Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review.

This review provides an update on the current clinical and preclinical understanding of chemotherapy induced peripheral neuropathy (CIPN). The overview of the clinical syndrome includes a review of its assessment, diagnosis and treatment. CIPN is caused by several widely-used chemotherapeutics including paclitaxel, oxaliplatin, bortezomib. Severe CIPN may require dose reduction, or cessation, of chemotherapy, impacting on patient survival. While CIPN often resolves after chemotherapy, around 30% of patients will have persistent problems, impacting on function and quality of life. Early assessment and diagnosis is important, and we discuss tools developed for this purpose. There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN. The preclinical perspective includes a discussion on the development of clinically-relevant rodent models of CIPN and some of the potentially modifiable mechanisms that have been identified using these models. We focus on the role of mitochondrial dysfunction, oxidative stress, immune cells and changes in ion channels from summary of the latest literature in these areas. Many causal mechanisms of CIPN occur simultaneously and/or can reinforce each other. Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN.

Postoperative MRI Evaluation of a Radiofrequency Cordotomy Lesion for Intractable Cancer Pain.

BACKGROUND AND PURPOSE: There are limited data on the use of postoperative imaging to evaluate the cordotomy lesion. We aimed to describe the cordotomy lesion by using postoperative MR imaging in patients after percutaneous cordotomy for intractable cancer pain. MATERIALS AND METHODS: Postoperative MR imaging and clinical outcomes were prospectively obtained for 10 patients after percutaneous cordotomy for intractable cancer pain. Area, signal intensity, and location of the lesion were recorded. Clinical outcomes were measured by using the Visual Analog Scale and the Brief Pain Inventory-Short Form, and correlations with MR imaging metrics were evaluated. RESULTS: Ten patients (5 men, 5 women; mean age, 58.5 ± 9.6 years) were included in this study. The cordotomy lesion was hyperintense with central hypointense foci on T2-weighted MR imaging, and it was centered in the anterolateral quadrant at the C1-C2 level. The mean percentage of total cord area lesioned was 24.9% ± 7.9%, and most lesions were centered in the dorsolateral region of the anterolateral quadrant (66% of the anterolateral quadrant). The number of pial penetrations correlated with the percentage of total cord area that was lesioned (r = 0.78; 95% CI, 0.44-0.89; P = .008) and the length of T2-weighted hyperintensity (r = 0.85; 95% CI, 0.54-0.89; P = .002). No significant correlations were found between early clinical outcomes and quantitative MR imaging metrics. CONCLUSIONS: We describe qualitative and quantitative characteristics of a cordotomy lesion on early postoperative MR imaging. The size and length of the lesion on MR imaging correlate with the number of pial penetrations. Larger studies are needed to further investigate the clinical correlates of MR imaging metrics after percutaneous cordotomy.

Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy.

There is increasing evidence implicating astrocytes in multiple forms of chronic pain, as well as in the specific context of chemotherapy-induced peripheral neuropathy (CIPN). However, it is still unclear what the exact role of astrocytes may be in the context of CIPN. Findings in oxaliplatin and paclitaxel models have displayed altered expression of astrocytic gap junctions and glutamate transporters as means by which astrocytes may contribute to observed behavioral changes. The current study investigated whether these changes were also generalizable to the bortezomib CIPN. Changes in mechanical sensitivity were verified in bortezomib-treated animals, and these changes were prevented by co-treatment with a glial activation inhibitor (minocycline), a gap junction decoupler (carbenoxolone), and by a glutamate transporter upregulator (ceftriaxone). Immunohistochemistry data at day 30 in bortezomib-treated animals showed increases in expression of glial fibrillary acidic protein (GFAP) and connexin 43 but a decrease in GLAST expression. These changes were prevented by co-treatment with minocycline. Follow-up Western blotting data showed a shift in connexin 43 from a non-phosphorylated state to a phosphorylated state, indicating increased trafficking of expressed connexin 43 to the cell membrane. These data suggest that increases in behavioral sensitivity to cutaneous stimuli may be tied to persistent synaptic glutamate resulting from increased calcium flow between spinal astrocytes.

Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat.

Spinal microglia are widely recognized as activated by and contributing to the generation and maintenance of inflammatory and nerve injury related chronic pain; whereas the role of spinal astrocytes has received much less attention, despite being the first glial cells identified as activated following peripheral nerve injury. Recently it was suggested that microglia do not appear to play a significant role in chemotherapy-induced peripheral neuropathy (CIPN), but in contrast astrocytes appear to have a key role. In spite of the generalizability of astrocyte recruitment across chemotherapy drugs, its correlation to the onset of the behavioral CIPN phenotype has not been determined. The astroglial and microglial markers glial fibrillary acidic protein (GFAP) and OX-42 were imaged here to examine glial reactivity in multiple models of CIPN over time and to contrast this response to that produced in the spinal nerve ligation (SNL) model. Microglia were strongly activated following SNL, but not activated at any of the time points observed following chemotherapy treatments. Astrocytes were activated following both oxaliplatin and bortezomib treatment in a manner that paralleled chemotherapy-evoked behavioral changes. Both the behavioral phenotype and activation of astrocytes were prevented by co-administration of minocycline hydrochloride in both CIPN models, suggesting a common mechanism.

Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes.

Systemic injection of lipopolysaccharide (LPS) induces a robust immune response as well as thermal and mechanical hyperalgesia. Spinal and peripheral glial cells have been implicated as important mediators in this hyperalgesia but the specific contributions of microglia versus astrocytes are not entirely clear. To better define these mechanisms, this study examined the febrile response, nociceptive sensitivity, glial cell reactivity and cytokine production in the dorsal root ganglion (DRG) and spinal cord in rats following systemic treatment with LPS and the effects of minocycline in countering these responses. Intraperitoneal LPS injection resulted in an increase in core body temperature and produced hyperalgesia to heat and mechanical stimuli. Western blot studies revealed increased expression of microgial cell, macrophage and satellite cell markers in DRG and microglial and astrocyte markers in spinal cord following LPS treatment. Real-time RT-PCR indicated that LPS treatment increased cytokine mRNA expression levels in both the DRG and the spinal cord. Minocycline suppressed all LPS-induced behavioral effects but not the febrile response. Moreover, minocycline prevented LPS-induced microglia/macrophage activation and cytokine responses in spinal cord and DRG, but did not affect the activation of astrocytes/satellite cells. These data demonstrate that LPS-induced changes in nociceptive sensitivity are likely mediated by activation of microglial cells and/or macrophages in the spinal cord and DRG.

Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline.

Treatment with the chemotherapeutic agent oxaliplatin produces a robust painful neuropathy similar to various other neuropathic conditions which result in loss of nerve fibers innervating the skin. This loss of intraepidermal nerve fibers (IENFs) appears to play an important role in neuropathy, but has yet to be investigated in oxaliplatin-induced neuropathic pain. For this study, mechanical hyperalgesia and IENF density were measured in rats receiving oxaliplatin, given at a dosage of 2 mg/kg every other day for four injections. The immunomodulatory agent minocycline (25 mg/kg) was also administered and was given 24 h prior to the first dose of oxaliplatin and continued throughout oxaliplatin treatment. Immunohistochemistry using the pan-neuronal marker PGP9.5 was used to investigate IENF densities in hind paw skin on Day 15 and Day 30. The results show that a robust mechanical sensitivity developed in oxaliplatin treated animals, as did a pronounced decrease in epidermal nerve fibers, and these outcomes were effectively prevented by minocycline treatment. This is the first study to show changes in IENF density in oxaliplatin treated animals, and confirm not only a relationship between IENF loss and hypersensitivity but also prevention of both with minocycline treatment.

Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline.

Loss of intraepidermal nerve fibers (IENFs) has been speculated to play a critical role in the development of various neuropathies. In this study, the density of IENFs were studied over time during the induction of Taxol (Bristol-Myers Squibb, NY, USA)-induced chemoneuropathy and compared with the changes in IENFs in animals co-treated with Taxol plus the protective agent minocycline. Rats were injected (intraperitoneally) with 2mg/kg of Taxol every other day for four injections (day 1, 3, 5, and 7). Minocycline (25mg/kg) was given in a separate group of rats 24h prior to the first dose of Taxol and every day for the next 9days (day 0 through 9). Animals were tested for mechanical paw withdrawal thresholds prior to any drug administrations and again on day 7, 14, and 30. Immunohistochemistry using the pan-neuronal marker protein gene product 9.5 was performed on glabrous skin of the hind-paw foot pad to stain for IENFs also on day 7, 14, and 30. The results show that Taxol-treated animals developed mechanical sensitivity and corresponding IENF loss. Animals receiving minocycline plus Taxol showed no hyperalgesia or loss of IENFs. This study confirms, for the first time, that a loss of IENFs occurs as a neuropathy develops, and further shows a protection against both IENF loss and hyperalgesia with minocycline treatment. The progression of Taxol-induced mechanical hypersensitivity coincides with loss of intraepidermal nerve fibers, and the hyperalgesia and nerve fiber loss were prevented with minocycline treatment.

Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's disease: decreased firing rates and altered firing patterns.

The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns.

Effects of isoflurane, pentobarbital, and urethane on apoptosis and apoptotic signal transduction in rat kidney.

BACKGROUND: Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Anesthetic agents have been shown to modulate apoptotic signal transduction in various tissues. We examined the effects of 6 h of different general anesthetic techniques on renal cell apoptosis in rat kidneys. METHODS: Twenty-one male Sprague-Dawley rats were randomly allocated into four groups: (i) control, non-anesthetized rats (n= 3) and rats anesthetized with (ii) inhaled isoflurane (n= 6), (iii) intraperitoneal pentobarbital (n= 6), and (iv) intraperitoneal urethane (n= 6). Animals were sacrificed 6 h after the induction of anesthesia. RESULTS: Apoptosis was assessed by terminal deoxynucleotidyl transferase-fluorescein end-labeling analysis. RNA was extracted from the left kidney to probe cDNA microarrays. Gene expression was measured as a percentage of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and subsequently confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with the control (no anesthesia), urethane significantly (P < 0.001) induced apoptosis in both the renal cortex and medulla. Isoflurane significantly (P < 0.001) inhibited apoptosis in the medulla. Microarray analysis revealed that urethane up-regulated more (74) genes than pentobarbital (16) and isoflurane (10). Isoflurane down-regulated more genes (85) than pentobarbital (74) and urethane (12). These anesthetic-induced modulations were significant (P < 0.05) for 60 isoflurane-, 30 pentobarbital- and 4 urethane-modulated genes. CONCLUSION: Our results suggest that general anesthetic drugs have an effect on renal cell apoptosis and apoptotic signal transduction, and thus may potentially affect the risk of subsequent acute renal failure.

Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy.

Pain arises from numerous causes in cancer patients. Well known to cancer care providers, but perhaps less well so to others, is that the main causes of pain in cancer patients in fact arise due to cancer treatments more so than the disease itself. In this paper clinical and laboratory findings on the characteristics of chemotherapy-induced neuropathic pain are reviewed and a scheme for the underlying mechanisms is outlined.

Psychophysical elements of place and modality specificity in the thalamic somatic sensory nucleus (ventral caudal, vc) of awake humans.

Discrete anatomic structures in the monkey somatic sensory thalamus may segregate input arising from different peripheral receptors and from different parts of the body. It has been proposed that these structures serve as components of modality- and place-specific pathways from the periphery to the cortex. We now test this hypothesis by examining the modality- and place-specific segregation of sensations at sites where microstimulation (microA currents) within the region of ventral caudal (Vc; human principal somatic sensory nucleus) evokes somatic sensations. Microstimulation was delivered in an ascending staircase protocol consisting of different numbers of pulses (4-100) presented at different frequencies (10-200 Hz) during awake thalamic surgery for movement disorders. The results demonstrate that the part of the body where microstimulation evoked sensation (projected field) and the descriptors of nonpainful sensations were usually uniform across the staircase. These results strongly support the existence of psychophysical elements of place and modality specificity in the Vc thalamus. The proportion of sites at which the sensation included more than one part of the body almost always stayed constant over current intervals (plateaus) of 10 microA. Similar plateaus were not found for sites with more than one descriptor, suggesting that elements of modality-specificity are smaller than and located within those for place-specificity. The intensity of sensations varied with the number of stimulation pulses for mechanical/tingle and cool sensations. The results provide strong evidence for psychophysically defined elements that are responsible for modality specificity of nonpainful sensations, place specificity, and intensity coding of somatic sensation in the human thalamus.

Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia.

Changes in the signaling of wide dynamic range neurons and the expression of glutamate transporters in the lumbar spinal dorsal horn of rats with Taxol-induced hyperalgesia are detailed in this report. Deep spinal lamina neurons have significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli, increased responses to both skin heating and cooling, and increased after-discharges and abnormal windup to transcutaneous electrical stimuli. The expression of glutamate transporter proteins in the dorsal horn is decreased at the time point corresponding to the physiological changes. These results suggest a state of increased excitability develops in spinal pain-signaling neurons as a consequence of decreased glutamate clearance. These changes in dorsal horn neurobiology likely in turn contribute to the hyper-responsiveness to sensory stimuli seen in animals treated with Taxol and may play a role in the pain seen in cancer patients receiving Taxol.

Pain and temperature encoding in the human thalamic somatic sensory nucleus (Ventral caudal): inhibition-related bursting evoked by somatic stimuli.

Stimulus-evoked inhibitory events have not been demonstrated in thalamic spike trains encoding of pain and temperature stimuli. We have now tested the hypothesis that the human thalamic response to mechanical and thermal stimuli is characterized by low-threshold calcium spike (LTS)-associated bursts of high-frequency action potentials preceded by prolonged inhibition. The results included 57 neurons recorded in the human thalamic principal somatic sensory nucleus (ventral caudal, Vc) of 24 patients during awake surgery. Neurons were classified by the grading of their response with stimulus intensity into the painful range (graded or non-graded) and the stimulus response (to mechanical, cold, or heat stimuli). Firing rates were analyzed by the response to all stimuli combined (stimuli overall) and to the stimulus characteristic of the stimulus response type (optimal stimulus), e.g., cold stimuli for neurons of the cold stimulus response type. All neuronal categories had clear stimulus-evoked LTS bursting as identified by the criteria for selecting bursts in the spike train, by significant preburst inhibition, and by preburst inter-spike interval not significantly <100 ms. Stimulus-evoked LTS burst rates were significantly higher for neurons in the cold stimulus response type independent of the firing rate between bursts. The parameters of preburst inhibition were largely independent of the neuronal category and the stimuli included in the analysis, which suggests inhibitory mechanisms are similar across neuronal types. Therefore LTS bursting is a substantial, nonlinear component of the spontaneous and stimulus-evoked activity of thalamic neurons in awake humans.

Response properties of dorsal root reflexes in cutaneous C fibers before and after intradermal capsaicin injection in rats.

C fiber dorsal root reflexes (DRR) contribute to neurogenic inflammation and possibly also to touch-evoked pain (allodynia) induced by intradermal capsaicin. The responses of C fibers in the sural nerve to graded mechanical stimuli before and following intradermal capsaicin were studied in 39 adult male rats. Two-thirds of 111 fibers were without spontaneous activity, while the remaining fibers averaged 1.41+/-0.25 spontaneous antidromic spikes per second. Among the quiescent C fibers only two had excitatory receptive fields, whereas the active C fibers showed three patterns of activity, an excitatory response, an inhibitory response, or no response to mechanical stimulation. The excitatory responses were to high intensity mechanical stimuli alone, while inhibitory responses were evoked in a graded fashion by both noxious and innocuous mechanical stimuli. Intradermal injection of capsaicin increased spontaneous and evoked DRRs in all C fibers with excitatory responses to mechanical stimuli, but none acquired responses to innocuous stimuli. Capsaicin initially produced inhibition of spontaneous activity in C fibers with inhibitory or no receptive fields, but this later resumed and achieved a rate higher than baseline. Mechanical stimuli re-applied following the resumption of spontaneous discharges failed to produce any response. Spontaneous DRRs were increased by topical application of 1 mM beta-alanine (a competitive antagonist for GABA transporters) and abolished by ipsilateral spinal nerve L5 lesion, verifying antidromic origin. The role of C fiber DRRs in normal sensory transmission and during hyperalgesia is discussed.

Cyclooxygenase inhibitors and thalidomide ameliorate vincristine-induced hyperalgesia in rats.

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight.

Sensitization of dorsal root reflexes in vitro and hyperalgesia in neonatal rats produced by capsaicin.

The maturation of dorsal root reflexes (DRRs) in lumbar roots was characterized in neonatal rats at 1, 2 and 3 weeks after birth using an in vitro isolated spinal cord preparation with attached dorsal roots and dorsal root ganglia (DRG). Changes of DRRs in rats of increasing age were also tested by administration of capsaicin to the DRG and related to spinal mechanisms of hyperalgesia by defining the behavioral responses of neonatal rats to intradermal capsaicin. DRRs evoked by stimulating the adjacent root in 1 week old rats are characterized by highly desynchronized waveforms with power spectra concentrated at frequencies greater than 200 Hz. DRRs in 1 week old rats show very little change in amplitude or area with increasing afferent stimulation strength. In contrast DRRs in 2 and 3 weeks old rats are highly synchronized with power concentrated at frequencies less than 100 Hz and show a graded increase in amplitude and area with increasing stimulus strength. The recovery of DRR amplitude in a paired pulse stimulus protocol is faster in 1 week rats than in 2 or 3 weeks old rats. Finally, DRRs in 2 and 3 week old rats show increased amplitude and area following application of capsaicin to the DRG of the stimulating root whereas those in 1 week old rats do not. These changes parallel the behavioral responses of neonatal rats as 2 and 3 weeks old rats show secondary mechanical hyperalgesia following intradermal capsaicin, but 1 week old rats do not. Our data indicate that the spinal circuitry for DRRs in the neonatal period undergoes rapidly dynamic development in the rat. This development is sufficiently rapid that mechanisms of spinal sensitization induced by capsaicin can be studied in rats 2 weeks old and older.

Changes in sensory processing in the spinal dorsal horn accompany vincristine-induced hyperalgesia and allodynia.

Abnormal sensation and pain are major dose-limiting factors in cancer chemotherapy with vincristine. In this study, we have adapted a model of this condition by using repeated daily intraperitoneal injections of vincristine in rats. Mechanical allodynia and hyperalgesia without change in responses to thermal stimuli were first observed following 5-8 days of vincristine treatment (0.1mg/kg/day) and then persisted throughout the remainder of the treatment interval (2-3 weeks). Electrophysiological recording from wide dynamic range (WDR) neurons in the lumbar (L4-L5) spinal dorsal horn in hyperalgesic rats demonstrated significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli (von Frey filaments with a bending force greater than 58.02mN, skin compression 1.3 and 3N, 1mm(2)), increased acute A- and C-fiber responses, after-discharges and abnormal 'wind-up' to electrical stimuli (5mA, 2ms) at 0.1Hz applied across the receptive field. These results suggest a state of central sensitization develops in spinal WDR neurons with repeated vincristine treatment that contributes to the spontaneous pain and hyperalgesia seen in patients and the hyperresponsiveness to sensory stimuli seen in animals treated with vincristine.

Physiological changes in primate somatosensory thalamus induced by deafferentation are dependent on the spinal funiculi that are sectioned and time following injury.

The importance of spike bursts in thalamo-cortical processing of sensory information has received an increasing amount of interest over the past several years. Previously it has been reported that short high-frequency spike trains (3-8 action potentials occurring at 67-167 Hz), or spike bursts, are increased in both human and non-human primate thalamus following deafferentation. Here we examine the effects of lesion of the ventral spinal quadrant alone versus combined lesion of the ventral and dorsal spinal quadrants on the evoked and spontaneous spike trains in thalamic neurons. A total of 1175 neurons were sampled from 13 animals, three intact, six with ventral quadrant lesions (three with prolonged survival and three with short-term survival after spinal lesion) and four with combined ventral and dorsal quadrant lesions. Detailed analysis was conducted on 256 of these neurons, which revealed that thalamic neurons of animals with ventral quadrant lesions had elevated burst and non-burst spike rates while neurons from animals with combined ventral-dorsal lesions showed two types of change. Neurons in the forelimb areas showed increased bursts without a change in non-burst activity, while neurons in lateral VPL without receptive fields showed very low non-burst activity, but high burst spike rates. The magnitude of the effects produced by ventral-lateral spinal lesions was more pronounced in the short-term survival animals than in the long-term survival animals. These results show that the effects of deafferentation on the physiological properties of thalamic neurons are dependent on the afferent tract or tracts that are lesioned and the time after lesion.

Tuning of membrane properties regulates subliminal synapses in dorsal horn neurons of intact rats.

Functional plasticity in receptive field properties underlies the mechanism whereby spinal dorsal horn neurons encode changes in pain sensitivity following peripheral injury. Activation of "silent" or subliminal excitatory synapses was hypothesized to account for this injury-induced neural plasticity. To better characterize the mechanisms governing subliminal inputs, we adapted whole-cell patch clamp to the study of dorsal horn neurons in intact, anesthetized rats. In this report we show that the membrane properties of spinal cells correlate to functional class defined by action potential responses to cutaneous stimuli. In addition, we report the discovery of a novel "silent" population of neurons with solely subliminal excitatory inputs at rest that can be activated by membrane depolarization. Finally, an induced change in baseline membrane potential to a level nearer that of a different functional class results in a corresponding change in the responses to cutaneous stimuli of a given cell to that of the new functional class. In summary our findings suggest that biophysical membrane properties are key factors determining the functional profile of spinal neurons. The rapid change of such properties may regulate the function of silent synapses in spinal neurons and underlie rapid development of neural plasticity.