Compression Of Dorsal Root Ganglion Research Articles

Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion

P2X receptors on dorsal root ganglion (DRG) neurons have been strongly implicated in pathological nociception after peripheral nerve injuries or inflammation. However, nothing is known of a role for purinergic receptors in neuropathic pain produced by a chronic compression of DRG (CCD) – an injury that may accompany an intraforaminal stenosis, a laterally herniated disc or other disorders of the spine leading to radicular pain. In a rat model of DRG compression, hyperexcitable neurons retain functioning axonal connections with their peripheral targets. It is unknown whether such hyperexcitability might enhance chemically mediated nociceptive stimulation of the skin. In this study, CCD facilitated the nocifensive behavior and mechanical hyperalgesia-induced by the P2X 3 agonist, α,β-methylene ATP (α,β-meATP). An injection of α,β-meATP into the hind paw of CCD rats resulted in a significantly greater decrease in the mean threshold to von Frey stimuli and a greater duration of paw lifts than in sham-operated control rats. CCD also increased the levels of P2X 3 receptor protein and the number of P2X 3 immunoreactive, small diameter DRG neurons in the compressed ganglion. P2X 3 receptors were co-labeled with the isolectin IB4, consistent with a role in nociception. In addition, a α,β-meATP induced significantly larger fast-inactivating currents in CCD- than in sham-operated acutely dissociated DRG neurons. These currents were accompanied by the generation of action potentials – but only in the CCD neurons. U0126, a specific inhibitor of the MEK1/2, greatly down-regulated the enhanced current. Taken together, these observations suggest that enhanced purinergic responses after CCD are mediated by P2X 3 receptors.

Proteomic analysis of differential proteins related to the neuropathic pain and neuroprotection in the dorsal root ganglion following its chronic compression in rats

The aim of the study was to identify the differential protein expressions related to neuropathic pain and neuroprotection in the dorsal root ganglion (DRG) following chronic compression of DRG (CCD) in rats. We conducted a proteomics study of L(4) and L(5) DRG after CCD for 28 days. A total of 98 protein spots were detected with significant changes in their expression levels after CCD and 15 protein spots were identified by the matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis. Of these proteins, annexin A2, protein kinase C epsilon (PKCepsilon), glyceraldehyde-3-phosphate dehydrogenases (GAPDH), and heat shock protein 70 (HSP70) were up-regulated significantly compared with the normal control. These four proteins and p11, which was annexin A2 light chain, were further examined by Western blotting. The results of Western blotting and the proteomic analysis showed consistent data. Moreover, real-time quantitative RT-PCR experiments indicated that CCD-induced increase in protein levels was associated with an up-regulation of annexin A2 and PKCepsilon gene expression. In conclusion, this study highlights the molecular process in DRG underlying neuropathic pain. CCD is associated with the up-regulation of annexin A2 and PKCepsilon and their related genes. The up-regulation of GAPDH and HSP70 suggests that there exist concurrent processes of nervous injury and neuroprotection in the course of neuropathic pain.

Radicular Low Back Pain

Radicular Low Back Pain

Differing Alterations of Sodium Currents in Small Dorsal Root Ganglion Neurons after Ganglion Compression and Peripheral Nerve Injury

Voltage-gated sodium channels play important roles in modulating dorsal root ganglion (DRG) neuron hyperexcitability and hyperalgesia after peripheral nerve injury or inflammation. We report that chronic compression of DRG (CCD) produces profound effect on tetrodotoxin-resistant (TTX-R) and tetrodotoxin-sensitive (TTX-S) sodium currents, which are different from that by chronic constriction injury (CCI) of the sciatic nerve in small DRG neurons. Whole cell patch-clamp recordings were obtained in vitro from L4 and/or L5 dissociated, small DRG neurons following in vivo DRG compression or nerve injury. The small DRG neurons were classified into slow and fast subtype neurons based on expression of the slow-inactivating TTX-R and fast-inactivating TTX-S Na+ currents. CCD treatment significantly reduced TTX-R and TTX-S current densities in the slow and fast neurons, but CCI selectively reduced the TTX-R and TTX-S current densities in the slow neurons. Changes in half-maximal potential (V1/2) and curve slope (k) of steady-state inactivation of Na+ currents were different in the slow and fast neurons after CCD and CCI treatment. The window current of TTX-R and TTX-S currents in fast neurons were enlarged by CCD and CCI, while only that of TTX-S currents in slow neurons was increased by CCI. The decay rate of TTX-S and both TTX-R and TTX-S currents in fast neurons were reduced by CCD and CCI, respectively. These findings provide a possible sodium channel mechanism underlying CCD-induced DRG neuron hyperexcitability and hyperalgesia and demonstrate a differential effect in the Na+ currents of small DRG neurons after somata compression and peripheral nerve injury. This study also points to a complexity of hyperexcitability mechanisms contributing to CCD and CCI hyperexcitability in small DRG neurons.

Lidocaine suppresses subthreshold oscillations by inhibiting persistent Na+ current in injured dorsal root ganglion neurons

The aim of this study was to determine the effect and mechanism of low concentration of lidocaine on subthreshold membrane potential oscillations (SMPO) and burst discharges in chronically compressed dorsal root ganglion (DRG) neurons. DRG neurons were isolated by enzymatic dissociation method. SMPO, burst discharges and single spike were elicited by whole cell patch-clamp technique in current clamp mode. Persistent Na(+) current (I(NaP)) and transient Na(+) current (I(NaT)) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 micromol/l) in current clamp mode, I(NaP) was blocked by 0.2 micromol/l TTX in voltage clamp mode. SMPO, burst discharges and I(NaP) were also suppressed by low concentration of lidocaine (10 micromol/l) respectively. However, single spike and I(NaT) could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that I(NaP) mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 micromol/l) suppresses SMPO by selectively inhibiting I(NaP), but not I(NaT), in chronically compressed DRG neurons.

A transient receptor potential vanilloid 4 contributes to mechanical allodynia following chronic compression of dorsal root ganglion in rats

The aim of the present study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in mediating mechanical allodynia in rodent models of chronic compression of the dorsal root ganglion (CCD). First, the levels of TRPV4 mRNA and protein expression in the dorsal root ganglion (DRG) were assessed using real-time RT-PCR and Western blotting analysis respectively at 7, 14, and 28 days post-CCD. Then, the effects of spinal administration of TRPV4 antisense oligodeoxynucleotide (ODN) and mismatch ODN on CCD-induced mechanical allodynia were evaluated. Lastly, the calcium responses to hypotonic solution and 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) were assessed following sham surgery, CCD, spinal application of TRPV4 antisense ODN and mismatch ODN. The results showed that the levels of TRPV4 mRNA and protein expression increased significantly at 7-28 days post-CCD when compared with the sham group, with the highest level at 7 days post-CCD. TRPV4 antisense ODN, but not mismatch ODN, partly reversed the CCD-induced mechanical allodynia. Additionally, TRPV4 antisense ODN had no effect on the baseline nociceptive response. The percentage of DRG neurons responsive to hypotonic solution and 4alpha-PDD and the fluorescence ratio of calcium response were also enhanced significantly in both the CCD group and the mismatch ODN group. These increased responses were significantly inhibited by TRPV4 antisense ODN. In conclusion, TRPV4 plays a crucial role in CCD-induced mechanical allodynia.

Multiple Sites for Generation of Ectopic Spontaneous Activity in Neurons of the Chronically Compressed Dorsal Root Ganglion

In a chronically compressed dorsal root ganglion (CCD) in the rat, a model of foraminal stenosis and radicular pain in human, a subpopulation of neurons with functional axons exhibits spontaneous activity (SA) that originates within the ganglion. Intracellular electrophysiological recordings were obtained from the somata of neurons of the compressed ganglion both in vitro and in vivo. The SA was classified into two types according to the presence (type I) or absence (type II) of subthreshold membrane potential oscillation. Neurons with type I SA had significantly higher somal excitability than those with type II SA. In most cases, depolarization of the membrane potential by current injection increased the discharge rates of type I--but not type II SA. Both types occasionally coexisted in the same neuron. Several lines of evidence suggested that the origin of SA in the DRG was most likely the soma for type I SA and the axon for type II. Therefore CCD neurons have multiple sites for generation of action potentials other than the terminal endings. In vivo recordings revealed the same two types of SA in a subpopulation of neurons with functionally characterized peripheral receptive fields. Thus, SA might not only produce spurious sensory input to the afferent pathways but also add to or block impulse transmission generated by natural stimulation of peripheral receptors. SA originating in the compressed ganglion is likely to interfere with sensory transmission in nociceptive and non-nociceptive neurons, thereby contributing to radicular pain, paresthesias, hyperalgesia and allodynia.

Different suppressive effect of lidocaine on persistent Na + current and transient Na + current in dorsal root ganglion neurons

Objective To investigate the different suppressive effect of lidocaine on persistent Na + current and transient Na + current in injured or uninjured dorsal root ganglion neurons. Methods Totally 23 SD rats were randomly divided into 2 groups; control group ( n = 10) and chronically compressed DRG (dorsal root ganglion) group (CCD group, n = 13). Rats were anesthetized and DRG was isolated. Single DRG neuron was isolated by enzymatic disassociation method. Persistent Na + current (I NaP) and transient Na + current (I NaT) were elicited in voltage clamp mode. Results The presence of I NaP was testified in most DRG neurons (38/46 neurons in CCD group and 31/39 neurons in control group, P>0.05). However, the current density of I NaP in CCD group (4.6 ± 0.6 pA/pF, n = 38 neurons) was greater than that in control group (2.5 ± 0.4 pA/pF, n = 31 neurons) ( P<0.05). The characteristics of I NaP was observed and found that I NaP could be blocked by 0.2 μmol/L tetrodotoxin easily. Furthermore, the does-effect relationship of Iidocaine on I NaP and I NaT were also examined. I NaP and I NaT were suppressed by different concentrations of lidocaine, the range for I NaP was 5-20 μmol/L and for I NaT was 0.05-2 mmol/L. Conclusion I NaP and I NaT were suppressed by different concentrations of lidocaine. I NaP was suppressed by very low concentration of lidocaine (5-20 μmol/L). However, I NaT could only be blocked by high concentration of lidocaine (0.05-2 mmol/L).

Time-dependent effect of epidural steroid on pain behavior induced by chronic compression of dorsal root ganglion in rats

Although epidural steroid injection has been commonly used to treat radicular pain, its clinical efficacy remains controversial. In a rat model of radicular pain induced by chronic compression of lumbar dorsal root ganglion (CCD), we examined the effect of epidural steroid on CCD-induced pain behavior. Triamcinolone [a glucocorticoid receptor (GR) agonist] or RU38486 (a GR antagonist) was given epidurally once either on day 3 (early treatment) or day 10 (late treatment) after CCD. The results showed that 1) early treatment with triamcinolone and RU38486 alone, respectively, reduced and exacerbated mechanical allodynia and thermal hyperalgesia, 2) late treatment with triamcinolone alone failed to improve mechanical allodynia and only transiently attenuated thermal hyperalgesia, and 3) late treatment with RU38486 alone improved mechanical allodynia and thermal hyperalgesia in CCD rats. Moreover, a second dose of triamcinolone given on day 10 paradoxically exacerbated pain behavior in CCD rats that received a first dose of triamcinolone on day 3. These results indicate that the effect of epidural steroid on radicular pain may be time-dependent. Clinical implications for epidural steroid treatment are discussed in light of these preclinical findings.

Increase of 200-kDa Neurofilament-Immunoreactive Afferents in the Substantia Gelatinosa in Allodynic Rats Induced by Compression of the Dorsal Root Ganglion

An experimental study on mechanical allodynia, c-Fos expression, and 200-kDa-neurofilament immunoreactive (IR) afferent expression in the substantia gelatinosa related to compression of dorsal root ganglion (DRG). To evaluate the presence of allodynia in DRG compression model and to demonstrate that the structural changes of spinal dorsal horn related to DRG compression. A previous experimental report has demonstrated that the peripheral nerve injury may trigger some structural changes of the superficial spinal dorsal horn. These changes of the spinal dorsal horn were thought to be important for the modulation of pain sensations such as allodynia. Sixty-eight male rats were used. The left L5 lamina was exposed and a drill hole was made in it. A stainless rod was placed close to the left L5 DRG through the drill hole. Behavioral testing with von Frey filament was performed. On day 28 after surgery, c-Fos expression in the spinal dorsal horn by non-noxious stimulation was examined. L5 spinal cord and bilateral L5 DRG specimens were stained with antibody for 200-kDa neurofilament (RT97). In addition, 2 or 3 spinal cord sections per rats were processed for immunoelectron microscopy. In the DRG compression group, the mechanical withdrawal threshold was decreased, c-Fos expression by non-noxious stimulation was observed in the spinal dorsal horn, and there were many RT97-IR afferents in the superficial spinal dorsal horn. Immunoelectron microscopic observations showed that RT97-IR terminals made synaptic contact with neurons in the superficial spinal dorsal horn. There were no significant differences in the distribution of RT97-IR neurons in DRG between compression and sham group. DRG compression induced allodynia and that RT97-IR afferents increased in the superficial dorsal horn of the spinal cord. The increase of RT97-IR afferents may be related to the mechanisms for the observed allodynia.

The role of ERK activation in the neuronal excitability in the chronically compressed dorsal root ganglia

We examined the roles of phosphorylation of extracellular signal-regulated protein kinases (pERK) in regulating the excitability of neurons in the dorsal root ganglion (DRG) after chronic compression. A chronic compression of DRG (CCD) induced a significant increase in pERK in intact L4/L5 DRGs of rats as assessed by Western blot analysis. The treatment of U0126, the mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor, suppressed excitability in CCD-injured DRG neurons but not in naïve DRG neurons. Furthermore, the inhibition of ERK signaling increased A-type fast inactivating potassium current. Taken together, the excitation of CCD neurons might be attributed to the CCD-induced activation of ERK, which suppressed the A-type fast inactivating potassium conductance in CCD neurons.

Dissociation of Dorsal Root Ganglion Neurons Induces Hyperexcitability That Is Maintained by Increased Responsiveness to cAMP and cGMP

Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that after chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-protein kinase A (PKA) and cGMP-protein kinase G (PKG) signaling pathways. We report here that when tested under identical conditions, dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, increased repetitive firing to depolarizing pulses, increased spontaneous firing and resting depolarization. A novel feature of this hyperexcitability is its early expression-as soon as testing can be conducted after dissociation (approximately 2 h). Both forms of injury increase the electrophysiological responsiveness of the neurons to activation of cAMP-PKA and cGMP-PKG pathways as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons.

A New “Kine” of Pain: MCP-1 and Sensory Neuron Excitability. Focus on “MCP-1 Enhances Excitability of Nociceptive Neurons in Chronically Compressed Dorsal Root Ganglia”

In 1998, [Hu and Xing (1998)][1] developed a method for nerve injury by chronically compressed dorsal root ganglia (CCD). Robert LaMotte and his colleagues at Yale have utilized this technique to explore the consequences of injury on nociception and excitability of primary sensory neurons. This

CAMP and cGMP Contribute to Sensory Neuron Hyperexcitability and Hyperalgesia in Rats With Dorsal Root Ganglia Compression

Numerous studies have implicated the cAMP-protein kinase A (PKA) pathway in producing hyperexcitability of dorsal root ganglia (DRG) sensory neurons under conditions associated with pain. Evidence is presented for roles of both the cAMP-PKA and cGMP-protein kinase G (PKG) pathways in maintaining neuronal hyperexcitability and behavioral hyperalgesia in a neuropathic pain model: chronic compression of the DRG (CCD treatment). Lumbar DRGs were compressed by a steel rod inserted into the intervertebral foramen. Thermal hyperalgesia was revealed by shortened latencies of foot withdrawal to radiant heat. Intracellular recordings were obtained in vitro from lumbar ganglia after in vivo DRG compression. Activators of the cAMP-PKA pathway, 8-Br-cAMP and Sp-cAMPS, and of the cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMPS, increased the hyperexcitability of DRG neurons already produced by CCD treatment, as shown by further decreases in action potential threshold and increased repetitive discharge during depolarization. The adenylate cyclase inhibitor, SQ22536, the PKA antagonist, Rp-cAMPS, the guanylate cyclase inhibitor, ODQ, and the PKG inhibitor, Rp-8-pCPT-cGMPS, reduced the hyperexcitability of CCD DRG neurons. In vivo application of PKA and PKG antagonists transiently depressed behavioral hyperalgesia induced by CCD treatment. Unexpectedly, application of these agonists and antagonists to ganglia of naïve, uninjured animals had little effect on electrophysiological properties of DRG neurons and no effect on foot withdrawal, suggesting that sensitizing actions of these pathways in the DRG are enabled by prior injury or stress. The only effect observed in uncompressed ganglia was modest depolarization of DRG neurons by PKA and PKG agonists. CCD treatment also depolarized DRG neurons, but CCD-induced depolarization was not affected by agonists or antagonists of these pathways.

Effects of gabapentin on spontaneous discharges and subthreshold membrane potential oscillation of type A neurons in injured DRG

Ectopic spontaneous discharges play a critical role for both initiation and maintenance of the neuropathic pain state. Gabapentin (GBP) has been shown to be effective in animal models of neuropathic pain as well as in chronic pain patients. To investigate the peripheral mechanisms of GBP, the effects of GBP on spontaneous discharges and subthreshold membrane potential oscillation (SMPO) of chronically compressed dorsal root ganglion (DRG) were examined electrophysiolocally in vitro. The rate of spontaneous discharges was transitorily enhanced when GBP was applied to the DRG. When the concentration was under 5 μM, only enhanced effect was observed, while spontaneous discharges were completely suppressed when the concentration of GBP was beyond 5 μM. The similar doses of GBP blocking the spontaneous discharges failed to block the propagation of impulses by electrical nerve stimulation. Furthermore, we found that the SMPO of injured DRG cells can be selectively abolished by GBP without interrupting spike propagation. The results suggest that the inhibitory effect of GBP on SMPO might be one of the membrane mechanisms of action of GBP. This may partially explain the antinociceptive action of GBP by directly suppression nociceptive afferent input to the spinal cord.

Effect of acute nerve root compression on endoneurial fluid pressure and blood flow in rat dorsal root ganglia

The objective of the current study was to test the hypothesis that crush injury to nerve root increases endoneurial fluid pressure (EFP) and decreases blood flow in the associated dorsal root ganglion (DRG). A total of 21 adult, female Sprague–Dawley rats had their left L5 nerve root and DRG exposed. The L5 nerve root was clamped for 2 s with a vascular suture clip just proximal to the DRG (compression group). Sham-operated animals without compression were used for control (control group). EFP was recorded with a servo-null micropipette system using a glass micropipette with tip diameter of 4 μm before and after 3 h of treatment. After the final measurement of EFP, DRG was excised and processed for histology. Blood flow in the DRG was continuously monitored by laser Doppler flow meter for 3 h. Three hours after treatment, EFP was 4.7 ± 2.7 cm H 2O in the compression group and 2.2 ± 1.2 cm H 2O in the control group ( P < 0.05). Edema was the principal pathologic findings seen consistently in the DRG from animals in the compression group. Blood flow in the compression group was reduced 10 min after compression. This reduction was statistically significant compared with that of the control ( P < 0.01). An acute compression to the nerve root increased endoneurial edema, increased EFP in the associated DRG, and reduced DRG blood flow. This combination of increased EFP and decreased blood flow in the DRG may result in neuronal ischemia and sensory dysfunction. These acute pathophysiologic changes may thus have a role in the pathogenesis of low back pain and sciatica due to disc herniation and spinal canal stenosis.

Dynamical mechanisms for sensitive response of aperiodic firing cells to external stimulation

An interesting phenomenon that aperiodic firing neurons have a higher sensitivity to drugs than periodic firing neurons have been reported for the chronically compressed dorsal root ganglion neurons in rats. In this study, the dynamical mechanisms for such a phenomenon are uncovered from the viewpoint of dynamical systems theory. We use the Rose–Hindmarsh neuron model to illustrate our opinions. Periodic orbit theory is introduced to characterize the dynamical behavior of aperiodic firing neurons. It is considered that bifurcations, crises and sensitive dependence of chaotic motions on control parameters can be the underlying mechanisms. And then, a similar analysis is applied to the modified Chay model describing the firing behavior of pancreatic beta cells. The same dynamical mechanisms can be obtained underlying that aperiodic firing cells are more sensitive to external stimulation than periodic firing ones. As a result, we conjecture that sensitive response of aperiodic firing cells to external stimulation is a universal property of excitable cells.

A Novel Bursting Mechanism of Type A Neurons in Injured Dorsal Root Ganglia

Using intracellular recording in vivo, the bursting behaviors were investigated in the neurons of chronically compressed dorsal root ganglia of the adult rat. In most cases, the first spike of a burst emerged from amplitude-increasing damped subthreshold membrane potential oscillation (SMPO) and the discharge terminated by an amplitude-decreasing damped SMPO. The rhythms of these bursting behaviors are all irregular. Since some researchers found that the stochastic dynamics can also produce similar bursting pattern, the deterministic dynamics of interevent interval (IEI) series obtained from raw membrane potential recording was detected by extraction of the hierarchy of unstable periodic orbits (UPOs) in the windowed IEI series. The results showed a number of statistically significant UPOs of order-one, order-two, and order-three. These orbits form a complex but predictable lattice of regions in which the dynamics of the bursting occurrence is deterministic. Based on a complete classification scheme, the investigated bursting can be depicted by the elliptic bursting dynamics. The significance of the finding that a neuron in the injured dorsal root ganglion has such dynamics is also discussed.

Epidural Hyaluronic Acid in a Rat Model of Chronic Dorsal Root Ganglion Compression

Background: Hyaluronic acid (HA) is a naturally occurring polysaccharide that has been shown to be beneficial in various clinical settings, such as in opthalmic surgery or for intra-articular injections. This study was designed to evaluate the effect of epidurally injected HA as an agent for decreasing pain in an animal model of chronic dorsal root ganglion compression. Methods: A small stainless steel rod was inserted into L4-5 intervertebral foramen in the rat, to develop intervertebral foramen stenosis and chronic DRG compression. Twenty-seven rats were assigned to the saline group (n = 9), HA group (n = 9), or the no treatment (control) group (n = 9). In the saline group and the HA group, 0.1 ml of 0.9% saline and the same volume of HA were injected into the epidural space through an epidural catheter. Behavioral tests for thermal hyperalgesia was performed for five weeks after epidural injection. Results: The hindpaw on the injured side in the control group and in the saline group showed a significant reduction in the latency of foot withdrawal to noxious heat. Rats in the HA group showed a significant reduction of hyperalgesia in the thermal test (P

Subthreshold membrane potential oscillation mediates the excitatory effect of norepinephrine in chronically compressed dorsal root ganglion neurons in the rat

Injured dorsal root ganglion (DRG) neurons often develop adrenergic sensitivity. To investigate the mechanisms of this phenomenon, the effects of norepinephrine (NE) on membrane potential of large- and medium-sized A-type neurons from chronically compressed DRG were recorded electrophysiologically in vitro. NE induced a depolarization in both control (26/36) and injured (56/62) neurons, whereas the incidence and amplitude of NE-induced depolarization in the injured neurons were significantly higher than that in controls. Following NE-induced depolarization, a subthreshold membrane potential oscillation (SMPO) was triggered or enhanced that initiated or increased repetitive firing in a fraction of injured neurons (15/56). After the SMPO was selectively abolished by application of tetrodotoxin (TTX), NE-induced depolarization failed to produce repetitive firing, even with a greater depolarization. Application of Rp-cAMPS (500 μM), a selective inhibitor of protein kinase A (PKA), decreased both SMPO and repetitive firing evoked by NE application or by intracellular current injection. Conversely, Sp-cAMPS (500 μM), a PKA activator, had a facilitating effect on both the SMPO and the repetitive firing. These results strongly suggest that a PKA mediated triggering and enhancement of SMPO may be responsible for the excitatory effects of NE on sensory neurons in neuropathic rats.