP cascade may contribute to the development and maintenance of central sensitization of STT neurons in
part by reducing the effectiveness of spinal inhibition. Our findings
that an increase either in NO or cGMP level within the spinal cord can
sensitize the responses of STT cells to peripheral mechanical stimuli
and that this sensitization is accompanied by a reduction in spinal
inhibition mediated by a descending inhibitory pathway from the PAG or
spinal IAA receptors suggest that these effects produced by NO and cGMP
involve the same mechanism. Furthermore, the finding that a reduction
in IAA-induced inhibition produced by applying a NO releasing agent,
SIN-1, can be prevented when guanylate cyclase is blocked provides
evidence that NO and cGMP act through the same signal transduction
cascade (Schmidt et al. 1993).
8-bromo-cGMP is a membrane-soluble analogue of cGMP and has been used
to elevate intracellular cGMP levels (Hartell 1994a,b
; Ito and Karachot 1990
; Okada 1992
). An
increased cGMP within the lumbar spinal cord is associated with
hyperalgesia produced by intraplantar injection of carregeenan
(Garry et al. 1994b
). cGMP formation is triggered by
glutamate release (cf. Lerea et al. 1992
;
MacDermott et al. 1986
; Manzoni et al.
1990
; Mayer and Miller 1990
; Otsuka and
Yoshioka 1993
; Schoepp and Conn 1993
;
Watling 1992
), which increases cGMP content in neurons
through activation of NOS to produce NO from L-arginine
(Bredt and Snyder 1989
, 1990
; Garthwaite and Balazs 1978
; Garthwaite et al.
1988
). This process involves Ca2+ influx through
receptor-operated ion channels, such as
N-methyl-D-aspartate (NMDA) and some non-NMDA
receptors (Garthwaite et al. 1988
; Lerea et al.
1992
; MacDermott et al. 1986
; Mayer and
Miller 1990
). We have discussed in previous papers (Lin
et al. 1996a
,b
, 1997
) that a prolonged central
sensitization of spinal dorsal horn neurons is initiated by the
activation of NMDA and neurokinin 1 (NK1) receptors due to the release
of excitatory amino acids (EAAs) and substance P (SP) from primary
afferent nociceptors following peripheral tissue injury or chemical
irritation (Davies and Lodge 1987
; Dougherty et
al. 1992b
, 1994
, 1995
;
Dougherty and Willis 1992
; Haley et al.
1990
) and is maintained by triggering several second-messenger
cascades, mainly through Ca2+-dependent mechanisms
(Garthwaite et al. 1988
; Lerea et al.
1992
; MacDermott et al. 1986
; Mayer and
Miller 1990
). NMDA-induced hyperalgesia was blocked by
intrathecal administration of an inhibitor of guanylate cyclase,
methylene blue (Meller et al. 1992
). Spinal
administration of a guanylate cyclase inhibitor or cGMP-dependent
protein kinase (PKG) inhibitor could block the sensitization of STT
cells or allodynia and hyperalgesia after intradermal injection of
capsaicin (Lin et al. 1997
; Sluka and Willis
1997
), which is associated with an increased release of EAAs
and SP within the spinal cord due to selective activation of
nociceptive primary afferent C-fibers (Baumann et al.
1991
; Dougherty et al. 1992a
,
1994
; Gamse et al. 1979
; Sorkin
and McAdoo 1993
). Therefore one of the routes by which the
NO-cGMP cascade is triggered to mediate central sensitization of dorsal
horn neurons is by activation of EAA and NK1 receptors during noxious stimulation.
On the other hand, we have observed in this study that inhibition of
STT cells resulting from activation of spinal IAA receptors was
attenuated when the responses of STT cells to mechanical stimuli were
enhanced during spinal infusion of 8-bromo-cGMP. This and our other
studies showing that administration of a protein kinase C (PKC)
activator or NO donor reduced the effectiveness of IAA receptor-mediated inhibition of STT cells (Lin et al.
1996b, 1999b
) suggest that spinal disinhibition
could be responsible in part for central sensitization via certain
second-messenger cascades. The duration of this effect on inhibition
parallels the changes in responses to mechanical stimuli during spinal
infusion of 8-bromo-cGMP. Even iontophoretic release of 8-bromo-cGMP
produced a short-lasting attenuation of the inhibition produced by IAA
agonists. Thus these findings suggest a close association between
central sensitization and spinal disinhibition.
PKG can be activated by the NO/cGMP cascade (Garthwaite et al.
1988; Schmidt et al. 1993
) and, in turn, exerts
its modulatory effects by phosphorylation of cell proteins (Butt
et al. 1992
; Hartell 1994a
; Lincoln and
Cornwell 1993
). In other neural systems, protein kinases A and
C were found to phosphorylate certain subunits of IAA receptors,
decreasing inhibitory currents (Leidenheimer et al.
1991
, 1992
; Rapallino et al.
1993
; Ragozzino and Eusebi 1993
; Vaello
et al. 1994
). Recently, PKG-mediated phosphorylation of
GABAA receptors has been demonstrated (Leidenheimer
1996
; McDonald and Moss 1994
; Wexler et
al. 1998
). With the use of whole cell voltage clamp,
GABAA receptor-elicited currents recorded from dorsal root
ganglion cells were decreased by increases in intracellular cGMP
(Bradshaw and Simmons 1995
). Superfusion of cerebellar
slices with NO donors reduced Cl
currents elicited by
GABA in cerebellar granule cells (Robello et al. 1996
;
Zarri et al. 1994
). It is therefore hypothesized that
the activation of the PKG system either by intradermal injection of
capsaicin or by exogenous administration of 8-bromo-cGMP produces down-regulation of glycine and GABA receptors by protein
phosphorylation of receptors and that this contributes to central sensitization.
Results from our series of studies (Lin et al. 1997,
1999a
,b
), including the current one, did not show
significant changes in the inhibition of HT and superficial WDR STT
cells mediated by PAG and IAA receptors when either a NO releasing
agent or a cGMP analogue was administered. We have discussed in our
preceding papers (Lin et al. 1999a
,b
) possible reasons
why the NO/cGMP cascade can produce heterogeneous cellular effects,
even though our data cannot provide direct evidence about this. It is
hard to assess the differences between effects on deep dorsal horn and
superficial dorsal horn neurons without knowing the distance of
recorded neurons from the source of SIN-1 or 8-bromo-cGMP when these
are administered by microdialysis. To address this problem, one
approach used was to apply SIN-1 or 8-bromo-cGMP by iontophoresis, in
addition to delivering these agents by microdialysis. The drugs
presumably did not spread very far since the iontophoresis currents
were applied for only around 2 min at intensities of 70-100 nA. The results showed that drugs administered by iontophoresis produced similar effects to those produced when the drug was given by
microdialysis, with the exception that microdialysis administration of
drug produced a longer lasting effect. Because NO is a diffusible
molecule, acting in a nonsynaptic manner, it can freely diffuse for a
considerable distance to reach its target (Baringa
1991
). Therefore our results support the view that different
neurons may respond differently to NO release.
In conclusion, cGMP modulates the processing of STT neuronal nociceptive transmission in part by influencing the spinal inhibition mediated by glycine and GABA receptors. The modulation varies with the location of the STT cells on which cGMP acts. An increase in cGMP level within the spinal cord consistently sensitizes deep WDR STT neurons, and this sensitization is accompanied by an attenuation of spinal inhibition. Moreover, the current data support the view that cGMP is involved in the production of hyperalgesia and allodynia in the same way as NO, suggesting that NO and cGMP function in the same signal transduction cascade.
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ACKNOWLEDGMENTS |
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The authors thank K. Gondesen, G. Robak, and Drs. Elie Al-Chaer and Yi Feng for technical and collegial assistance in preparation of the experimental animals, and G. Gonzales for expert assistance with the illustrations.
This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-09743 and NS-11255.
Present address of Y. B. Peng: PNMB/NIDR/NIH, Bldg. 49, Rm. 1WW14, 49 Convent Dr., Bethesda, MD 20892-4410.
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FOOTNOTES |
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Address for reprint requests: W. D. Willis, Dept. of Anatomy and Neurosciences, Marine Biomedical Institute, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1069.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 April 1998; accepted in final form November 1998.
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REFERENCES |
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