Depolarization Of Axons Research Articles

ID: 204783 Placement of Genicular Nerve Peripheral Nerve Stimulator for Chronic Knee Pain

Peripheral nerve stimulation (PNS) is an evolving modality for treating different chronic pain conditions. The intervention was predicated on the gate theory of pain, which posits nociceptive and non-nociceptive inputs modulate the other's intensity in the dorsal horn of the spine. Although gate theory was one of the first explanations of PNS, competing theories now include overstimulation of c-fibers, exhaustion of neurotransmitters, fixed depolarization of afferent axons, and electrically induced changes to long term potentiation.1 No unified mechanism has been established, though the efficacy of PNS is evident.

ID: 207193 Placement of a Suprascapular Peripheral Nerve Stimulator for Treatment of Chronic Shoulder Pain

Peripheral nerve stimulation (PNS) is an evolving modality for treating different chronic pain conditions. The intervention was predicated on the gate theory of pain, which posits nociceptive and non-nociceptive inputs modulate the other's intensity in the dorsal horn of the spine. Competing theories now include overstimulation of c-fibers, exhaustion of neurotransmitters, fixed depolarization of afferent axons, and electrically induced changes to long term potentiation.1 No unified mechanism has been established, though the efficacy of PNS is evident.

Sustained Maximal Voluntary Contraction Produces Independent Changes in Human Motor Axons and the Muscle They Innervate

The repetitive discharges required to produce a sustained muscle contraction results in activity-dependent hyperpolarization of the motor axons and a reduction in the force-generating capacity of the muscle. We investigated the relationship between these changes in the adductor pollicis muscle and the motor axons of its ulnar nerve supply, and the reproducibility of these changes. Ten subjects performed a 1-min maximal voluntary contraction. Activity-dependent changes in axonal excitability were measured using threshold tracking with electrical stimulation at the wrist; changes in the muscle were assessed as evoked and voluntary electromyography (EMG) and isometric force. Separate components of axonal excitability and muscle properties were tested at 5 min intervals after the sustained contraction in 5 separate sessions. The current threshold required to produce the target muscle action potential increased immediately after the contraction by 14.8% (p<0.05), reflecting decreased axonal excitability secondary to hyperpolarization. This was not correlated with the decline in amplitude of muscle force or evoked EMG. A late reversal in threshold current after the initial recovery from hyperpolarization peaked at −5.9% at ∼35 min (p<0.05). This pattern was mirrored by other indices of axonal excitability revealing a previously unreported depolarization of motor axons in the late recovery period. Measures of axonal excitability were relatively stable at rest but less so after sustained activity. The coefficient of variation (CoV) for threshold current increase was higher after activity (CoV 0.54, p<0.05) whereas changes in voluntary (CoV 0.12) and evoked twitch (CoV 0.15) force were relatively stable. These results demonstrate that activity-dependent changes in motor axon excitability are unlikely to contribute to concomitant changes in the muscle after sustained activity in healthy people. The variability in axonal excitability after sustained activity suggests that care is needed when using these measures if the integrity of either the muscle or nerve may be compromised.

Synaptic plasticity by antidromic firing during hippocampal network oscillations

Learning and other cognitive tasks require integrating new experiences into context. In contrast to sensory-evoked synaptic plasticity, comparatively little is known of how synaptic plasticity may be regulated by intrinsic activity in the brain, much of which can involve nonclassical modes of neuronal firing and integration. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] functionally couple neurons into transient ensembles. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. This activity is facilitated by GABA(A)-mediated depolarization of axons and electrotonic coupling. The possible effects of antidromic firing on synaptic strength are unknown. We find that facilitation of spontaneous SPW-Rs in hippocampal slices by increasing gap-junction coupling or by GABA(A)-mediated axon depolarization resulted in a reduction of synaptic strength, and electrical stimulation of axons evoked a widespread, long-lasting synaptic depression. Unlike other forms of synaptic plasticity, this synaptic depression is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Synaptic stimulation delivered after antidromic firing, which was otherwise too weak to induce synaptic potentiation, triggered a long-lasting increase in synaptic strength. Rescaling synaptic weights in subsets of neurons firing antidromically during SPW-Rs might contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information.

Regional differences in ulnar nerve excitability may predispose to the development of entrapment neuropathy

Objective To assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow. Methods Nerve excitability studies were undertaken in 11 healthy controls. Studies were undertaken with stimulation of the ulnar nerve at the elbow and wrist. Recordings were obtained from abductor digiti minimi in both sets of studies. Results Recordings obtained following stimulation of the nerve at the elbow demonstrated significant differences to those obtained following stimulation of the nerve at the wrist. Specifically, there was a left shift in stimulus–response curves at the elbow compared to the wrist, with prolonged strength-duration time constant, and reduced rheobase ( P < 0.05). These changes were accompanied by increased refractoriness and reductions in superexcitability and late subexcitability ( P < 0.05). Conclusions The present findings may suggest relative depolarization of ulnar nerve axons at the elbow. Significance These changes may reflect regional differences in axonal Na +/K + pump function and thereby predispose the ulnar nerve to conduction failure and axonal degeneration when exposed to trauma.

Central Contributions to Contractions Evoked by Tetanic Neuromuscular Electrical Stimulation

Tetanic electrical stimulation applied over human muscle or peripheral nerve generates contractions by depolarizing motor axons beneath the stimulating electrodes. However, the simultaneous depolarization of sensory axons can also contribute to the contractions by the synaptic recruitment of spinal motoneurons. Maximizing this central contribution may be beneficial for reducing muscle atrophy or restoring movement for persons with movement disorders.

Differential effects of Na-K-ATPase pump inhibition, chemical anoxia, and glycolytic blockade on membrane potential of rat optic nerve

Na +-K +-ATPase pump failure during either anoxia or ouabain perfusion induces rapid axonal depolarization by dissipating ionic gradients. In this study, we examined the interplay between cation and anion transporting pathways mediating axonal depolarization during anoxia or selective Na +-K +-ATPase inhibition. Compound resting membrane ( V m) potential of rat optic nerve was measured in a grease gap at 37 °C. Chemical anoxia (2 mM NaCN or NaN 3) or ouabain (1 mM) caused a loss of resting potential to 42 ± 11% and 47 ± 2% of control after 30 min, respectively. Voltage-gated Na +-channel blockade was partially effective in abolishing this depolarization. TTX (1 μM) reduced depolarization to 73 ± 10% (chemical anoxia) and 68 ± 4% (ouabain) of control. Quaternary amine Na + channel blockers QX-314 (1 mM) or prajmaline (100 μM) produced similar results. Residual ionic rundown largely representing co-efflux of K + and Cl − during chemical anoxia in the presence of Na +-channel blockade was further spared with DIDS (500 μM), a broad-spectrum anion transport inhibitor (95 ± 8% of control after 30 min in anoxia + TTX vs. 73 ± 10% in TTX alone). Addition of DIDS was slightly more effective than TTX alone in ouabain (74 ± 5% DIDS + TTX vs. 68 ± 4% in TTX alone, P < 0.05). Additional Na +-entry pathways such as the Na-K-Cl cotransporter were examined using bumetanide, which produced a modest albeit significant sparing of V m during ouabain-induced depolarization. Although cation-transporting pathways play the more important role in mediating pathological depolarization of central axons, anion-coupled transporters also contribute to a significant, albeit more minor, degree.

Vigabatrin enhances promoted release of GABA in neonatal rat optic nerve.

Vigabatrin (gamma-vinyl GABA) is an antiepileptic drug and blocks GABA transaminase activity resulting in elevations in cellular GABA levels in the brain. Nipecotic acid (NPA) promotes release of GABA from neonatal optic nerve astrocytes, resulting in a bicuculline-sensitive depolarization of the optic nerve axons. The NPA-induced depolarization of vigabatrin-treated rats (100 mg/kg, i.p.) more than doubled, suggesting an elevation in free GABA levels; the GABA transporter inhibitor, NO-711 reduced the depolarization. These results are consistent with the known ability of vigabatrin to block the GABA degradation enzyme GABA-transaminase, suggesting that vigabatrin elevates astrocytic GABA levels, thereby favoring greater release of GABA through the GABA transporter.

Spatial heterogeneity of intracellular Ca2+ signals in axons of basket cells from rat cerebellar slices.

1. Using tight-seal whole-cell recording and digital fluorescence imaging, we studied intracellular calcium (Ca2+i) dynamics in cerebellar basket cells, whose dendrites, axon and presynaptic terminals are coplanar, an optimal configuration for simultaneous optical measurements of all functional domains. 2. In Cs(+)-loaded neurones, depolarizing pulses induced large Ca2+i transients in single axonal varicosities and synaptic terminals, contrasting with much weaker signals between varicosities or in the somato-dendritic domain. 3. Axonal branch points consistently displayed [Ca2+]i rises of similar magnitude and time course to those in axonal terminals and varicosities. 4. In biocytin-filled basket cells, varicosity-like swellings were present along the axon including its branch points. Thus, axonal enlargements are not due to fluorescence-induced cell damage. 5. The spatial heterogeneity of Ca2+i signals was also observed in K(+)-loaded cells upon depolarizing trains, suggesting that this behaviour is an intrinsic property of Ca2+i homeostasis in basket cells. 6. We conclude that depolarization of basket cell axons evokes high local Ca2+i signals in synaptic terminals, en passant varicosities and branch points. While high [Ca2+]i in presynaptic structures presumably triggers transmitter release, Ca2+i transients at branch points may control signal transmission in the axonal arborization.

Spatiotemporal gradients of intra-axonal [Na+] after transection and resealing in lizard peripheral myelinated axons.

1. Post-transection changes in intracellular Na+ ([Na+]i) were measured in lizard peripheral axons ionophoretically injected with the Na(+)-sensitive ratiometric dye, sodium-binding benzofuran isophthalate (SBFI). 2. Following axonal transection in physiological saline [Na+]i increased to more than 100 mM in a region that quickly extended hundreds of micrometers from the transection site. This post-transection increase in [Na+]i was similar when the bath contained 5 microM tetrodotoxin, but was absent in Na(+)-free solution. Depolarization of uncut axons in 50 mM K+ produced little or no elevation of [Na+]i until veratridine was added. These results suggest that the post-transection increase in [Na+]i was due mainly to Na+ entry via the cut end, rather than via depolarization-activated Na+ channels. 3. The spatiotemporal profile of the post-transection increase in [Na+]i could be accounted for by movement of Na+ from the cut end with an apparent diffusion coefficient of 1.3 x 10(-5) cm2 s-1. 4. [Na+]i began to decline toward resting levels by 20 +/- 15 min (mean +/- S.D.) post-transection, except in regions of the axon within 160 +/- 85 microns of the transection site, where [Na+]i remained high. The boundary between axonal regions in which [Na+]i did or did not recover probably defines a locus of resealing of the axonal membrane. 5. [Na+]i returned to resting values within about 1 h after resealing, even in axonal regions where the normal transmembrane [Na+] gradient had completely dissipated. The recovery of [Na+]i was faster and reached lower levels than expected by diffusional redistribution of Na+ along the axon. Partial recovery occurred even in an isolated internode, indicating that the internodal axolemma can actively extrude Na+.

Involvement of the Na,K-ATPase in the induction of ion channels by palytoxin.

The effects of ouabain, ATP, and vanadate on palytoxin induction of ion channels were examined with the aim of elucidating the role of Na,K-ATPase in palytoxin action. Palytoxin-induced membrane depolarization of crayfish giant axons and single channel currents of frog erythrocytes and mouse neuroblastoma N1E-115 cells were examined using the intracellular microelectrode and patch-clamp techniques. External application of palytoxin in nanomolar concentrations induced depolarization in the crayfish giant axons, and the depolarization was inhibited by pretreatment of the axon with ouabain (10 microM). Internally perfused axons were less sensitive to palytoxin unless ATP (6 mM) was added internally. In patch-clamp experiments, picomolar palytoxin in the patch electrode induced single channels in both cell-attached and inside-out patches of erythrocytes and neuroblastoma cells. The induced channels had a conductance of about 10 pS, reversed near 0 mV in physiological saline solution, and was permeable to Na+, K+, Cs+, and NH4+, but not to choline. Single channel activities induced by palytoxin were inhibited by ouabain (10 microM) and vanadate (1 mM), but promoted by ATP (1 mM). The modulating effects of ouabain, vanadate, and ATP on palytoxin action suggest that the Na,K-ATPase is involved in the induction of single channels by palytoxin. Palytoxin-induced and ouabain-inhibitable single channels were observed in planar lipid bilayer incorporated with purified Na,K-ATPase. The results indicate that an interaction between palytoxin and Na,K-ATPase leads to opening of a 10-pS ion channel. They further raise the possibility that a channel structure may exist in the sodium pump which is uncovered by the action of palytoxin.

Acetylsalicylic acid inhibits cerebral cortical vasodilatation caused by superior sagittal sinus stimulation in the cat*

Acetylsalicylic acid (ASA; aspirin) is one of the most widely used pain reliefs in the world and is certainly effective in the treatment of acute attacks of migraine of moderate severity. It has usually been considered that the action of ASA in migraine is related to peripheral inhibition of mediators of inflammation. Migraine involves episodic head pain that is thought generally to involve intracranial pain structures innervated by the ophthalmic (first) division of the trigeminal nerve, particularly vascular structures that have come to be known as the trigeminovascular system. In this study the effect of ASA on the cerebrovascular effects of the trigeminovascular system were assessed directly with measurements of cerebral blood flow. The trigeminovascular system was activated by stimulation of the superior sagittal sinus (SSS), a midline large venous sinus that is pain sensitive in humans. The SSS was stimulated electrically and cerebral blood flow measured using laser Doppler flowmetry (CBFLDF ). Stimulation of the SSS resulted in a stimulus-locked frequency-dependent increase in CBFLDF that reached a mean maximum at 2 Hz with a 60 ± 6% reduction in calculated cerebrovascuiar resistance. Administration of ASA (30 mg/kg i.v.) resulted in a small non-sustained increase in blood pressure but no change in resting CBFLDF . The CBFLDF response to SSS stimulation was reduced at all but one frequency of stimulation to a maximum of a 43 ± 10% reduction in cerebrovascular resistance. Since electrical stimulation involves consecutive depolarization of trigeminovascular axons and bypasses the peripheral nerve vessel interaction it is likely that this effect of ASA is mediated in the central nervous system. Such a possibility draws attention to a possibly novel therapeutic locus of action for ASA and to the importance of central nervous system processing of trigeminovascular inputs that are integral to the clinical expression of migraine.

The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

1. Electrotonic responses to 150 ms current pulses were recorded from isolated rat dorsal roots incubated for at least 3 h with either normal (5 mM) or high (25 mM) D-glucose solutions, and with either normal (25 mM) or low (5 mM) bicarbonate concentrations. 2. On replacement of O2 by N2 for 50 min, all the roots depolarized, but the changes in electrotonus differed systematically. With normal glucose, the depolarization was accompanied by an increase in input conductance. In contrast, for the hyperglycaemic roots the depolarization was slower and accompanied by a fall in input conductance which was exacerbated in low bicarbonate concentrations. 3. The changes induced by hyperglycaemic hypoxia in low bicarbonate could be mimicked by exposure of the roots either to 100% CO2 or to a combination of 3 mM tetraethylammonium chloride and 3 mM 4-aminopyridine, to block both fast and slow potassium channels. 4. These results indicate that the primary mechanism of hypoxic depolarization of these sensory axons is altered by hyperglycaemia. In normoglycaemia, the changes in electrotonus are consistent with an increase in axonal potassium conductance. The block of potassium channels seen in hyperglycaemic hypoxia is attributed to intra-axonal acidification by anaerobic glycolysis and may contribute to the pathogenesis of diabetic neuropathy.

GABA A receptor-mediated excitation of nociceptive afferents in the rat isolated spinal cord-tail preparation

Algogens such as capsaicin, bradykinin, acetylcholine, 5-hydroxytryptamine and potassium ions applied to exposed tail skin of the rat isolated spinal cord-tail preparation evoke a ventral root response consisting of depolarization and spiking activity. l-glutamate and kainate also evoke similar reflexes. All these compounds evoke depolarization of afferent axons or dorsal root ganglion cells. Since GABA depolarizes unmyelinated afferent fibers, the ability of GABA receptor agonists to activate cutaneous nociceptive afferents has been examined. GABA superfused over exposed tail skin evoked a ventral root reflex essentially identical to that produced by capsaicin (3 μM). The EC 50 was 27 μM. Muscimol, 3-aminopropane sulphonate, isoguvacine and beta-alanine had effects comparable to GABA, with EC 50 values of 9.6, 26, 56 and 870 μM respectively. Baclofen (100 μM) or glycine (10 mM) had no effect. Bicuculline applied to the tail competitively antagonized GABA (Schild slope = − 1.03) with a pA2 of 5.8. Spinal application of 1 μM morphine blocked the actions of GABA and capsaicin. These data indicate that GABA A receptors can depolarize and excite nociceptive afferents. GABA could be involved in nociception by contributing to firing of C-fibres, or by analogy to presynaptic inhibition in the spinal cord, may act to decrease neuropeptide transmitter release in cutaneous tissue.

Actions of three structurally distinct sea anemone toxins on crustacean and insect sodium channels

The membrane actions of three recently isolated polypeptide neurotoxins from the sea anemones Stichodactyla helianthus (toxin ShI), Condylactis gigantea (toxin CgII) and Calliactis parasitica (toxin CpI) were investigated on action potentials and voltage-clamp membrane currents of the giant axon of the crayfish Procambarus clarkii. The first two toxins were also tested on the cockroach (Periplaneta americana) giant axon. All three toxins were particularly lethal to crustaceans, moderately toxic to an insect (cockroach), and essentially non-toxic to a mammal (mouse). ShI and CgII were 50- to 100-fold more potent on crayfish than on cockroach axons; this difference in activity was correlated with the relative reversibility of their effects on these arthropod axons. The crustacean selectivity of these toxins is therefore due largely to their greater affinity for crustacean sodium channels. All three toxins prolonged crayfish giant axon action potentials by selectively slowing Na channel inactivation without greatly affecting activation. Before toxin treatment, inactivation was nearly exponential, with a time constant less than 1 msec. After treatment, the inactivation time course could be described as the sum of two exponentially decaying components, plus a large steady-state component. The major component possessed the slower (10–20 msec) time constant. The steady-state component increased with depolarization, causing the sodium channel steady-state inactivation curve to reach a minimum between −60 and −20 mV and then increase at more positive potentials. All three toxins shifted the peak sodium current-voltage relation to the left. This voltage shift was greater at 20°C than at 10°C. Maintained membrane depolarization during toxin wash-in delayed the appearance of modified Na channels. Also, prolonged depolarization of toxin-treated axons converted modified sodium channels back to normal ones. The toxins did not affect potassium and leakage currents. Our results indicate that the three crustacean-active sea anemone toxins share a common electrophysiological action on arthropod sodium channels, at least at the macroscopic level.

Depolarization of Ib afferent axons in the cat spinal cord during homonymous muscle contraction.

1. Intra-axonal records from the intraspinal course of Ib and Ia afferent fibres innervating the gastrocnemius medialis muscle were obtained in chloralose or Nembutal-anaesthetized cats during submaximal contractions of the muscle. 2. Afferent fibres in continuity with their muscle of origin were functionally identified by their responses to muscle stretch or contraction. 3. In six out of eight Ib afferents, primary depolarizations (PADs) were recorded during contraction. They were independent of the presence of orthodromic impulses fired by tendon organs. 4. These observations support the assumption that the reduction of Ib autogenetic inhibition in homonymous and synergic motoneurones during GM contractions is due to presynaptic inhibition of transmission in Ib pathways.

Ergot alkaloids block neurogenic extravasation in dura mater: proposed action in vascular headaches.

Although the ergot alkaloids (ergots) are useful drugs for the acute treatment of migraine headaches, their mechanism of action remains obscure. When administered to rats in clinically relevant doses, ergots blocked the development of neurogenic plasma extravasation in dura mater. Plasma extravasation was induced by depolarization of perivascular axons following capsaicin injection or unilateral electrical stimulation of the trigeminal nerve. The ergot action could not be accounted for by vasoconstriction alone because neurogenic plasma leakage was not blocked by angiotensin or phenylephrine. Furthermore, ergots did not block plasma extravasation induced by administering sensory neuropeptides that mediate enhanced permeability. We propose that the therapeutic effects of ergots in vascular headaches may result from peripheral blockade of small fiber (C or A-delta)-dependent neurogenic inflammation within the dura mater.

Potentials Associated With the Blood-Brain Barrier of an Insect: Recordings from Identified Neuroglia

ABSTRACT The blood-brain barrier of the insect nervous system is thought to be formed by the neuroglia. It is associated with a positive interstitial potential relative to the bathing medium (‘sheath’ potential), and with positive changes in potential that can be induced by raising the potassium level in the bathing medium. In central nervous connectives of the cockroach, Periplaneta americana, these potential differences (p.d.s) were measured just below the perineurium at the same magnitude as comparable p.d.s recorded deeper, indicating that they are produced by the perineurium. The interstitial p.d. apparently results from the presence of a paracellular resistance, and from the generation of less electromotive force (e.m.f.) by the basolateral membrane than by the apical (adglial). Recordings from cells identified by injection of peroxidase showed that the initial change in interstitial p.d. induced by high K was accompanied by: a depolarization of greater magnitude across the basolateral membrane, a small depolarization of the apical membrane, and no depolarization of sub-perineurial glial cells or axons. It therefore appears that the depolarization of the basolateral membrane by high K gives rise, by electrical coupling, to the shift in interstitial p.d. and the depolarization of the apical membrane. There was then a gradual depolarization of all membranes, consistent with a leak of K into the sub-perineurial interstitial system, and where the depolarization of the basolateral membrane would be produced by coupling to the apical. If the perineurium contains an intercellular resistance, then it must restrict diffusion of water-soluble substances.

Role of K + in GABA (γ-aminobutyric acid)-evoked depolarization of peripheral nerve

Isolated, desheathed sciatic nerves of the leopard frog or bull frog were used in studies to determine different sources/components of the depolarizing effect of GABA (gamma-aminobutyric acid) on myelinated fibers. During the depolarization induced by 1 mM GABA--which was reflected by an increase of 38.3% (S.E. +/- 2.2) in the amplitude of the evoked half-maximal A-fiber compound action potential--the level of extracellular potassium ([K+]o) measured at depths less than or equal to 200 microns in the nerve with ion-selective microelectrodes, increased by 0.096 mM (S.E. +/- 0.007). Changes in excitability preceded K+]o, and there was a significant difference between their peak latencies. Artificially raised levels of [K+]o, similar to those induced by GABA, caused extremely small changes (less than 10%) in the size of the evoked action potential. From the magnitude and time course of the GABA-evoked augmentation of levels of [K+]o, it can be concluded that potassium ions probably arise indirectly and play a secondary role in what appears to be a mainly receptor-mediated depolarization of axons. A much greater sensitivity to GABA was found for fibers of the dorsal roots in comparison with those of the ventral roots (maximal changes in excitability of 50% and 6% respectively). This suggests that the depolarization of ventral root fibers could be caused by [K+]o accumulation, and that there may be a preferentially localized distribution of receptors for GABA on the sensory axons of peripheral nerve.

Physiological and ultrastructural observations on regenerated carotid sinus nerves after removal of the carotid bodies in cats

Carotid bodies were excised bilaterally in cats and the cut carotid sinus nerves allowed to regenerate freely into the region of the carotid bifurcation for 31 to 315 days. Electrophysiological recordings from regenerated nerves showed spontaneous activity and mechanoreceptive units in some nerves. None of the nerves were excited by physiological or chemical stimuli known to excite chemoreceptors, but electrical stimulation of the regenerated axons evoked reflex ventilatory responses. Serial section light-microscopic analysis of the regenerated nerves revealed bundles of axons branching from the carotid sinus nerve near the site of transection and coursing into the area of the carotid bifurcation. Electron-microscopic examination of the most distal region of the regenerated nerve which could be identified showed axonal bundles comprised of myelinated and unmyelinated fibers characteristic of the mature sinus nerve; axonal sprouts were rarely encountered. Carotid body type 1 or type II cells were never observed. Infrequently, neuronal specializations containing mitochondria and synaptic vesicles were seen in connective tissue in the distal regions of the regenerated nerve. The vascularity of the regenerated nerve was at least comparable to that of the normal carotid sinus nerve. The results indicate that chemoreceptivity is not a property of carotid sinus nerve sensory axons when they are allowed to regenerate freely into the area of the carotid bifurcation after removing the carotid body. Consequently, these observations do not provide support for theories which consider chemoreception to be an intrinsic property of carotid sinus neurons. It is concluded that some extrinsic factor normally provided by the carotid body is essential to the transduction process which initiates depolarization of the sensory axons terminating within this organ.