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M Devor

Publications and source records attributed to M Devor.

At least 37 records · Page 2Linked to original sources
PubMed1997

Association of postganglionic sympathetic neurons with primary afferents in sympathetic-sensory co-cultures.

Functional coupling between sympathetic postganglionic neurons and sensory neurons is thought to play an essential role in the pathogenesis of certain chronic pain syndromes following peripheral tissue and nerve injury. The mechanism(s) underlying this interaction are enigmatic. The relative anatomical inaccessibility of sympathetic and sensory neurons in vivo complicates study of their interrelationships. We have developed a system for long-term co-culturing of explants of sympathetic chain ganglia and dorsal root ganglia from newborn rats. Co-cultures were labelled for tyrosine hydroxylase-like immunoreactivity and studied at the light and electron microscopic levels. Explanted ganglia of both types survived well in co-culture. They maintained their tissue type-specific histological properties, including neuronal and glial morphology, and characteristic glial-neuronal associations. Moreover, neurons maintained their characteristic neurochemical identity, at least to the extent that sympathetic neurons continued to express tyrosine hydroxylase and dorsal root ganglion neurons did not. Sympathetic neurons emitted numerous outgrowing processes (axons) some of which came into association with sensory neurons in the explanted dorsal root ganglia. Some apparently specific sympathetic-sensory contacts were observed, suggesting that a functional interaction may develop between sympathetic axons and sensory neurons in vitro.

Animals↗
PubMed1997

An electron-microscopic analysis of biopsy samples of the trigeminal root taken during microvascular decompressive surgery.

During surgical exposure of the trigeminal root for the treatment of trigeminal neuralgia, biopsy specimens of the nerve root were taken in 12 consecutive patients. The biopsies were taken from areas as close as possible to the site of vascular compression, when present. The tissue was prepared for electron-microscopic evaluation. Except for 1 case, massive disruption of tissue ultrastructure was observed. The major findings included zones of de- and dysmyelination, juxtaposition of denuded axons, apparent axon loss and degeneration, and collagen deposition. Adjacent areas of normal root structure were present in most specimens. The ultrastructural changes observed in the biopsy samples demonstrate important pathology within the trigeminal root. Dysmyelination and the proximity of denuded axons in close apposition to each other support neurophysiological theories of pain production including ectopic electrogenesis, ephaptic contacts, and crossed after-discharge. The findings in this study demonstrate a pathophysiological basis for the syndrome of trigeminal neuralgia.

Adult↗
PubMed1996

Chemically mediated cross-excitation in rat dorsal root ganglia.

Primary afferent neurons in mammalian dorsal root ganglia (DRGs) are anatomically isolated from one another and are not synaptically interconnected. As such, they are classically thought to function as independent sensory communication elements. However, it has recently been shown that most DRG neurons are transiently depolarized when axons of neighboring neurons of the same ganglion are stimulated repetitively. Here we further characterize this functional coupling. In electrophysiological recordings made from excised rat DRGs, we found that DRG "cross-depolarization" is excitatory in that it is accompanied by an increase in the probability of spiking in response to otherwise subthreshold test pulses delivered intracellularly. Cross-depolarization contributes to this mutual cross-excitation. However, at least as important a contribution comes from a net increase in the neurons' input resistance (Rin) triggered by the stimulation of neighboring neurons. This change in Rin occurs even when cross-depolarization is absent or is balanced out. The amplitude of cross-depolaration was found to be voltage-dependent, with a reversal potential at approximately -23mV. Reversibility and the change in Rin both indicated that activity of neighboring neurons causes a membrane conductance change that is chemically mediated. Thus, far from being isolated, most DRG neurons participate in ongoing mutual interactions in which neuronal excitability is continuously modulated by afferent spike activity. This intraganglionic dialog appears to be mediated, at least in part, by an activity-dependent diffusable substance(s) released from neuronal somata and/or adjacent axons, and detected by neighboring cell somata and/or axons.

Action Potentials↗
PubMed1996

Sympathetic modulation of activity in rat dorsal root ganglion neurons changes over time following peripheral nerve injury.

1. We recorded from centrally connected axons isolated from the proximal stump of the sciatic nerve in intact rats and in rats whose nerves had been transected 4 days-6 mo previously. Afferent axons selected for study had spontaneous impulse activity that originated ectopically in dorsal root ganglia (DRGs) L4 and L5. The sympathetic supply of these DRGs was excited by repetitive electrical stimulation of ventral roots T13 and L1. We examined quantitatively changes in afferent ongoing firing evoked by sympathetic stimulation. Results are based on observations from 161 neurons in rats with sciatic nerve injury and from 58 neurons in control rats with intact sciatic nerves. Of these 219 neurons, 204 had myelinated fibers (A neurons) and 15 had unmyelinated fibers (C neurons), on the basis of measurements of conduction velocity. 2. In rats with nerve injury the majority of the spontaneously active neurons tested (95 of 161) responded to sympathetic stimulation with a change in ongoing firing frequency: 41 neurons exhibited a significant increase in discharge frequency that was often followed by suppression (28 of 41), and 54 neurons responded with a decrease in ongoing activity (simple suppression). In control rats, in contrast, only 1 of the 58 spontaneously active sensory neurons tested responded to sympathetic stimulation. 3. In A neurons, the response pattern changed systematically with time after sciatic nerve injury. At 4-22 days after nerve lesion, excitation was much more common than suppression. At 60-93 days, excitation and suppression occurred about equally. At 110-171 days, suppression was by far the more common response. 4. Of the 14 C neurons, 2 were excited by sympathetic stimulation (at 4-22 days postoperative) and 10 were suppressed (2 at 4-22 days, 8 at > 60 days). The only spontaneously active C neuron found in control rats was not affected by sympathetic stimulation. 5. The magnitude of responses in the three postoperative intervals investigated was similar. This was so for both the excitatory and the simple suppressive responses. The average latency between onset of stimulation and excitatory responses in afferent A fibers (approximately 10 s) was significantly less than the latency to simple suppressive responses (approximately 20 s). 6. The mean spontaneous firing rate of A neurons decreased with time after nerve lesion. No change was observed in C neuron activity. The mean firing rate of A neurons was significantly higher than that of C neurons 4-93 days after nerve lesion, but not later. In all three postoperative periods investigated, the mean rate of spontaneous activity was the same in A neurons that responded to sympathetic stimulation and A neurons that did not. 7. The results show that nerve injury triggers sympathetic-sensory coupling within rat DRGs. Excitatory coupling is preferentially present in the period shortly after nerve injury, and is subsequently replaced by suppressive coupling. This suggests that there is a gradual change in the underlying coupling mechanism.

Animals↗
PubMed1996

Adrenoreceptor subtype mediating sympathetic-sensory coupling in injured sensory neurons.

1. Teased axon recordings were made from 167 spontaneously active A beta- and A delta-afferents that ended in sciatic nerve end neuromas of 6-12 days standing. When challenged with a standard bolus of systemically applied adrenaline, 100 (60%) responded, either with an increase in baseline firing frequency (excitation, 96/100) or with a decrease (suppression, 4/100). 2. Experiments using receptor type-selective antagonists indicated that the adreno-sensitivity was mediated by alpha 2 adrenoreceptors in 65% of the afferents sampled, by alpha 1 adrenoreceptors in 13%, and about equally by alpha 1 and alpha 2 adrenoreceptors in approximately 10%. In the remaining 13%, neither type of antagonist blocked adrenaline-evoked excitation, at least not at the doses used. Both excitatory and suppressive responses were primarily sensitive to alpha 2 antagonists. 3. Experiments using receptor type-selective agonists substantiated the conclusion that sympathetic-sensory coupling at sites of nerve injury is mediated primarily by alpha 2 adrenoreceptors. 4. Recordings were also made from 14 afferent neurons with spontaneous ectopic discharge originating in dorsal root ganglia (DRGs) L4 and L5. The rats had undergone transection of the ipsilateral sciatic nerve 8-93 days previously. All neurons responded to systemic adrenaline and/or trains of activity evoked in postganglionic sympathetic efferents with either excitation or suppression. As in the neuroma endings, responses in the large majority of cases were blocked by alpha 2-selective, but not by alpha 1-selective adrenoreceptor antagonists. 5. The results indicate that sympathetic-sensory coupling, both at nerve injury sites and in axotomized DRG neurons, is mediated primarily by alpha 2 adrenoreceptors. In a minority of afferent neurons, however, it appears to be mediated by alpha 1 adreno-receptors or by both alpha 1 and alpha 2 adrenoreceptors. These functional results are consistent with receptor-type expression profiles from studies based on in situ hybridization and immunocytochemistry.

Adrenergic Agonists↗
PubMed1994

Structural basis of neuron-to-neuron cross-excitation in dorsal root ganglia.

Lanthanum was used as a tracer substance to determine whether small molecules in the bulk extracellular space in dorsal root ganglia have access to the narrow cleft that separates sensory neurons from their surrounding satellite cell sheath. Results showed that lanthanum is able to diffuse into this cleft, especially when the tissue is incubated with the tracer before fixation. Lanthanum gained access to the cleft at the seam where adjacent satellite cell processes meet. There appears to be preferential access in the axon hillock-initial segment region. Large diameter light neurons, which generally support fast conducting myelinated axons and carry information about non-nociceptive sensory events, proved more likely to admit lanthanum than small diameter dark neurons, which tend to have thin myelinated and unmyelinated axons and typically carry nociceptive information. Peripheral axotomy triggered a reduction in the access of lanthanum to the neuron-satellite cell cleft. These data bear on the mechanism of non-synaptic cell-to-cell cross-excitation within dorsal root ganglia, and in particular, lend support to the hypothesis that this interaction is mediated chemically rather than electrically.

Animals↗
PubMed1994

Compliance with social and safety recommendations in an outpatient comprehensive geriatric assessment program.

BACKGROUND: A unique contribution of a comprehensive outpatient geriatric assessment is its focus on social and safety issues in the frail elderly. The impact of such programs depends on the caregiver and/or patient complying with safety and social recommendations offered by the assessment team. Compliance in this setting has not been previously described. METHODS: A telephone survey was conducted of self-reported compliance in 124 frail geriatric patients with a high prevalence of dementia 3-21 months after completing a comprehensive geriatric assessment program at the University of California, San Diego, Medical Center. RESULTS: The social and safety recommendations constituted 52.8% of all the recommendations offered. The overall compliance rate (total number of safety and social recommendations followed/total number offered x 100) was 50.2% (95% CI: 43.7-56.6). Highest compliance was achieved with recommendations to complete a prior directive for health care (80.6%) and to wear a medic-alert bracelet (57.5%). Patients complied poorly with recommendations to change a living situation (36.2%). Analysis of variance showed compliance to increase with time between the assessment and survey. Stratifying for time, we found higher compliance in patients with greater impairment in functional or cognitive status. Most noncompliance was due to disagreement with the recommendations offered or failure to implement acceptable recommendations. CONCLUSIONS: Compliance with social and safety recommendations offered in a comprehensive geriatric assessment program approximates compliance observed in other clinical settings. In this setting compliance increases over time. When controlled for time, impairment in functional or cognitive status is associated with greater compliance.

Accidents, Home↗
PubMed1994

Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats.

1. Teased-fiber recordings were made from the axons of dorsal root ganglion (DRG) neurons in rats that underwent transection of the sciatic nerve 4-22 days previously. Many of the neurons had spontaneous ectopic discharge originating from within the DRG. 2. When postganglionic sympathetic efferents ending in the DRG were activated by tetanic stimulation of the T13 and L1 ventral roots (VRs), the ongoing afferent discharge was altered in more than one-half of the DRG neurons sampled. In most of the responsive units (62%), activity was augmented by this sympathetic stimulation; in the remainder (38%), activity was suppressed. Single-pulse stimuli of sympathetic efferents had no effect. 3. Responses to sympathetic stimulation began after a substantial delay (mean 14.3 s), peaked after 10-20 s, and then returned toward baseline over an additional 20-30 s. 4. Both excitatory and suppressive responses to sympathetic stimulation, as well as corresponding responses to systemically applied adrenaline, were blocked by the alpha-adrenoreceptor antagonist phentolamine. 5. Most of the active DRG neurons that responded to sympathetic stimulation, as well as others that did not, were excited by tetanic stimulation of neighboring afferent neurons that share the same DRG. These "crossed afterdischarge" responses were not blocked by phentolamine. Single-pulse stimuli of neighboring afferents had no effect. 6. Sympathetic-sensory coupling in DRGs of nerve-injured animals provides a previously unsuspected substrate for sympathetic involvement in neuropathic sensory dysfunction.

Animals↗
PubMed1994

Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels.

1. We used the tested fiber method to record from single myelinated afferents axons ending in a chronic nerve injury site (neuroma) in the rat sciatic nerve or L4,5 dorsal root. Axons were chosen for study that fired spontaneously with a stable tonic or interrupted (bursty) autorhythmic firing pattern. 2. Agents that block voltage-sensitive Na+ channels [tetrodotoxin (TTX), lidocaine], voltage-sensitive Ca2+ channels (Cd2+, Co2+, Ni2+, verapamil, D600, nifedipine, and fluarizine), volt-age-sensitive K+ channels [tetraethylammonium (TEA), 4-aminopyridine (4-AP)], and Ca(2+)-activated K+ channels (gK+Ca2+;quinidine, apamine) were applied topically to the neuroma. Effects on baseline rhythmogenesis and on the duty cycle of bursting were documented. Spike pattern analysis was used to determine whether changes in firing frequency were associated with changes in impulse initiation (electrogenesis), or resulted from (partial) block of impulse propagation downstream from the site of electrogenesis. Effects of veratridine were also noted. 3. Na+ channel blockers consistently quenched neuroma firing, and they did so by suppressing the process of impulse initiation. Only rarely was propagation block the dominant process. In bursty fibers the duration of on-periods shortened as the duration of off-periods lengthened, without a significant change in the baseline interspike interval (ISI). Veratridine accelerated firing, also via the impulse generating process. 4. Ca2+ channel blockers had essentially no effect on baseline firing rate (i.e., ISI). 5. Ca2+ channel blockers, as well as blockers of gK+Ca2+, had substantial, but inconsistent effects on burst pattern. It is not clear whether this reflects variability in the experimental conditions, or heterogeneity among the fibers sampled. 6. Blockade of K+ channels failed to evoke rhythmogenesis in acutely cut axons as it does in chronically injured axons, even in the presence of veratridine. This is consistent with other evidence that ectopic neuroma firing depends on postinjury remodeling of membrane electrical properties. 7. The data indicate that, in chronically injured axons, the inward currents that underly electrogenicity, enable ectopic discharge, and, together with outward K+ currents, set the fundamental firing rhythm (ISI), operate primarily with the use of voltage-sensitive Na+ rather than Ca2+ channels. 8. The on-off duty cycle in bursty fibers was affected by Na+ channel ligands and also, although less so, and less consistently by, Ca2+ channel ligands. This indicates that both may play a role in the slow modulations of membrane potential that presumably underly interrupted autorhythmicity.

Afferent Pathways↗
PubMed1993

Ongoing activity in neuroma afferents bearing retrograde sprouts.

Electrophysiological recordings were made from axons teased from the sciatic nerve 17-34 mm (mean 26.8 mm) central to a chronic nerve-end neuroma in adult rats. 23 fibers (2% of those sampled) appeared to have had a sprout(s) that grew in the retrograde (central) direction for at least this distance. Nine of the 23 (39%) carried spontaneous ongoing discharge. The parent fiber was myelinated (an A-fiber) in most instances, but unmyelinated (a C-fiber) in some. Thus, following nerve injury, a subset of afferent axons undergo retrograde sprouting, and many of them fire spontaneously. These contribute, along with the afferents whose trapped ends terminate at the injury site, to the ectopic afferent barrage generated in neuromas.

Animals↗
PubMed1993

Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia.

In humans, trauma to a peripheral nerve may be followed by chronic pain syndromes which are only relieved by blockade of the effects of sympathetic impulse traffic. It is presumed that, after the lesion, noradrenaline released by activity of sympathetic postganglionic axons excites primary afferent neurons by activating alpha-adrenoceptors, generating signals that enter the 'pain pathways' of the central nervous system. The site of coupling is unclear. In some patients local anaesthesia of the relevant peripheral nerve does not alleviate pain, implying that ectopic impulses arise either within the central nervous system, or in proximal parts of the primary afferent neurons. In experimentally lesioned rats, activity can originate within the dorsal root ganglia. Here we report that, after sciatic nerve ligation, noradrenergic perivascular axons in rats sprout into dorsal root ganglia and form basket-like structures around large-diameter axotomized sensory neurons; sympathetic stimulation can activate such neurons repetitively. These unusual connections provide a possible origin for abnormal discharge following peripheral nerve damage. Further, in contrast to the sprouting of intact nerve terminals into nearby denervated effector tissues in skin, muscle, sympathetic ganglia and sweat glands, the axons sprout into a target which has not been partially denervated.

Animals↗
PubMed1993

Close apposition among neighbouring axonal endings in a neuroma.

Axons in intact peripheral nerve trunks constitute independent afferent and efferent communication channels. However, when nerves are severed, several different forms of axon-axon cross-excitation develop in association with the injury site. In this study we have examined experimental sciatic nerve-end neuromas in rats with special interest in the compartmentalization of individual axons, and the barriers that separate close neighbours. At postinjury times at which functional coupling is known to occur, neuromas were found to contain many examples of axons in which adjacent membrane faces come into close contact without an intervening Schwann cell process. These occur in bundles containing from two to as many as 30 individual nerve fibres wrapped in a common Schwann cell sheath. The surface area of close apposition between axon pairs ranges up to several tens of micron2. Closely apposed axon profiles may be outgrowing branches of a single parent axon, but anterograde tracer data indicate that many belong to independent neurons. Closely apposed axons are separated from one another, and from associated Schwann cell processes, by a cleft about 130 A wide. No synapses, gap junctions or tight junctions were observed. Extracellular tracer studies using La3+ and Ruthenium Red indicated that the cleft system is patent, permitting the free diffusion of small molecules between the space adjacent to the axolemma and the bulk extracellular compartment. Together, these data provide a structural basis for interfibre interactions based on local electrical current flow (ephaptic crosstalk), as well as coupling mediated by K+ ions and neurotransmitter molecules.

Animals↗
PubMed1993

Practice patterns and the adequacy of residency training in consultation medicine.

OBJECTIVE: To describe consultation practice patterns of graduates of an internal medicine residency program and to determine whether they consider themselves to be adequately trained to practice in the area of internal medicine consultations. DESIGN: The authors surveyed graduates of the internal medicine residency program at the University of California, San Diego, School of Medicine from 1980 to 1989. Respondents described their practice types and the mechanics of consultations they currently perform, as well as the adequacy of their training in and frequency of encountering 74 clinical problems in the area of internal medicine consultation. Topics were categorized as Group I: excessive training; Group II: adequate training, frequently encountered; Group III: adequate training, infrequently encountered; Group IV: inadequate training, frequently encountered; and Group V: inadequate training, infrequently encountered. SETTING: University teaching hospital. PARTICIPANTS: Of 214 graduates, 91 returned surveys adequate for analysis. RESULTS: Internists prefer verbal communication with their colleagues and seeing surgical patients in the office prior to admission. Residents perceive that they have been excessively trained in preoperative evaluations of the asymptomatic and chronically ill adult and in several postoperative complications. Topics seen frequently in clinical practice but inadequately taught include: issues in convalescence and rehabilitation from surgical procedures, use of psychotropic medications, and management of eating disorders. CONCLUSIONS: To prepare residents for practice, program directors in consultation medicine might consider incorporating outpatient preoperative evaluation assessments, encouraging a liaison between surgeons and internists, and modeling verbal communication among colleagues. Consideration should be given for more didactic training for Group IV topics.

Adult↗
PubMed1993

Method for distinguishing between drug action on impulse propagation versus impulse generation.

Systemic or regional application of local anaesthetics or tetrodotoxin eliminate repetitive impulse discharge, but do they do so by blocking impulse propagation or by suppressing impulse initiation? A method is described for making this distinction based on differences in the pattern of discharge change during the onset of the block. Suppression of conductances involved in downstream impulse propagation produces integer multiplication of the fundamental interspike interval (interspike interval (ISI) doubling, tripling, etc.) In contrast, progressive block of conductances responsible for either the creation of the generator potential, or for its encoding into a spike train, causes a smooth increase in the rhythmic ISI. These two patterns of block, predicted on the basis of fundamental principles and numerical simulations, were verified in in vivo single-axon recordings.

Action Potentials↗
PubMed1993

Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation.

Nerve injury frequently triggers hyperexcitability and the ectopic initiation of impulses in primary afferent axons. An important consequence is neuropathic paresthesias and pain. Electrogenesis in normal afferents depends on appropriate Na+ channel concentrations. Therefore, we have asked whether injury might trigger changes in axolemmal Na+ channel distribution that could account for neuropathic hyperexcitability. We used an Na+ channel-specific antibody, 7493, to immunolocalize Na+ channels ultrastructurally in membranes of normal rat axons, and to assess remodeling following nerve section and neuroma formation. Selective labeling of nodal axolemma and, more weakly, of Schwann cell membrane, confirmed the efficacy of our immunolabeling protocol. In neuromas at postoperative times associated with peak ectopic activity, we found clear evidence of Na+ channel accumulation. Specifically, soon after myelin was stripped from large-diameter axons, the exposed, formerly internodal axolemma became immunopositive. Small-diameter unmyelinated axons and axon sprouts in the neuroma were also marked with 7493 IgG. Activated phagocytic macrophages and endothelial cells were 7493 negative. Both large- and small-diameter axons in neuromas end in swollen, organelle-packed "end bulbs." Most, but not all, of these acquired Na+ channel immunolabeling. We propose that remodeling results from a modification of the normal process of Na+ channel turnover in neural membranes. Na+ channel protein accumulates in preterminal axolemma and neuroma end bulbs due to a combination of permissive factors (especially myelin removal) and promotional factors (removal of normal downstream targets). This accumulation is a likely precursor of afferent hyperexcitability in injured nerve.

Animals↗