| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of 1Anesthesiology, 2Neurobiology and 3Neuroengineering, Duke University Medical Center, Durham, North Carolina 27710; and 4Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021
Submitted 6 April 2004; accepted in final form 1 June 2004
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
, and bradykinin, which alter the sensitivity of voltage-gated ion channels in a manner that may result in hyperalgesia or allodynia (Cesare and McNaughton 1996
; Kidd and Urban 2001; Meyer et al. 2000; Millan 1999; Nicol and Cui 1994; Weinreich et al. 1995; Woolf and Salter 2000). This altered sensitivity is mediated by the activation of intracellular signal transduction pathways, thereby making it important to identify the pathways that may increase or decrease nociceptor sensitivity (Costigan and Woolf 2000; Schild and Kunze 1997; Szolcsanyi 1993; Woolf and Salter 2000). Many such studies have focused on the cAMP-protein kinase C (PKC) pathway, the activation of which generally has been shown to increase nociceptor sensitivity to chemical, thermal, or physical stimuli (Aley and Levine 1999; Cesare et al. 1999; Evans et al. 1999; Lopshire and Nicol 1998; Piper and Docherty 2000).
In this study, we investigated how the modulation of cGMP-dependent pathways affects voltage-gated sodium and potassium channels in nociceptors. In such neurons, the nitric oxide (NO)-dependent and -independent cGMP-PKG pathways have been shown to induce several physiological responses. Most of these studies have focused on the effects of NO-dependent pathway (Lewin and Walters 1999; White 1999; Yoshimura et al. 2001) because release of NO may lead to nociceptor sensitization (Malmberg and Yaksh 1993; Meller et al. 2003; Moore et al. 1991), peripheral injections of NO precursors cause pain (in humans) (Holthusen and Arndt 1994), and inhibition of nitric oxide synthase (NOS) reduces hyperalgesia (Baron et al. 2002; Tedesco et al. 2002). Moreover, NO has been shown to block action potential conduction (Redford et al. 1997) and reduce the activity of a variety of voltage-gated sodium channel subtypes (Kim et al. 2000; Renganathan et al. 2002; Yoshimura et al. 2001).
To augment these studies, we investigated the effects of cGMP [actually the membrane-permeant cGMP analogue 8-(4-chlorophenylthio)-3',5' (CPT)-cGMP] per se on nociceptor excitability and selected ion channels present in these neurons. This is important because intrathecal injections of cGMP cause hyperalgesia in mice (Garry and Hargreaves 1994) and injection of dibutyryl-cyclic GMP into a rat paw reduces PGE2-induced hyperalgesia (Soares and Duarte 2001) and also because activation of guanaylyl cyclase (GC) reduces chemically induced pain (Abacioglu et al. 2000). To obtain a deeper understanding of the underlying causes of these effects, we measured in capsaicin-sensitive nociceptive neurons how the addition of CPT-cGMP modulates electrical excitability, evoked action potential morphology, and voltage-gated sodium and potassium channel function. Capsaicin-sensitive neurons are a common type of nociceptor that contains tetrodotoxin-resistant (TTX-R) sodium channels (Kim et al. 1999; Liu et al. 2001), which contribute to the rising phase of the action potential and are important in the pathological states relating to hyperalgesia and allodynia (Kim et al. 1999; Liu et al. 2001). Capsaicin-sensitive neurons also possess transient (IA) and delayed (IK) potassium channels, which regulate action potential activity (Liu and Simon 2003). Consequently, we examined the extent to which CPT-cGMP altered each of these three types of ion channels. To our knowledge, this is the first time that the effect of a membrane-permeant cGMP analogue has been evaluated on three different channels types in the same neuron type. However, because a membrane-permeable cGMP analogue would be expected to adsorb at the bilayer/solution interface, it could alter indirectly the ion channel function by virtue of altering the mechanical properties (i.e., bending and compressibility moduli) of the bilayer surroundingthe ion channel (Cantor 2002; Huang 1986; Hwang et al. 2003; Lundbaek and Andersen 1994, 1999; Nielsen et al 1998; Partenskii and Jordan 2002). For this reason, we also tested the effect of CPT-cGMP on gramicidin A channels in planar lipid bilayers, which permits the monitoring of changes in bilayer material properties (Lundbaek and Andersen 1999).
We found that the addition of CPT-cGMP decreased nociceptor excitability. Importantly, CPT-cGMP had no effect on gramicidin A channels, indicating that this molecule has little, if any, bilayer modifying actions, and we conclude that the changes in excitability are due to activation of cGMP-dependent pathways. CPT-cGMP was relatively ineffective in inhibiting IK currents, whereas it markedly inhibited TTX-R type sodium currents that would account, at least in part, for its ability to decrease nociceptor excitability.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Unless stated otherwise, all chemicals came from Sigma Chemical. Cell culture materials were purchased from GIBCO (Life Technologies, Rockville, MD).
Electrophysiology
Trigeminal ganglion (TG) neurons from adult Sprague-Dawley rats were excised from rats that were anesthetized with pentobarbital sodium (50 mg/kg). After excision, the subjects were killed with 150 mg/kg pentobarbital sodium. Care of animals conformed to standards established by the National Institutes of Health. All animal protocols were approved by the Duke University Institutional Animal Care and Use Committee.
Cell culture
TG neurons were cultured using methods described previously (Liu and Simon 1996). TG ganglia were excised, dissected, and collected in modified Hank's balanced salt solution (mHBSS). After washing in mHBSS, the ganglia were diced into small pieces and incubated in mHBSS for 30–50 min at 37°C in 0.1% collagenase (Type Xl-S). Individual cells were dissociated by triturating the tissue through a fire-polished glass pipette that was followed with a 10-min incubation at 37°C in 10 µg/ml DNase I (Type lV) in F-12 medium (Life Technologies, Gaithersburg, MD). After washing three times with F-12 media, the cells were cultured in DMEM supplemented with 10% fetal bovine serum. The cells were then plated on poly-D-lysine-coated glass coverslips (15 mm diam) and cultured overnight at 37°C. Only neurons without, or with short, processes were used for the electrophysiological measurements. All experiments were done at room temperature (22–24°C)
Patch-clamp recordings
For whole cell voltage-clamp experiments we, used glass pipettes (R-6 borosilicate, Drummond Scientific, Broomall, PA.) with resistances 
2 M
. Recordings were obtained using an Axopatch-200B patch-clamp amplifier (Axon Instruments, Foster City, CA), and the output was digitized with a Digidata 1322A converter (Axon Instruments). The intra- and extracellular solutions used to isolate the different ion channels are given in Table 1. When recording currents having a large magnitude, voltage errors may occur. To reduce such errors, we either reduced the concentrations of the major permeable permeant ion (Table 1) and/or further compensated for the series resistance and capacitance (
90% compensation). For most neurons, the uncompensated series resistance resulted in voltage-clamp errors within 5 mV. If the errors were 5 mV, the results were not included in the analysis. Because nociceptors have many of the same properties as neurons with TRPV1 receptors (Baccaglini and Hogan 1983; Petruska et al. 2000; Tominaga et al. 1998), at the end of each experiment, all the neurons were tested for the presence of TRPV1 receptors by applying 10 µM capsaicin. If capsaicin triggered an inward current more than –200 pA from a holding potential of –60 mV, the neuron was defined as being capsaicin sensitive and used in the subsequent analysis.
|
) and affect voltage-gated sodium currents (Renganathan et al. 2002). Internal and external solutions
The concentrations of the various compounds that were used in measuring membrane excitability, and the sodium, and potassium IK and IA currents are given in Table 1.
Current-ramp and -clamp measurements
For the current-ramp measurements the resting potential was adjusted to –80 mV and current ramps, ranging from 0 to –2 nA over 1.5 s, were applied to the neuron before, during (after 3 min incubation) the application of 0.1 and 1 mM CPT-cGMP, and 3 min after washout. Because similar results were obtained for 0.1 and 1.0 mM CPT-cAMP, the effects of these two concentrations were combined. The 3-min intervals were used in all subsequent experiments because they were sufficiently long to reduce the sensitivity of the neuron to evoke action potentials (see Fig. 2). In the same neurons, action potentials (APs) were measured by step depolarization's of 20-ms duration in 0.05-nA steps ranging from 0.1 to –2 nA (Fig. 2). For a control response, we obtained the magnitude of the injected current when the shape of the APs became essentially independent of a larger injected current (Liu et al. 2001). The sampling rate was 10 kHz.
|
Voltage-gated sodium currents
Measurements of TTX-R currents were achieved by preincubating the neurons for 
5 min in 0.2 µM TTX (Kim et al. 1999; Tate et al. 1998). TTX was present throughout all the subsequent manipulations. The peak current-voltage (Ip-V) relationship was determined using a voltage step protocol in which the voltage was increased in 5-mV step increments from the holding potential of –80 mV to test potentials 40 mV. Peak currents were analyzed using pCLAMP 8 and plotted against the applied voltage to obtain the Ip-V relation of sodium current activation. The voltage-dependence of inactivation h(
) was determined by measuring the peak maximal sodium currents following the delivery of –100 to 20 mV in 5-mV steps (Liu et al. 2001). With this protocol, both persistent and slowly inactivating sodium currents were observed, although the vast majority of the currents were of the slowly inactivating type (Dib-Hajj et al. 1999).
IA and IK currents
IA currents were obtained from the total outward current using TEACl to block IK; IK was obtained from the total outward current using 4-aminopyridine (4-AP) to block IA currents (Liu and Simon 2003). The IA and IK current-voltage relation was determined using a voltage step protocol in which the cells were depolarized for 250 ms from a holding potential of –80 to test potentials varying between –70 and +60 mV in 10-mV increments. The voltage dependence of channel availability was determined using 250-ms prepulses varying between –120 and 40 mV in 10-mV steps before returning to the holding potential of –80 mV. There was a 4-s interval between each depolarization.
Chamber/solution delivery
The recording chamber containing the neurons had a volume of 350 µl and was continuously perfused at 6 ml/min by the relevant extracellular solution. CPT-cAMP was dissolved in the extracellular buffer immediately before the experiments were performed.
Statistics and curve fitting
The electrophysiological results were analyzed and fitted using pClamp (Axon Instruments) and SigmaPlot (SPSS, Chicago IL) software. G-V and inactivation-voltage parameters were fit to the Boltzmann relation: X = C + {Xmax/[1 + exp (V0.5 –Vm/k)]}, where V0.5 is the membrane potential (Vm) at which 50% of activation or inactivation was observed, k is the slope of the function, and C is a constant (= 0 in the G-V relation). The inactivation time course was fit to a single-exponential decay (R2 0.98) and the values summarized in the text refer to the responses at 50 mV. The results were analyzed for statistical significance using, where appropriate, the paired and unpaired t-test. Statistical significance is defined as P < 0.05. All electrophysiological results are presented as means ± SD.
Measurements with planar bilayers
Planar lipid bilayers were formed at 25 ± 1°C using the pipette method described previously (50) from n-decane solutions (2–3% wt/vol) of dioleoloylphosphatidylcholine (DOPC; Avanti Polar Lipids, Alabaster, AL) across a hole (1.6 mm diam) in a Teflon partition that separates two aqueous solutions of 1 M NaCl (buffered to pH 7 with 10 mM HEPES and NaOH). D-Ala-gA-, (AGALAVVVWLWLWLW, the D-residues are underlined) was added from ethanolic stock solutions to the electrolyte solution on either side of the bilayer. CPT-cGMP or 8-bromoadenosine-3',5' (8-Br)-cAMP (see Fig. 1) were added to the electrolyte solution, stirred for 5 min, and incubated for 30 min to assure maximal adsorption to the bilayer.
|
; Olbrich et al. 2000), including biological membranes.
Single-channel current transitions were detected using the algorithm described by Andersen (1983) implemented in software written in AxoBasic (Axon Instruments). Single-channel current transition amplitude histograms and lifetime histograms were constructed as previously described (Anderson 1983; Sawyer et al. 1989). The lifetime histograms were transformed into survivor distributions, and the average channel lifetimes (
) were determined by fitting a single exponential distribution: N(t) = N(0) · exp{–t/}, where N(t) denotes the number of channels with a lifetime longer than time t, and is the time constant to each histogram (Durkin et al. 1993; Sawyer et al. 1989). The final results for each experimental condition are based on the means ± SD of at least three independent measurements.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
In capsaicin-sensitive neurons, the bath application of CPT–cGMP decreases the number of evoked action potentials from 14 ± 11 to 7 ± 7 (n = 15; Fig. 2, A and inset). After a 3-min washout, the number of action potentials recovered to 11 ± 11 (n = 15). Action potentials of long-duration having characteristic humps on the repolarization phase, such as those seen in Fig. 2B, are indicative of capsaicin-sensitive nociceptors (Baccaglini and Hogan 1983). Comparison of the morphology of the action potentials under these three conditions revealed that CPT-cAMP produced a 9-mV decrease in the action potential amplitude (from 136 ± 11 to 127 ± 19 mV, n = 15), a 7-mV increase in the threshold potential (see 
in Fig. 2B; from –21 ± 7 to –14 ± 7 mV, n = 15), and a 1-ms increase in the action potential duration (from 2.4 ± 1.1 to 3.4 ± 1.1 ms, n = 15). After a 3-min washout, these parameters were, to various extents, reversible. Because CPT-cGMP decreased nociceptor sensitivity and had multiple effects on the action potential shape, it suggested to us that several types of ion channels were affected. We consequently explored whether voltage-gated sodium and potassium channels in these neurons are affected by CTP-cGMP.
TTX-R Sodium currents
Because capsaicin-sensitive neurons have much larger TTX-R than TTX-sensitive (TTX-S) currents (Kim et al. 1999), we investigated the effect of CPT-cGMP on TTX-R currents. We found that CPT-cAMP reduced the amplitude of the TTX-R currents 37%, shifted the conductance-voltage relation in the depolarizing direction by 4 mV, and shifted the inactivation-voltage relation 3 mV in the hyperpolarizing direction (Table 2). These effects were partially reversible after a 3-min washout (Fig. 3). For the sake of completeness, as well as because the action potential from these neurons has both TTX-R and -sensitive components, we also measured the effect of 1 mM CPT-cGMP on the total sodium current (not shown). Not surprisingly, the results were quite similar to those found for the TTX-R currents. That is, 1 mM CPT-cGMP inhibited the total sodium current 54%, produced a 5-mV depolarizing shift in the G-V relation and produced a 4-mV hyperpolarizing shift in the inactivation–voltage relation (see Table 2).
|
|
We also tested the effects of 1 mM CPT-cGMP on IA and IK currents. We reported previously that IA currents were depressed 32% by 1 mM CPT-cGMP (Liu and Simon 2003) and Fig. 4A. Here we report that CPT-cGMP did not significantly alter the G-V relation but produced a small, but statistically significant, 3-mV hyperpolarizing shift in the inactivation–voltage curve (see Table 2).
|
CPT-cGMP does not affect lifetime of conductance of gA channels
As would be expected for membrane-permeant molecules, the "membrane-permeable" cyclic nucleotides, e.g., CPT-cGMP (and also 8-Br-cAMP) are somewhat amphipathic (Fig. 1). This may be cause for concern because of the known ability of amphipathic (and even nonpolar) aromatic molecules like genistein, phloretin, and benzene to alter the lifetime and conductance of gramicidin A channels in lipid bilayers (Lundbaek and Andersen 1994, 1999)—changes that reflect drug-induced changes in the bilayer material properties. Given that CPT-cGMP (and other membrane-permeable cyclic nucleotides) alters the function of many different membrane proteins, we decided to examine whether CPT-cGMP (and also 8-Br-cAMP) could exert some (or all) of their effects by altering the properties of the host bilayer? We did so by evaluating whether CPT-cGMP and 8-Br-cAMP alter the lifetime and conductance of gramicidin A channels.
Figures 5 and 6 show that addition of 100 µM CPT-cGMP had no effect on gramicidin A channel single-channel current amplitude (i) and average lifetime (). These experiments were done in 0.1 M KCl (buffered to pH 7) to increase our ability to detect changes in the single-channel currents as would be expected if the negatively charged nucleotides adsorb to the bilayer/solution interface. The current traces (Fig. 5) are from different bilayers because CPT-cGMP, even at 100 µM, causes bilayers to become unstable and break. For this reason, we cannot evaluate whether CPT-cGMP increases the channel appearance rate. (Given this instability, most experimental results were obtained in 1.0 M NaCl, buffered to pH 7, as this increases bilayer stability but not to the point where we can evaluate whether addition of the nucleotides alters the channel appearance rate.) The histograms (Fig. 5) show single-channel current transition amplitude and lifetime distributions as well as single-exponential fits to the lifetime distributions. Table 3 summarizes the results obtained with both CPT-cGMP and 8-Br-cAMP in 0.1 M KCl and 1.0 M NaCl. We conclude that these two compounds have little, if any, effect on gramicidin channel function. The lack of effect of these compounds on gramicidin A channel function indicates that the effects of CTP-cGMP are unlikely to arise from changes in bilayer elastic properties, although the decrease in bilayer stability (decrease in lysis tension) certainly indicates that the cyclic nucleotides (or some contaminant) interacts with the bilayer. These results are somewhat surprising considering that both these compounds permeate cell membranes.
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
; Garry and Hargreaves 1994; Lewin and Walters 1999; Meller et al. 2003; Moore et al. 1993; Soares and Duarte 2001). We have explored the consequences of modulating this pathway on three types of ion channels found in nociceptors and found that CPT-cGMP alters TTX-R sodium currents and the transient IA potassium currents but has no effect on the delayed rectifier IK currents. This differential regulation suggests that the effect is specific due to the cGMP-PKG pathway. By investigating the effect on gramicidin A channels, we could conclude that the changes in TTX-R and IA channel function do not arise from "nonspecific" changes in bilayer elasticity, which could alter the function of the imbedded channels. But we also note that the decreased bilayer stability demonstrates that this membrane-permeable, and thus presumably amphiphilic, molecule can bind to the bilayer. Our primary finding was that increases in cGMP decrease the sensitivity of capsaicin-sensitive nociceptive neurons to evoke action potentials (Fig. 2). This result should be of interest to researchers seeking to identify cGMP-dependent pathways and their downstream targets that will decrease nociceptor activity. Although we found that IA currents also are inhibited by cGMP, which should increase nociceptor excitability, the inhibition of the TTX-R channels appears to be the more important factor in reducing nociceptor excitability.
Blocking of action potentials by cGMP
We have found that the addition of CTP-cGMP decreases nociceptor excitability (Fig. 2). It was previously found that NO could block action potentials in demyelinated axons (Redford et al. 1997). It follows that the decrease in nociceptor excitability can arise from both NO-dependent and -independent pathways, most likely by converging on the more downstream pathways that involve guanylyl cyclase or PKG (White 1999).
One common pathway that could explain why both NO-dependent and -independent pathways decrease neuronal sensitivity is that they both inhibit voltage-gated sodium channels. Renganathan et al. (2002) have shown that the activation of NO-dependent pathways inhibits both TTX-S and -R currents. However, in that study, it also was reported that addition of 2 mM of 8-bromo-cGMP produced a small increase in these sodium currents. In contrast, we have shown that another cell permeable analogue, 1 mM CPT-cGMP, significantly decreased the TTX-R sodium currents (Fig. 3). This discrepancy can perhaps be rationalized by differences in the protocols. Renganathan et al. (2002) used cesium fluoride (CsF) in their intracellular solution, no doubt because such solutions give better sealing and stability. However, CsF is well known to increase basal levels of cGMP, which makes it difficult to compare the effects of adding membrane-permeable cGMP analogues in our experiments with effects measured using CsF.
In summary, we have shown that in the presence of CPT-cAMP, the sensitivity of voltage-gated sodium channels in capsaicin-sensitive nociceptors is depressed.
Channel selectivity of response to cGMP
One aspect of this study was to investigate the effects of the addition of CPT-cGMP on three different channel types in the same type of neuron. It was found that increasing the CPT-cGMP concentration was generally inhibitory with the order of inhibition of the peak currents being TTX-R IA >> IK 0%. Although we have not investigated the origin of the inhibition, at least for sodium channels, the inhibition arises, in part, from the shifts the voltage dependence of the activation and inactivation parameters (Table 2). These changes could arise because CPT-cGMP binds directly with the channels or, more likely, alters their state of phosphorylation. Given that CPT-cGMP is membrane permeable, CPT-cGMP is likely to be amphipathic and therefore adsorb to the bilayer/solution interface, which could produce a change in the bilayer mechanical properties that in turn alter channel behavior (Cantor 2002; Lundbaek and Andersen 1994, 1999). This is unlikely to be major contributing mechanism, however, because 100 µM CPT-cGMP did not alter the conductance of gramicidin A channels, indicating that it does not adsorb to any significant extent in the interfacial region of the bilayer. Nor does CPT-cGMP (or 8-Br-cAMP) alter the single-channel lifetimes (Fig. 6 and Table 3), again indicating that these compounds have little, if any, effects on bilayer properties. Consistent with this conclusion, the effect of CPT-cGMP is specific, in the sense that the IK currents were unaffected by CPT-cGMP (Fig. 4)—again suggesting that the effects on IA and sodium channels are not due to nonspecific membrane alteration.
Although not a focus of the present study, the results raise questions concerning the mechanism by which membrane-permeant cyclic nucleotides cross cell membranes. If these charged compounds to not adsorb significantly to the membrane/solution interface, do they cross the membrane by a simple solubility-diffusion mechanism?
Cyclic AMP and cyclic GMP have opposite effects on nociceptor excitability
There have been many studies showing that the cAMP-PKA pathway generally sensitizes nociceptors (Aley and Levine 1999; Cesare et al. 1999; Evans et al. 1999; Kress et al. 1996; Lopshire and Nicol 1998; Piper and Docherty 2000). What we have shown in this study is that the cGMP-PKG pathway has a general inhibitory effect on nociceptor excitability. That is, in nociceptors these two pathways appear be antagonistic. In this regard, some receptors, such as the TRPV1 receptor, have been shown to activate both cAMP (Liu et al 2001)- and cGMP (Dymshitz and Vasko 1994; Wood et al. 1989)-mediated pathways, meaning the effect that its activation has on a particular channel type will be reflective of both pathways (Liu and Simon 2003; Liu et al. 2001; Morris and Malbon 1999).
In summary, we found that the activation of cGMP pathways will decrease nociceptor excitability thereby making it more difficult to initiate and propagate action potentials. This decrease occurs primarily as a consequence of the TTX-R currents. Because TTX-R currents are found in nociceptors and have been shown to be involved in allodynia, hyperalgesia and various disease states (Baker and Wood 2001; Waxman 1999), the ability to understand how they may be decreased will be relevant for pain management.
|
GRANTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: L. Liu, 229 Bryan Research Bldg., Research Drive, Durham, NC 27710 (E-mail:lieju{at}neuro.duke.edu).
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Aley KO and Levine JD. Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci 19: 2181–2186, 1999.
Anderson OS. Ion movement through gramicidin A channels. Single-channel measurements at very high potentials. Biophys J 41: 119–133, 1983.[Web of Science][Medline]
Baccaglini PI and Hogan PG. Some rat sensory neurons in culture express characteristics of differentiated pain cells. Proc Natl Acad Sci USA 80: 594–598, 1983.
Baker MD and Wood JN. Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci 22: 27–31, 2001.[Medline]
Baron MJ, Lazdunski M, and Voilley N. Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci 22: 10662–10670, 2002.
Cantor RS. Size distribution of barrel-stave aggregates of membrane peptides: influence of the bilayer lateral pressure profile. Biophys J 82: 2520–2525, 2002.[Web of Science][Medline]
Cardenas CG, Del Mar LP, and Scroggs RS. Variation in serotonergic inhibition of calcium currents in four types of rat sensory neurons differentiated by membranes properties. J Neurophysiol 74: 1870–1879, 1995.
Cesare P and McNaughton P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc Natl Acad Sci USA 93: 15435–15439, 1996.
Cesare P, Moriondo A, Vellani V, and McNaughton PA. Ion channels gated by heat. Proc Natl Acad Sci USA 96: 7658–7663, 1999.
Costigan M and Woolf CJ. Pain: molecular mechanisms. Pain 1: 35–44, 2000.[CrossRef][Web of Science]
Dib-Hajj S, Tyrrell L, Cummins TR, Black JA, Wood PM, and Waxman SG. Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett 462: 117–120, 1999.[CrossRef][Web of Science][Medline]
Durkin JT, Providence LL, Koeppe RE II, and Andersen OS. Energetics of heterodimer formation among gramicidin analogues with an NH2-terminal addition or deletion. Consequences of a missing residue at the join in channel. J Mol Biol 231: 1102–1121, 1993.[CrossRef][Web of Science][Medline]
Dymshitz J and Vasko MR. Endothelian-1 enhances capsaicin-induced peptide release and cGMP accumulation in cultures of rat sensory neurons. Neurosci Lett 167: 128–132, 1994.[CrossRef][Web of Science][Medline]
Evans AR, Vasko MR, and Nicol G. The cAMP transduction cascade mediates the PGE2-induced inhibition of potassium currents in rat sensory neurons. J Physiol 516: 163–178, 1999.
Evans E and Needham D. Physical properties of surfactant bilayer membranes: thermal transitions, elasticity, rigidity, cohesion, and colloidal interactions. J Phys Chem 91: 4219–4228, 1987.[CrossRef][Web of Science]
Garry MG and Hargreaves KM. Intrathecal injection of cyclic 3'-5' guanosine monophosphate (cGMP) produces hyperalgesia in mice. Eur J Pharmacol 260: 129–131, 1994.[CrossRef][Web of Science][Medline]
Holthusen H and Arndt JO. Nitric oxide evokes pain in humans on intracutaneous injection. Neurosci Lett 165: 71–74, 1994.[CrossRef][Web of Science][Medline]
Huang HW. Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime. Biophys J 50: 1061–1070, 1986.[Web of Science][Medline]
Hwang T-C, Koeppe RE II, and Andersen OS. Genistein can modulate channel function by a phosphorylation-independent mechanism: importance of hydrophobic mismatch and bilayer mechanics. Biochemistry 42: 13646–13658, 2003.[CrossRef][Medline]
Kidd BL and Urban LA. Mechanisms of inflammatory pain. Br J Anesth 87: 3–11, 2001.
Kim H-C, Chung M-K, Kim J-S, and Lee J-H. Voltage-dependent sodium and calcium currents in acutely isolated adult rat trigeminal root ganglion neurons. J Neurophysiol 81: 1123–1134, 1999.
Kim SJ, Song S-K, and Kim J. Inhibitory effects of nitric oxide on voltage-dependent calcium currents in rat dorsal root ganglion cells. Biochem Biophys Res Commun 271: 509–514, 2000.[CrossRef][Web of Science][Medline]
Kress M, Rodl J, and Reeh PW. Stable analogues of cyclic AMP but not cyclic GMP sensitize unmylelinated primary in rat skin to heat stimulation but to inflammatory mediators in vitro. Neuroscience 74: 609–617, 1996.[CrossRef][Web of Science][Medline]
Lewin MR and Walters ET. Cyclic GMP pathway is critical for inducing long-term sensitization of nociceptive sensory neurons. Nat Neurosci 2: 18–23, 1999.[CrossRef][Web of Science][Medline]
Liu L, Oortgiesen M, Li L, and Simon SA. Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive neurons. J Neurophysiol 85: 745–758, 2001.
Liu L and Simon SA. Capsaicin-induced currents with distinct desensitization and Ca2+ dependence in rat trigeminal ganglion cells. J Neurophysiol 75: 1503–1514, 1996.
Liu L and Simon SA. Modulation of IA currents by capsaicin in rat trigeminal ganglion neurons. J Neurophysiol 89: 1347–1401, 2003.
Lopshire JC and Nicol G. The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. Neuroscience 18: 6081–6092, 1998.[Medline]
Lundbaek JA and Andersen OS. Spring constants for channel-induced lipid bilayer deformations—estimates using gramicidin channels. Biophys J 76: 889–895, 1999.[Web of Science][Medline]
Lundbaek JA and Andersen OS. Lysophospholipids modulate channel function by altering the mechanical properties of lipid bilayers. J Gen Physiol 104: 645–673, 1994.
Malmberg AB and Yaksh TL. Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 54: 291–300, 1993.[CrossRef][Web of Science][Medline]
Meller ST, Cummings CP, Traub RJ, and Gebhart GF. The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience 60: 367–374, 2003.[CrossRef]
Meyer RA, Campbell JN, and Srinivasa NR. Peripheral neural mechanisms of nociception. In: Textbook of Pain, edited by Melzak R and Wall P. Edinburgh, UK: Churchill Livingstone, 2000, p. 13–44.
Millan M. The induction of pain: an integrative review. Prog Neurobiol 57: 1–164, 1999.[CrossRef][Web of Science][Medline]
Moore PK, Oluyomi AO, Babbedge RC, Wallace P, and Hart SL. L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol 102: 198–202, 1991.[Web of Science][Medline]
Moore PK, Wallace P, Gaffen Z, Hart SL, and Babbedge RC. Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects. Br J Pharmacol 110: 219–224, 1993.[Web of Science][Medline]
Morris AJ and Malbon CC. Physiological regulation of G protein -linked signaling. Physiol Rev 79: 1373–1430, 1999.
Nicol G and Cui M. Enhancement by prostaglandin E2 of bradykinin activation of embryonic rat sensory neurones. J Physiol 480: 485–492, 1994.
Nielsen C, Goulian M, and Andersen OS. Energetics of inclusion-induced bilayer deformations. Biophys J 74: 1966–1983, 1998.[Web of Science][Medline]
Olbrich K, Rawicz W, Needham D, and Evans E. Water permeability and mechanical strength of polyunsaturated lipid bilayers. Biophys J 79: 321–327, 2000.[Web of Science][Medline]
Partenskii MB and Jordan PC. Membrane deformation and the elastic energy of insertion: perturbation of membrane elastic constants due to peptide insertion. J Chem Phys 117: 1–9, 2002.[CrossRef]
Petruska JC, Napaporn J, Johnson RD, Gu JG, and Cooper BY. Subclassified acutely dissociated cells of rat DRG: histochemistry and patterns of capsaicin-, proton-, and ATP-activated currents. J Neurophysiol 84: 2365–2379, 2000.
Piper AS and Docherty RJ. One-way cross-desensitization between P2X purinoceptors and vanilloid receptors in adult rat dorsal root ganglion neurones. J Physiol 532.3: 685–696, 2000.
Redford EJ, Kapoor R, and Smith KJ. Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120: 2149–2157, 1997.
Renganathan M, Cummins TR, and Waxman SG. Nitric oxide blocks fast, slow, and persistent Na+ currents in C-type DRG neurons by a cGMP-independent mechanism. J Neurophysiol 87: 761–765, 2002.
Sawyer DB, Koeppe RE II, and Andersen OS. Induction of conductance heterogeneity in gramicidin channels. Biochemistry 28: 6571–6583, 1989.[CrossRef][Medline]
Schild JH and Kunze DL. Experimental and modeling study of Na+ current heterogeneity in rat nodose neurons and its impact on neuronal discharge. J Neurophysiol 78: 3198–3209, 1997.
Soares AC and Duarte IG. Dibutyryl-cyclic GMP induces peripheral antinociception via activation of ATP-sensitive K(+) channels in the rat PGE2-induced hyperalgesic paw. Br J Pharmacol 134: 127–131, 2001.[CrossRef][Web of Science][Medline]
Szabo G, Eisenman G, and Ciani S. The effects of macrotetralide actin antibiotics on the electrical properties of phospholipid bilayer membranes. J Membr Biol 1: 346–382, 1969.[CrossRef][Web of Science]
Szolcsanyi J. Actions of capsaicin on sensory receptors. In: Capsaicin in the Study of Pain, edited by Wood J. New York: Academic, 1993, p. 1–26.
Tate S, benn S, Hick C, Trezise D, John V, Mannion RJ, Costagin M, Plumpton C, Grose D, Gladwell Z, Kendell G, Dale K, Bountra C, and Woolf CJ. Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci 1: 653–655, 1998.[CrossRef][Web of Science][Medline]
Tedesco LS, Fuseler J, Grisham M, Wolf R, and Roerig SC. Therapeutic administration of nitric oxide synthase inhibitors reverses hyperalgesia but not inflammation in a rat model of polyarthritis. Pain 95: 215–223, 2002.[CrossRef][Web of Science][Medline]
Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, and Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21: 531–543, 1998.[CrossRef][Web of Science][Medline]
Waxman SG. The molecular pathophysiology of pain: abnormal expression of sodium channel genes and its contribution to hyperexcitability of primary sensory neurons. Pain Suppl 6: S133–S140, 1999.
Weinreich D, Koschorke GM, and Undem BJ. Prevention of the excitatory actions of bradykinin by inhibition of PGI2 formation in nodose neurons of the guinea pig. J Physiol 483: 735–746, 1995.
White RE. Cyclic GMP and ion channel regulation. In: Advances in Second Messengers and Phosphoprotein Research. New York: Academic, 1999, p. 251–277.
Wood JN, Coote PR, Minhas A, McNiel M, Mullany I, and Burgess G. Capsaicin-induced ion fluxes increase cGMP but not cAMP levels in rat sensory neurons in culture. J Neurosci 53: 1203–1211, 1989.
Woolf CJ and Salter MW. Neuronal plasticity: increasing the gain in pain. Science 288: 1765–1768, 2000.
Yoshimura N, Seki S, and de Groat WC. Nitric oxide modulates Ca2+ channels in dorsal root ganglion neurons innervating rat urinary bladder. J Neurophysiol 86: 304–311, 2001.
This article has been cited by other articles:
|
|
 |
|
  J.-H. Zheng, E. T. Walters, and X.-J. Song Dissociation of Dorsal Root Ganglion Neurons Induces Hyperexcitability That Is Maintained by Increased Responsiveness to cAMP and cGMP J Neurophysiol, January 1, 2007; 97(1): 15 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Song, Z.-B. Wang, Q. Gan, and E. T. Walters cAMP and cGMP Contribute to Sensory Neuron Hyperexcitability and Hyperalgesia in Rats With Dorsal Root Ganglia Compression J Neurophysiol, January 1, 2006; 95(1): 479 - 492. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
