ABSTRACT
Sensory and motor conduction velocities calculated from latencies of H reflexes and M waves in rat hind limbs have been used to assess experimental peripheral neuropathy. Amplitudes and latencies vary with recording location, and are seldom assessed directly. Using subcutaneous electrodes on the foot, we recorded consistent M waves and H reflexes while stimulating the sciatic or tibial nerve. The late wave disappeared when dorsal roots were cut, verifying that it was an H reflex. However, stimulus-response characteristics differed from those in humans: (a) the threshold was often higher than for M waves; (b) stimulus intensity eliciting a maximum H-reflex amplitude (Hmax) was often higher than adequate for a maximum M-wave amplitude; and (c) the amplitudes of H reflexes stimulated with intensities supramaximal for the M wave were over 90% of Hmax. H reflexes and M waves recorded repeatedly in rats can be useful in assessing sensory and motor function in models of neuropathy, using amplitudes as well as conduction velocities.
Subject(s)
H-Reflex/physiology , Hindlimb/physiology , Animals , Disease Models, Animal , Electric Stimulation , Electrophysiology , Female , Hindlimb/innervation , Humans , Motor Neurons/physiology , Neural Conduction/physiology , Neurons, Afferent/physiology , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Rats , Rats, Sprague-Dawley , Reaction Time/physiology , Rhizotomy , Sensory Thresholds/physiology , Spinal Nerve Roots/surgeryABSTRACT
The receptor-mediated axonal transport of [125I]-labeled neurotrophins by afferent and efferent neurons of the vagus nerve was determined to predict the responsiveness of these neurons to neurotrophins in vivo. [125I]-labeled neurotrophins were administered to the proximal stump of the transected cervical vagus nerve of adult rats. Vagal afferent neurons retrogradely transported [125I]neurotrophin-3 (NT-3), [125I]nerve growth factor (NGF), and [125I]neurotrophin-4 (NT-4) to perikarya in the ipsilateral nodose ganglion, and transganglionically transported [125I]NT-3, [125I]NGF, and [125I]NT-4 to the central terminal field, the nucleus tractus solitarius (NTS). Vagal afferent neurons showed minimal accumulation of [125I]brain-derived neurotrophic factor (BDNF). In contrast, efferent (parasympathetic and motor) neurons located in the dorsal motor nucleus of the vagus and nucleus ambiguus retrogradely transported [125I]BDNF, [125I]NT-3, and [125I]NT-4, but not [125I]NGF. The receptor specificity of neurotrophin transport was examined by applying [125I]-labeled neurotrophins with an excess of unlabeled neurotrophins. The retrograde transport of [125I]NT-3 to the nodose ganglion was reduced by NT-3 and by NGF, and the transport of [125I]NGF was reduced only by NGF, whereas the transport of [125I]NT-4 was significantly reduced by each of the neurotrophins. The competition profiles for the transport of NT-3 and NGF are consistent with the presence of TrkA and TrkC and the absence of TrkB in the nodose ganglion, whereas the profile for NT-4 suggests a p75 receptor-mediated transport mechanism. The transport profiles of neurotrophins by efferent vagal neurons in the dorsal motor nucleus of the vagus and nucleus ambiguus are consistent with the presence of TrkB and TrkC, but not TrkA, in these nuclei. These observations describe the unique receptor-mediated axonal transport of neurotrophins in adult vagal afferent and efferent neurons and thus serve as a template to discern the role of specific neurotrophins in the functions of these visceral sensory and motor neurons in vivo.
Subject(s)
Axonal Transport/physiology , Nerve Growth Factors/pharmacokinetics , Neurons, Efferent/metabolism , Nodose Ganglion/cytology , Rats, Sprague-Dawley/physiology , Animals , Gene Expression , Iodine Radioisotopes , Male , Neurons, Afferent/chemistry , Neurons, Afferent/cytology , Neurons, Afferent/metabolism , Neurons, Efferent/chemistry , Neurons, Efferent/cytology , Neuroprotective Agents/pharmacokinetics , Neurotrophin 3 , Nodose Ganglion/metabolism , Proto-Oncogene Proteins/genetics , Rats , Receptor Protein-Tyrosine Kinases/genetics , Receptor, Ciliary Neurotrophic Factor , Receptor, Nerve Growth Factor , Receptor, trkA , Receptor, trkC , Receptors, Nerve Growth Factor/genetics , Solitary Nucleus/cytology , Solitary Nucleus/metabolism , VagotomyABSTRACT
The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose-related peripheral neuropathy in humans. We produced a dose-dependent large-fiber sensory neuropathy, without detrimental effects on general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H-wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail-flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol-induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.
