Sensory Ganglion Cells Research Articles

GABA-induced response in spiral ganglion cells acutely isolated from guinea pig cochlea

The physiological and pharmacological properties of γ-aminobutyric acid (GABA)-induced responses were investigated in acutely isolated spiral ganglion cells (SGCs) of guinea pig by using either a nystatin-perforated patch recording configuration or a conventional whole-cell patch recording mode combined with rapid drug application. GABA and GABA A subtype receptor agonist, muscimol, induced inward currents in a concentration-dependent manner in 74% of all cells. The current-voltage relationship for the GABA response indicated the GABA-induced current in SGCs is carried by Cl −. Bicuculline (BIC), strychnine (STR), and picrotoxin (PTX) suppressed the GABA response in a concentration-dependent manner. BIC and STR, and PTX blocked the GABA response in a competitive manner and in a non-competitive manner, respectively. For inorganic antagonists, Cd 2+ and Ni 2+ also inhibited the GABA response. On the other hand, Zn 2+ failed to suppress the GABA response in SGCs. An antibiotic, benzylpenicillin, suppressed the GABA response. The GABA response was augmented by both a barbiturate derivative, pentobarbital (PB), and a benzodiazepine derivative, diazepam. The results suggest clearly that the physiological and pharmacological characteristics of GABA A receptor on acutely isolated guinea pig SGCs are quite similar to the common GABA A receptor found in other sensory ganglion cells.

Long-Term Presence of Virus-Specific Plasma Cells in Sensory Ganglia and Spinal Cord following Intravaginal Inoculation of Herpes Simplex Virus Type 2

The tissue sites of long-term herpes simplex virus type 2 (HSV-2)-specific antibody production in mice and guinea pigs were identified. In addition to secondary lymphoid tissue and bone marrow, HSV-specific plasma cells were detected in spinal cords of mice up to 10 months after intravaginal inoculation with a thymidine kinase-deficient HSV-2 strain and in lumbosacral ganglia and spinal cords of guinea pigs inoculated with HSV-2 strain MS. The long-term retention of virus-specific plasma cells in the peripheral and central nervous systems following HSV infection may be important for resistance to reinfection of neuronal tissues or may play a role in modulation of reactivation from latency.

How the carotid body works: Different strategies and preparations to solve different problems

This is a review of the different experimental approaches developed to solve the problems in our progress towards a comprehensive understanding of how arterial chemoreceptors operate. An analysis is performed oi the bases, advantages and limits of the following preparations: studies of ventilatory reflexes originated from carotid bodies (CBs) in the entire animal; recordings of CB chemosensory discharges in situ; CB preparations perfused in situ; CB explants in oculo; CB explants in ovo; CB preparations incubated in vitro; CB preparations superfused in vitro; CB preparations perfused and superfused in vitro: CB tissue slices in vitro; cells acutely dissociated from CBs; CB cells in tissue culture; petrosal ganglia superfused in vitro; petrosal ganglion cells in tissue culture; and co-cultures of CB and sensory ganglion cells. A brief historical account is given of the passage from one preparation to the next one. Emphasis is placed on personal experience with the different preparations whenever possible. Examples are given of the importance of selecting the appropriate experimental preparation for solving each particular theoretical problem. In fact, brilliant ideas on how the CB works have been unproductive until finding the adequate experimental approach to explore the validity of such ideas.

ACUTE SENSORY NEURONOPATHY ASSOCIATED WITH HEPATITIS C INFECTION

A 52-year-old African American woman was admitted to the hospital for evaluation of 2 weeks of abdominal pain, nausea and vomiting. She also complained of numbness and tingling of the extremities and urinary incontinence. Physical examination was remarkable for abdominal distension, sluggish bowel sounds, nystagmus and signs of peripheral sensory loss. Comorbid conditions included diabetes, hypertension and stable seizure disorder. CT scan of chest, abdomen and pelvis showed diffuse fatty liver and partial small bowel obstruction. CT scan and MRI of the brain and MRI of the spine were normal. Labs: WBC = 6700K/UL, Na = 133MEQ/L, K = 3.1MEQ/L, Glu = 121MG/DL, ALP = 92U/L, AST = 57U/L, ALT = 16U/L, Albumin = 3.2GM/DL, Total Protein = 9.2MG/DL, ESR =118. Lumbar puncture was negative. Urine toxicology, Rheumatology panel including ANA, Rheumatoid factor, Scleroderma and Sjogrens antibodies and ANCAs, serologies for HTLV1, HTLV2, HIV and Syphilis were negative. Hepatitis C antibody was positive and Hepatitis C RNA viral count was 2660 copies. Hospital Course: While the intestinal obstruction gradually improved, her neurologic condition stayed the same for several days. Nerve conduction velocity and electromyographic studies were done which showed severe sensory neuronopathy with intact motor conduction. EMG was normal. She was given a trial of intravenous immune-globulins with no immediate effect; however, her condition began to show some improvement 5 days later. Patient was started on physical therapy and subsequently discharged to a rehabilitation center. Discussion: Sensory neurono pathy occurs when sensory ganglion cells, or neurons, are affected by a pathologic process. This is different from sensory neuro pathy in which the primary destruction happens in peripheral nerves. There have been reports of acute sensory neuronopathy related to para-neoplastic syndromes, especially with small cell carcinoma of lung, and connective tissue disorders, particularly Sjogrens syndrome. Infection with HTLV1 is the most common infectious disease reported in relation with this condition. In our case, an extensive work up did not reveal any specific reason for neuronopathy besides Hepatitis C infection. Pathogenesis of this condition may be related to an immune reaction against antigens shared by both the neurons and hepatits C viruses.

Mathematical analysis of competition between sensory ganglion cells for neurotrophic factor in the skin

A model is presented of competition between sensory axons for trophic molecules (e.g. a neurotrophin such as NGF), produced in a region of skin small enough to permit their free diffusion throughout it; e.g., a touch dome, or a vibrissal follicle hair sinus. The variables specified are the number of high affinity trophic factor receptors per axon terminal and the concentration of trophic factor in the extracellular space. Previous models of this class predicted the loss of all the axons innervating the region except the one requiring least trophic factor for its maintenance, even with high rates of trophic factor production. In the present model, we have imposed upper limits to axonal growth, thereby introducing new equilibria, and we show by a global analysis using LaSalle’s theorem, and also by local analysis, that several axons can then coexist if the rate of production of trophic molecules is sufficiently high.

Excitatory neurotoxic properties of pontamine sky blue make it a useful tool for examining the functions of focal brain parts.

Pontamine sky blue (PSB) is used in brain studies to mark the position of microelectrode and micropipette tips. However, few studies have been made on the effects of PSB on neurons; therefore we examined these effects. When puffed on isolated sensory ganglion cells of rats, PSB increased membrane conductance, depolarized membrane potential, and reduced the amplitude of action potentials. When dripped on frog sympathetic ganglion, much like hexamethonium, PSB decreased the amplitude of compound action potentials of the postganglionic strand. A bath application of PSB to sartorius muscle fibers that had been treated with tetrodotoxin depolarized the membrane potential and increased the frequency and amplitude of miniature end-plate potentials. All these effects were reversible. When injected into the rat's pontine part corresponding to the location of the canine pontine defecation reflex center, PSB produced repetitive colorectal contractions and irreversibly abolished them in response to anal-canal stimulation. The excitatory and blocking effects of PSB and its staining ability make it a useful tool for examining the functions of focal brain parts.

A procedure to deliver herpes simplex virus to the murine trigeminal ganglion

Although initial herpes simplex virus (HSV) infections of the cornea are relatively easily treated, recurrent infections following reactivation of latent virus in the sensory ganglion cells are more difficult to treat. Untreated infections may result in severe consequences, including corneal scarring, glaucoma, and encephalitis. To develop such treatments, an experimental in vivo model was needed in which HSV can be applied directly to trigeminal ganglion cells. We have previously developed such a model to examine the mechanisms of HSV spread from trigeminal neurons to corneal epithelial cells. The current paper describes in detail the technical steps required for implementation of that model. Immunocytochemistry and electron microscopy have been used to validate the efficacy of the described procedures. This technique will be useful for future in vivo studies of neurotrophic viral infections of trigeminal ganglion cells.

P2 receptors in satellite glial cells in trigeminal ganglia of mice

There is strong evidence for the presence of nucleotide (P2) receptors in sensory neurons, which might play a role in the transmission of pain signals. In contrast, virtually nothing is known about P2 receptors in satellite glial cells (SGCs), which are the main glial cells in sensory ganglia. We investigated the possibility that P2 receptors exist in SGCs in murine trigeminal ganglia, using Ca2+ imaging, patch-clamp recordings, and immunohistochemistry. We found that ATP caused an increase in intracellular Ca2+ concentration ([Ca2+]i) in SGCs. As adenosine had no effect on [Ca2+]i, and the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid largely blocked the response to ATP we conclude that P1 receptors did not contribute to the responses. We obtained the following evidence that the responses to ATP were mediated by metabotropic P2Y receptors: (i) persistence of the responses in Ca2+-free solution, (ii) inhibition of the response by cyclopiazonic acid, (iii) [Ca2+]i increases in response to the P2Y agonists uridine triphosphate, adenosine thiodiphosphate, and 2-methylthio ADP, and (iv) failure of the P2X agonist α,β-methylene ATP to elicit a response. Agonists of P2Y1 receptors and uridine triphosphate, an agonist at P2Y2 and P2Y4 receptors, induced [Ca2+]i increases suggesting that at least these P2Y receptor subtypes are present on SGCs. Using an antibody against the P2Y4 receptor, we found immunopositive SGCs. Patch-clamp recordings of SGCs did not reveal any inward current due to ATP. Therefore, there was no evidence for the activation of ionotropic P2X receptors under the present conditions.The results indicate the presence of functional nucleotide (P2Y) receptors in SGCs.

S-100 proteins in the human peripheral nervous system.

This article reviews the distribution of S100 proteins in the human peripheral nervous system. The expression of S100 by peripheral glial cells seems to be a distinctive fact of these cells, independently of their localization and their ability to myelinate or not. S100 proteins expressing cells include satellite cells of sensory, sympathetic and enteric ganglia, supporting cells of the adrenal medulla, myelinating and non-myelinating Schwann cells in the nerve trunks, and the Schwann-related cells of sensory corpuscles. In addition, S100 proteins are expressed in peripheral neurons. Most of them express S100alpha protein, and a subpopulation of sensory neurons in dorsal root ganglia contains S100beta protein or S100alpha plus S100beta proteins.

Effect of FK506 on Neurotransmitter Content and Expression of GAP-43 in Neurotoxin-Lesioned Peripheral Sensory and Sympathetic Neurons

It has previously been shown that the capsaicin-lesioned peptidergic sensory neurons and the 6-hydroxydopamine (6-OHDA)-lesioned sympathetic noradrenergic neurons represent a useful model to study neurotrophin-induced nerve regeneration in the adult rat. The present study was aimed at investigating if the immunosuppressant drug FK506 (tacrolimus) has neuroregeneratory properties in these capsaicin- or 6-OHDA-lesioned peripheral nerves. FK506 was injected in a dose of 0.5 mg/kg/day for 10 days or in a dose of 1.5 mg/kg/day for 7 days. One day after the last FK506 injection neurotransmitter content was investigated in selected tissues. The content of the sensory neuron marker peptide calcitonin gene-related peptide (CGRP) was reduced after the capsaicin treatment in the hind paw skin by 35–40% and in the dorsal lumbar spinal cord by 48%. The treatment with FK506 did not induce a recovery of the CGRP content. Following the 6-OHDA treatment the noradrenaline content was reduced by 50–62% in the hind paw skin and by 73% in the heart atrium. FK506 alone did not increase the noradrenaline levels, whereas an additional local intraplantar treatment with nerve growth factor recovered noradrenaline levels almost completely. The expression of a marker protein for growth processes in cells of sympathetic or sensory ganglia, growth-associated protein-43, was significantly increased by the FK506 treatment. This study demonstrated that despite a stimulatory effect of FK506 on the expression of a growth-associated protein a recovery of the transmitter content is not evident in peripheral small diameter sensory or postganglionic sympathetic neurons of the adult rat.

Injury to retinal ganglion cells induces expression of the small heat shock protein Hsp27 in the rat visual system

Optic nerve transection results in apoptotic cell death of most adult rat retinal ganglion cells that begins at 4 days and leaves few surviving neurons at 14 days post-injury [Berkelaar et al. (1994) J. Neurosci. 14, 4368–4374]. The small heat shock protein Hsp27 has recently been shown to play a role in sensory neuron survival following peripheral nerve axotomy [Lewis et al. (1999) J. Neurosci. 19, 8945–8953]. To investigate the role of Hsp27 in injured CNS sensory neurons, we have studied the induction and cell-specific expression of Hsp27 in rat retinal ganglion cells 1–28 days after optic nerve transection. Immunohistochemical results indicate that Hsp27 is not present at detectable levels in the ganglion cell layer of control (uninjured) or sham-operated control rats. In contrast, Hsp27 is detected in retinal ganglion cells from 4 to 28 days following axotomy. Furthermore, the percentage of surviving retinal ganglion cells that are Hsp27-positive increased over the same time period. Hsp27 is also detected in glial fibrillary acidic protein-positive astrocytes in the optic layer of the superior colliculus from 4 to 28 days after optic nerve transection. These experiments demonstrate that transection of the optic nerve results in the expression of Hsp27 in three distinct regions of the rat visual system: sensory retinal ganglion cells in the eye, glial cells of the optic tract, and astrocytes in the optic layer of the superior colliculus. Hsp27 may be associated with enhanced survival of a subset of retinal ganglion cells, providing evidence of a protective role for Hsp27 in CNS neuronal injury.

Latency and reactivation of human cytomegalovirus.

The sequence analysis of herpesviruses suggests they have been evolving with their individual vertebrate hosts for millions of years, and their divergence parallels that of the hosts they infect. Given this time they have been learning to live with their individual hosts, it is not surprising that they have become extremely well adapted to doing so without causing much in the way of obvious disease. A key feature of their strategy for persisting in the host is the ability of all herpesviruses to establish latent infection-a state in which no, or only a very limited set of, viral genes are expressed in cells in which viral DNA persists. The alpha herpesviruses (herpes simplex and varicella zoster virus) establish latency in neuronal cells in sensory ganglia: these are long lived non-dividing cells and the alpha herpesviruses persist in these with expression of only the latency associated transcripts-although the function of these RNA transcripts remains incompletely understood. The principal gamma herpesvirus of humans, Epstein Barr virus (EBV), is latent mainly in B lymphocytes: EBV persistence in B cells is associated with expression of a limited set of viral genes encoding functions necessary for the maintenance of the episomal viral DNA as B cells divide.The mechanism by which the principal beta herpesvirus of humans-human cytomegalovirus (HCMV) persists, is also incompletely understood and the subject of this review. Understanding how HCMV persists has clinical relevance in that its transmission to seronegative recipients might be more easily prevented, and the mechanisms by which it produces disease in the neonate and immunocompromised hosts more easily understood, if we knew more about the cells in which the virus is latent and the way in which it reactivates.

Peripheral nerve lesion-induced uptake and transport of choleragenoid by capsaicin-sensitive C-fibre spinal ganglion neurons

In the present experiments the effect of systemic capsaicin treatment on the retrograde labelling of sensory ganglion cells was studied following the injection of choleratoxin B subunit-horseradish peroxidase conjugate (CTX-HRP) into intact and chronically transected peripheral nerves. In the control rats CTX-HRP injected into intact sciatic nerves labelled medium and large neurons with a mean cross-sectional area of 1,041 +/- 39 gm2. However, after injection of the conjugate into chronically transected sciatic nerves of the control rats, many small cells were also labelled, shifting the mean cross-sectional area of the labelled cells to 632 +/- 118 microm2. Capsaicin pretreatment per se induced a moderate but significant decrease in the mean cross-sectional area of the labelled neurons (879 +/- 79 microm2). More importantly, systemic pretreatment with capsaicin prevented the peripheral nerve lesion-induced labelling of small cells. Thus, the mean cross-sectional areas of labelled neurons relating to the intact and transected sciatic nerves, respectively, did not differ significantly. These findings provide direct evidence for a phenotypic switch of capsaicin-sensitive nociceptive neurons after peripheral nerve injury, and suggest that lesion-induced morphological changes in the spinal cord may be related to specific alterations in the chemistry of C-fibre afferent neurons rather than to a sprouting response of A-fibre afferents.

Delayed loss of spinal motoneurons after peripheral nerve injury in adult rats: a quantitative morphological study

The existence of retrograde cell death in sensory dorsal root ganglion (DRG) cells after peripheral nerve injury is well established. However, with respect to retrograde motoneuron death after peripheral nerve injury, available data are conflicting. This may partly be due to the cell counting techniques used. In the present study, quantitative morphometric methods have been used to analyse retrograde motoneuron death induced by spinal nerve injury in adult rats. For comparison, DRG cells were also included in the study. The C7 spinal nerve was transected about 10 mm distal to the DRG and exposed to the fluorescent tracer fast blue in order to retrogradely label the spinal motoneurons and DRG cells of the C7 segment. At 1-16 weeks postoperatively, the nuclei of fast-blue-labelled C7 motoneurons and DRG cells were counted in consecutive 50-microm-thick serial sections. For comparison, the physical disector technique and measurements of neuronal density were also used to calculate motoneuron number. The counts of fast-blue-labelled motoneurons revealed a delayed motoneuron loss amounting to 21% and 31% after 8 and 16 weeks, respectively (P<0.001). The remaining motoneurons exhibited 20% (P<0.05) soma atrophy. Using the physical disector technique, the motoneuron loss was 23% (P<0.001) after 16 weeks. Calculations of neuronal density in Nissl-stained sections failed to reveal any motoneuron loss, although after correction for shrinkage of the ventral horn a 14% (P<0.001) motoneuron loss was found. The fast-blue-labelled DRG neurons displayed 51% (P<0.001) cell loss after 16 weeks, and the remaining cells showed 22% (P<0.001) soma atrophy. In summary, cervical spinal nerve injury induces retrograde degeneration of both motoneurons and DRG cells. However, to demonstrate the motoneuron loss adequate techniques for cell counts have to be employed.

Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor.

The announcement in October 1986 that the Nobel Prize for physiology or medicine was to be awarded to Rita Levi-Montalcini and Stanley Cohen for the discoveries of NGF and EGF, respectively, caused many to wonder why Viktor Hamburger (in whose laboratory the initial work was done) had not been included in the award. Now that the dust has settled, the time seems opportune to reconsider the antecedent studies on the relation of the developing nervous system to the peripheral structures it innervates. The studies undertaken primarily to investigate this issue culminated in the late 1950s in the discovery that certain tissues produce a nerve growth-promoting factor that is essential for the survival and maintenance of spinal (sensory) ganglion cells and sympathetic neurons. In this review, the many contributions that Viktor and Rita made to this problem, both independently and jointly, are reexamined by considering chronologically each of the relevant research publications together with some of the retrospective memoirs they have published in the years since the discovery of NGF was first reported.

Sensory Ganglion Cell Culture for the Study of Diabetic Polyneuropathy

Sensory Ganglion Cell Culture for the Study of Diabetic Polyneuropathy

Morphometric and ultrastructural studies of the sciatic nerve regeneration in rats intoxicated with ethanol

The aim of the study was to examine the process of sciatic nerve regeneration and changes in the dorsal root ganglia (from which sensory fibres of the sciatic nerve extend) in animals intoxicated with ethanol. The experiment used 20 rats, divided into two groups: control and treated. The treated animals were intragastrically given 2g/kg b.w. of ethanol in 25% aqueous solution. In both groups the right sciatic nerve was transected and then sutured. After 5 months the animals were anaesthetized. The left and the right spinal dorsal ganglia-L5 and sections from the non-operated and operated sciatic nerves were collected for analysis. Ultrastructural examinations and morphometric measurements were conducted. It was found that ethanol administrated to rats inhibited regeneration of the transected and then sutured sciatic nerve, impairing the growth of axons in the transected nerve and destroying the regenerating sensory ganglion cells. The mechanism of the changes described may be associated with axonal transport disorders or with the suppressed production of biologically active substances, which affect nerve regeneration.

Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine‐induced painful peripheral neuropathy in the rat

Vincristine, along with other antimitotic chemotherapeutic drugs, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias, dysesthesias, and occasionally hypoesthesia, and by hyporeflexia (Holland et al. [1973] Cancer Res. 33:1258–1264; McLeod and Penny [1969] J Neurol Neurosurg Psychiatry 32:297–304; Postma et al. [1993] J Neurooncol. 15:23–27; Sandler et al. [1969] Neurology 19:367–374). Systemic administration of vincristine causes swelling of unmyelinated axons and disorientation of axonal microtubules (Tanner et al. [1998a1998a] J Comp Neurol. 395:481–492) at a time when it also produces allodynia and mechanical hyperalgesia (Aley et al. [1996] Neuroscience 73:259–265; Authier et al. [1999] Neuroreport 10:965–968) and enhanced responsiveness in C-fibers in the rat (Tanner et al. [1998b] J Neurosci. 18:6480–6491). Because slowing of A-fiber conduction velocities had also been demonstrated (Tanner et al. [1998b] J Neurosci. 18:6480–6491), and mechanical hyperalgesia can occur secondary to damage to large diameter sensory afferents (Basbaum et al. [1991] Can J Physiol Pharmacol. 69:647–651; Coggeshall et al. [1993] Pain 52:233–242; Woolf and Mannion [1999] Lancet 353:1959–1964), we sought to determine whether vincristine also induced ultrastructural changes in myelinated A-fibers. Moreover, since systemic treatment with vincristine did not cause profound microtubule depolymerization in the unmyelinated axons of the peripheral nerve, we hypothesized that the drug's effects may be more extensive in the cell body, because in the spinal ganglion, the blood-nerve barrier is less restrictive. We used quantitative ultrastructural methods to analyze the microtubule cytoskeleton in myelinated axons in the mid-shaft of the saphenous nerve and in the sensory ganglion cells. Vincristine induced swelling of the whole nerve and an increase in the cross-sectional areas of myelinated axons but no loss of myelinated axons. There was a significant decrease in axonal microtubules, as well as microtubule disorganization, in myelinated fibers from vincristine-treated rats. In the spinal ganglion, vincristine induced swelling of large diameter sensory neurons and a build-up of neurofilaments in the cell bodies and proximal axons, suggestive of impaired anterograde axonal transport. J. Comp. Neurol. 424:563–576, 2000. © 2000 Wiley-Liss, Inc.

ATP as a peripheral mediator of pain

This article reviews the extent to which recent studies substantiate the hypothesis that ATP functions as a peripheral pain mediator. The discovery of the P2X family of ion channels (for which ATP is a ligand) and, in particular, the highly selective distribution of the P2X 3 receptor within the rat nociceptive system has inspired a variety of approaches to elucidate the potential role of ATP as a pain mediator. ATP elicits excitatory inward currents in small diameter sensory ganglion cells. These currents resemble those elicited by ATP on recombinantly expressed heteromeric P2X 2/3 channels as well as homomultimers consisting of P2X 2 and P2X 3. In vivo behavioural models have characterised the algogenic properties of ATP in normal conditions and in models of peripheral sensitisation. In humans, iontophoresis of ATP induces modest pain. In rats and humans the response is dependent on capsaicin sensitive neurons and is augmented in the presence of inflammatory mediators. Since ATP can be released in the vicinity of peripheral nociceptive terminals under a variety of conditions, there exists a purinergic chain of biological processes linking tissue damage to pain perception. The challenge remains to prove a physiological role for endogenous ATP in activating this chain of events.

Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat

Vincristine, along with other antimitotic chemotherapeutic drugs, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias, dysesthesias, and occasionally hypoesthesia, and by hyporeflexia (Holland et al. [1973] Cancer Res. 33:1258-1264; McLeod and Penny [1969] J Neurol Neurosurg Psychiatry 32:297-304; Postma et al. [1993] J Neurooncol. 15:23-27; Sandler et al. [1969] Neurology 19:367-374). Systemic administration of vincristine causes swelling of unmyelinated axons and disorientation of axonal microtubules (Tanner et al. [1998a1998a] J Comp Neurol. 395:481-492) at a time when it also produces allodynia and mechanical hyperalgesia (Aley et al. [1996] Neuroscience 73:259-265; Authier et al. [1999] Neuroreport 10:965-968) and enhanced responsiveness in C-fibers in the rat (Tanner et al. [1998b] J Neurosci. 18:6480-6491). Because slowing of A-fiber conduction velocities had also been demonstrated (Tanner et al. [1998b] J Neurosci. 18:6480-6491), and mechanical hyperalgesia can occur secondary to damage to large diameter sensory afferents (Basbaum et al. [1991] Can J Physiol Pharmacol. 69:647-651; Coggeshall et al. [1993] Pain 52:233-242; Woolf and Mannion [1999] Lancet 353:1959-1964), we sought to determine whether vincristine also induced ultrastructural changes in myelinated A-fibers. Moreover, since systemic treatment with vincristine did not cause profound microtubule depolymerization in the unmyelinated axons of the peripheral nerve, we hypothesized that the drug's effects may be more extensive in the cell body, because in the spinal ganglion, the blood-nerve barrier is less restrictive. We used quantitative ultrastructural methods to analyze the microtubule cytoskeleton in myelinated axons in the mid-shaft of the saphenous nerve and in the sensory ganglion cells. Vincristine induced swelling of the whole nerve and an increase in the cross-sectional areas of myelinated axons but no loss of myelinated axons. There was a significant decrease in axonal microtubules, as well as microtubule disorganization, in myelinated fibers from vincristine-treated rats. In the spinal ganglion, vincristine induced swelling of large diameter sensory neurons and a build-up of neurofilaments in the cell bodies and proximal axons, suggestive of impaired anterograde axonal transport.