Biomedical subjects

M Devor

Publications and source records attributed to M Devor.

At least 55 records · Page 3Linked to original sources

PubMed1992

Na+ conductance and the threshold for repetitive neuronal firing.

The Hodgkin-Huxley equation for electrogenesis in the voltage clamped squid giant axon was used to predict the effect of altering maximal Na+ conductance (gNa+max) on the repetitive firing process. The main finding was that increasing gNa+max, without changing any other membrane parameter, reduced the threshold current required to evoke repetitive firing. That is, it rendered the membrane hyperexcitable. Threshold for evoking single action potentials was also affected, but much less so. Other consequences of increasing gNa+max were a decrease in the minimum sustainable rhythmic firing frequency (mRFF), a monotonic increase in firing frequency at any given suprathreshold stimulus intensity, an increase in the current value at which intense depolarizing stimuli block rhythmogenesis, an increase in the maximal sustainable firing frequency using intense currents (MRFF), and the consequent expansion of the dynamic range for stimulus encoding. Thus, the control of gNa+max through the regulation of Na+ channel synthesis and membrane incorporation at sites of rhythmogenesis (e.g. axon hillock-initial segment region, or peripheral sensory endings) is a potential regulatory mechanism for neuronal excitability and stimulus encoding.

Action Potentials↗

PubMed1992

Mutual excitation among dorsal root ganglion neurons in the rat.

Intracellular recordings were obtained from primary sensory neurons in excised dorsal root ganglia (DRGs). Most (90%) neurons sampled became depolarized during periods of repetitive stimulation of a branch of the dorsal root (DR) which contained only axons of neighboring neurons. DR stimulation also evoked a transient rise in extracellular K+ concentration ([K+]o), following similar kinetics. Thus, the mutual excitation among DRG neurons may be mediated by [K+]o. Activity-dependent cross-excitation in DRGs could contribute to neuropathic sensory abnormalities often triggered by nerve injury or disease.

Animals↗

PubMed1992

Ectopic discharge in injured nerves: comparison of trigeminal and somatic afferents.

Using the teased fiber recording method, we have compared pathophysiological properties of afferent axons injured in the infraorbital nerve (ION) vs the sciatic nerve in rats. Both myelinated and unmyelinated axons ending in ION neuromas produced much less ongoing discharge than those ending in sciatic nerve neuromas. Similarly, mechanosensitivity and acute injury discharge in ION neuromas were minimal. These differences may be related to the different spectrum of neuropathic symptomatology associated with nerve injury in the trigeminal vs the segmental innervation fields.

Afferent Pathways↗

PubMed1992

Estrogen replacement therapy and the risk of venous thrombosis.

PURPOSE: Estrogen replacement therapy is believed by many physicians to cause thrombophlebitis and to be contraindicated in women at risk for this disease. However, clinical data supporting this assumption are scant, and further investigation is required. PATIENTS AND METHODS: We tested the estrogen-thrombophlebitis association in a case-control study. Charts of all consecutive women aged 45 years or older with a primary or secondary discharge diagnosis of thrombophlebitis, venous thrombosis, or pulmonary embolism were reviewed; 121 cases and 236 controls matched for age, year of admission, admitting service, and socioeconomic status were obtained. Hormone use and nonuse were validated in a subset of randomly selected women. RESULTS: Cases and controls, whose average age was 65 years, did not differ significantly on matching variables or on current use of exogenous estrogen (5.1% of cases versus 6.3% of controls). Other analyses that variously excluded women with a past history of thrombosis, women less than 50 years of age, women with thrombosis occurring after admission, and women whose estrogen use was indeterminate also did not support an increased risk of thrombotic disease. Adjustment for the presence of independent thrombotic risk factors did not alter the odds ratio for estrogen use. CONCLUSION: This case-control study of older women, unselected for other thrombotic risk factors, does not support the commonly held assumption that replacement estrogen increases the risk of venous thrombosis.

Aged↗

PubMed1992

Eicosanoids, but not tachykinins, excite C-fiber endings in rat sciatic nerve-end neuromas.

Normal nociceptors are sensitized by hyperalgesic mediators such as eicosanoids and tachykinins. The possibility that these mediators contribute to hyperalgesic pain associated with neural injury was investigated by examining their effects on the excitability of injured afferent nerve endings. In amounts that sensitize normal nociceptors and are hyperalgesic in normal skin, the eicosanoids prostaglandin I2 (PGI2), and 8(R),15(S)-dihydroxyicosatetraenoic acid (8(R),15(S)-diHETE) both excited some C-fibers in chronic neuromas of rat sciatic nerve. In contrast, the selective tachykinin-receptor agonists septide and senktide did not excite C-fibers. None of the mediators affected A-fibers. We conclude that PGI2 and 8(R),15(S)-diHETE may contribute to post-injury pain and hyperalgesia by an action on injured afferent endings.

Animals↗

PubMed1992

Axonal cross-excitation in nerve-end neuromas: comparison of A- and C-fibers.

1. We recorded from single afferent axons ending in chronic sciatic nerve end neuromas in rats with the use of the teased-fiber method. Axons were sought that had ongoing impulse discharge originating in the neuroma. 2. Recording from myelinated (A-) fibers, tetanic stimulation of neighboring axons (50 Hz, 5 or 10 s, intensity adequate to drive A-fibers) caused an increase, and sometimes a decrease, in the rate of ongoing discharge in 68% of the fibers tested. In addition, some initially silent neuroma A-fibers (1.4%) were activated in this way. Both A beta and A delta fibers responded, although the likelihood of response was greater in A beta fibers. We call this form of interfiber cross-excitation "crossed afterdischarge." 3. In contrast to A-fibers, crossed afterdischarge was evoked with these stimulation parameters in < or = 5% of the spontaneously active unmyelinated (C-) fibers sampled. No initially silent C-fibers were activated. 4. C-fibers remained largely insensitive to cross-excitation by neighboring axons even when the strength of stimulus pulses was increased so as to include neighboring A + C-fibers. 5. The difference between A- and C-fibers could not be accounted for on the basis of the maturity of the neuroma, rate and pattern of ongoing discharge, or use of Flaxedil paralysis. 6. The difference between A- and C-fibers is discussed in terms of two alternative mechanisms that may underlie crossed afterdischarge: mediation by a neurotransmitter(s) in a nonsynaptic mode, and mutual K+ depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Ultrastructure of afferent axon endings in a neuroma.

Injured sensory axons with endings trapped in a nerve-end neuroma become a source of abnormal impulse discharge and neuropathic pain. We have examined the ultrastructure of such endings anterogradely transported WGA-HRP and freeze-fracture replication, with emphasis on the postinjury period during which the abnormal neural discharge is maximal. Most axons ended in a terminal swelling, depleted of myelin but surrounded by Schwann cell processes. These 'neuroma endbulbs' were richly packed with membrane-bound organelles, and had a smoothly undulating surface with (in neuromas of several weeks standing) a moderate number of short filopodia. Massive sprouting did not occur until several months postinjury. Both p- and e-faces of endbulb axolemma had larger intramembranous particles, on average, than corresponding internodal membrane of control axons. This change, interpreted as indicating remodelling of axolemmal channel (and perhaps receptor) content, may be related to the abnormal electrical behavior of neuroma afferents.

Animals↗

PubMed1991

Neuropathic pain and injured nerve: peripheral mechanisms.

Injury to sensory axons often has the paradoxical effect of inducing positive sensory disturbances; paraesthesias and chronic neuropathic pain. Such symptoms can be at least partially understood in terms of pathophysiological changes that occur in the electrical excitability of the injured sensory neuron. These changes result in the generation of an abnormal ongoing and evoked discharge, originating, alternatively, at various ectopic neural pacemaker sites. Many of the most effective therapeutic modalities recommended for neuropathic pain act by reducing this ectopic neural discharge.

Chronic Disease↗

PubMed1991

Mechano- and thermo-sensitivity in rats genetically prone to developing neuropathic pain.

By selective breeding, lines of rats were derived which consistently expressed high (HA) or low (LA) levels of autotomy following sciatic nerve injury, autotomy being a behavior pattern presumed to reflect the presence of neuropathic paraesthesias and pain. We report here that intact (unoperated) HA and LA rats differ in their responsiveness to cutaneous mechanical and thermal stimuli. Thus, the autotomy trait, which was identified by its expression under conditions of nerve injury, shares determinants with sensory processing channels in the intact animal.

Animals↗

PubMed1991

Neurogenesis in adult rat dorsal root ganglia: on counting and the count.

La Forte et al. (this issue) failed to find an increase in the numbers of dorsal root ganglion (DRG) neurons in rats of advancing age. However, their conclusion that our data (Devor and Govrin-Lippmann, 1985) to this effect were methodologically flawed is based on an incorrect application of our counting method. In fact, both their counting method and ours provide similar results when applied to the same tissue sections. We believe that the difference in results is biological. Specifically, DRG neurogenesis in adulthood occurs in animals in which growth continues throughout life (including the male Wistar-derived rats we used), but not in those whose body size stabilizes soon after sexual maturity (including the female Sprague-Dawley rats they used). With this caveat in mind, recent data of Schmalbruch (1987a,b) and others can be understood as corroborating our conclusions. However, an adequate, independent replication of our 1985 study has yet to be carried out.

Aging↗

PubMed1990

Spontaneous discharge of afferents in a neuroma reflects original receptor tuning.

Injured afferent axons trapped in chronic nerve-end neuromas frequently generate spontaneous discharge. We asked whether the patterns of discharge originating at such sites of ectopic electrogenesis bear a consistent relationship to the patterns of discharge characteristic of the corresponding intact afferent types before injury. Nerve-end neuromas were created in electrosensory lateral line nerves in 3 species of weakly electric Gymnotiform fish. Species were chosen in which normal afferent activity occurs at highly characteristic, non-overlapping, species-specific frequencies. Afferent impulse discharge was recorded in vivo from lateral line nerve end neuromas using the nerve-teasing technique. The distribution of firing frequencies of spontaneously active neuroma afferents was relatively uniform within a given fish species, and differed significantly from species to species. Mean values were somewhat lower than for corresponding intact afferents, but the rank order of frequencies across the species was preserved. These data indicate that differential membrane remodelling after axotomy tends to reestablish normal afferent fiber tuning despite failure of regeneration, and in the absence of peripheral electroreceptor reinnervation.

Action Potentials↗

PubMed1990

Neurochemical mediators of the behavioural effects of receptor-selective substance P agonists administered intrathecally in the rat.

Recently, two compounds have been developed, designated septide and senktide, which are highly selective agonists for the substance P receptor, types NK-1 and NK-3, respectively. Each of these, when injected intrathecally in awake rats, produced a distinct and non-overlapping constellation of sensory and behavioural effects which were subsets of the symptoms evoked by intrathecal administration of substance P. Prior systemic administration of 5-hydroxytryptamine (5-HT), alpha-adrenergic and opiate receptor antagonists, at doses sufficient to block the behavioural effects of the corresponding receptor agonists, did not alter responses to intrathecally injected septide or senktide. This was so, even for symptoms which suggested inhibitory mediation, hypoalgesia and (transient) motor flaccidity. Septide and senktide, administered by lumbar puncture and by indwelling catheter, produced identical results. Finally, in contrast to some other peptides, flaccid paralysis induced by senktide was not accompanied by spinal necrosis.

Animals↗

PubMed1990

Heritability of symptoms in an experimental model of neuropathic pain.

Male and female rats underwent transection and ligation of the sciatic and saphenous nerves, and the development of autonomy was monitored. The deafferented animals were then interbred, always selecting males and females that expressed relatively high and, alternatively, relatively low levels of autotomy. Offspring were similarly operated and interbred. By the sixth generation of selective breeding, lines were achieved in which autotomy was consistently high (HA) or consistently low (LA). There was no indication of sex linkage. Thermal and mechanical nocifensive responsiveness co-selected with propensity to express autotomy following nerve injury: response thresholds were lower in HA than in LA rats. F1 hybrids formed by crossing homozygous HA and LA animals showed low levels of autotomy, similar to LA stock. This indicates recessive inheritance of the autotomy trait. Backcrossing F1 hybrids onto the LA line yielded a low autotomy phenotype in almost all cases; backcrossing F1 hybrids onto HA stock yielded about 50% high autotomy and 50% low autotomy. These ratios are consistent with simple mendelian inheritance of a single gene. Taken together, the data suggest that autotomy is inherited as a single-gene autosomal recessive trait.

Afferent Pathways↗

PubMed1990

Cross-excitation in dorsal root ganglia of nerve-injured and intact rats.

1. Experiments based on teased fiber recording from rat sciatic nerve have shown that a small proportion of primary afferent neurons in intact dorsal root ganglia (DRGs) fire spontaneously. The prevalence of this discharge is substantially increased if the sciatic nerve has been chronically injured. 2. We now show that in most cases this ongoing DRG activity can be augmented by tetanic stimulation of the axons of neighboring neurons, where the active neuron itself has not been stimulated. In addition, some previously silent DRG neurons can be cross-excited by neighbors. This novel form of neuron-to-neuron communication is termed "DRG crossed afterdischarge." Cross-excitation never occurred at fixed latency in response to single stimulus pulses and is therefore not a case of ephaptic cross talk. 3. Crossed afterdischarge occurred only if the spontaneously active neuron and the stimulated neighbors shared the same DRG. It occurred in 83.5% of the spontaneously active neurons sampled that had myelinated (A) axons, but in only 4.4% of spontaneously active neurons with unmyelinated (C) axons. Among initially silent neurons, stimulation of neighbors evoked firing in 3.1% of A-fibers but in no C-fibers. 4. Crossed afterdischarge responses began within 500 ms of stimulation onset (with the use of 50-Hz tetani) and increased in magnitude for about the first 30 s of stimulation, declining thereafter. Intense excitations were often followed by a short period of depression until the original rate of ongoing discharge was restored. 5. The magnitude of crossed afterdischarge responses increased with increasing stimulation frequency until saturation. Minimal responses occurred with the use of tetani of as little as 1 Hz. Maximal responses occurred with the use of 100-200 Hz tetani. 6. The inclusion of C-fibers in the afferent volley produced little if any augmentation of responses. 7. Cross-excitation was demonstrated in DRGs in which many or all peripheral afferent axons were intact and continued to innervate hind limb skin. In these preparations natural cutaneous stimulation was shown to be capable of evoking crossed afterdischarge responses. The most effective stimuli were gentle or firm rubbing of the foot. Noxious pinch, heat, cold, and chemical stimulation was ineffective. 8. DRG crossed afterdischarge is a mechanism whereby sensation in response to peripheral stimulation may be distorted in time, space, and modality. Because its prevalence is much increased after axotomy, it might contribute to neuropathic sensory abnormalities, including pain, in patients with nerve injury.

Action Potentials↗

PubMed1990

Experimental pathophysiological correlates of clinical symptomatology in peripheral neuropathic pain syndromes.

Recent advances in the study of nerve pathophysiology in experimental models of nerve and spinal root injury indicate a striking parallel between the abnormal electrical behavior of sensory axons and clinical symptomatology. In conjunction with central pain processes, these pathophysiological mechanisms can account for many of the major features of neuropathic pain syndromes.

Animals↗

PubMed1989

Substance P-induced cutaneous plasma extravasation in rats is mediated by NK-1 tachykinin receptors.

Substance P (SP), a relatively non-selective tachykinin receptor agonist, and Septide and Senktide, highly selective NK-1 and NK-3 tachykinin receptor agonists, respectively, were injected intradermally in rats. The resulting cutaneous plasma extravasation (PE) was evaluated by measuring the amount of Evans blue that leached from the circulation into the skin. SP and Septide produced dose dependent PE, Septide being the more potent of the two. Senktide did not produce PE, even at doses 10,000 times higher. Neonatal capsaicin treatment significantly reduced SP- and Septide-induced PE. These data indicate that SP-induced PE is mediated by NK-1 tachykinin receptors.

Animals↗

PubMed1989

Na+ channel accumulation on axolemma of afferent endings in nerve end neuromas in Apteronotus.

In mammals, cut sensory axons trapped in a nerve end neuroma have been shown to develop hyperexcitability, and to become a source of ectopic afferent discharge and abnormal sensation. We have explored cellular mechanisms underlying neuroma electrogenesis. First we confirmed that ectopic neuroma discharge develops in injured afferents in the electrosensory lateral line nerve of the weakly electric fish Apteronotus, as it does in mammals. Then, using previously characterized antibodies that specifically recognize Na+ channel proteins in this species, we obtained light and electron microscopic evidence of abnormally intense immunolabelling of axolemma at the injury site. Accumulation of excess Na+ channels in afferent endings in neuromas could account for their electrical hyperexcitability.

Animals↗

PubMed1988

Contrasting time course of catecholamine accumulation and of spontaneous discharge in experimental neuromas in the rat.

Catecholamine-containing sympathetic axons in rat sciatic nerve-end neuromas were visualized histochemically. Within a few hours of ligating and sectioning the nerve, axons began to accumulate catecholamine histofluorescence. Density of labelled fibers peaked 2-5 days postoperative, then declined rapidly so that little or no label was observed beyond 12 days. Sympathectomy eliminated staining; neonatal treatment with capsaicin had no effect. Accumulation and dissipation of histofluorescence preceded the rise and fall of electrical hyperexcitability in neuromas by several days respectively.

Animals↗