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Marshall Devor

Publications and source records attributed to Marshall Devor.

At least 37 records · Page 2Linked to original sources
PubMed2002

Burst discharge in primary sensory neurons: triggered by subthreshold oscillations, maintained by depolarizing afterpotentials.

Afferent discharge generated ectopically in the cell soma of dorsal root ganglion (DRG) neurons may play a role in normal sensation, and it contributes to paraesthesias and pain after nerve trauma. This activity is critically dependent on subthreshold membrane potential oscillations; oscillatory sinusoids that reach threshold trigger low-frequency trains of intermittent spikes. Ectopic firing may also enter a high-frequency bursting mode, however, particularly in the event of neuropathy. Bursting greatly amplifies the overall ectopic barrage. In the present report we show that subthreshold oscillations and burst discharge occur in vivo, as they do in vitro. We then show that although the first spike in each burst is triggered by an oscillatory sinusoid, firing within bursts is maintained by brief regenerative post-spike depolarizing afterpotentials (DAPs). Numerical simulations were used to identify the cellular process underlying rebound DAPs, and hence the mechanism of the spike bursts. Finally, we show that slow ramp and hold (tonic) depolarizations of the sort that occur in DRG neurons during physiologically relevant events are capable of triggering sustained ectopic bursting, but only in cells with subthreshold oscillatory behavior. Oscillations and DAPs are an essential substrate of ectopic burst discharge. Therefore, any consideration of the ways in which cellular regulation of ion channel synthesis and trafficking implement normal sensation and, when disrupted, bring about neuropathic pain must take into account the effects of this regulation on oscillations and bursting.

Action Potentials↗
PubMed2002

Social variables affect phenotype in the neuroma model of neuropathic pain.

When the degree of genetic determination of a trait (i.e. its heritability) is high, one tends to presume that environmental factors will not modify its expression by much. Contrary to this expectation, we show here in rats that a psychosocial-behavioral variable, the identity of cagemates, can largely over-ride genetic predisposition to pain behavior. We used selection-line rats that consistently show high (HA) or low (LA) pain phenotype (autotomy) in the neuroma model of neuropathic pain. Normally, HA animals show autotomy after nerve injury while LA animals do not. However, when caged together with HA rats, LA rats showed high levels of autotomy. This occurred even when the individual HA cagemates were familiar preoperatively, and it did not depend on the actual performance of autotomy by the HA rats. Indeed, cage bedding soiled by HA rats was sufficient to induce a modest level of autotomy in LA animals. Chemical cues associated with HA rats, perhaps in combination with behavioral characteristics, are apparently able to induce pain phenotype despite the powerful protection otherwise rendered by the LA genotype. Social factors must be considered in behavior-related research on rodents that have undergone genetic modification. More generally, the overwhelming influence that psychosocial-behavioral variables have on pain perception, and on pain behavior, in humans may have evolutionary roots deeper than has previously been appreciated.

Animals↗
PubMed2002

Oscillatory mechanism in primary sensory neurones.

Ectopic spike activity, generated at low levels in intact sensory dorsal root ganglia and intensified following axotomy, is an important cause of neuropathic pain. The spikes are triggered by subthreshold membrane potential oscillations. The depolarizing phase of oscillation sinusoids is due to a phasic voltage-sensitive Na(+) conductance (gNa(+)). Here we examine the repolarizing phase for which K(+) conductance (gK(+)) is implicated. In vivo, gK(+) blockers have excitatory effects inconsistent with the elimination of oscillations. Indeed, using excised dorsal root ganglia in vitro, we found that gK(+) block does not eliminate oscillations; on the contrary, it has a variety of facilitatory effects. However, oscillations were eliminated by shifting the K(+) reversal potential so as to neutralize voltage-insensitive K(+) leak channels. Based on these data, we propose a novel oscillatory model: oscillation sinusoids are due to reciprocation between a phasically activating voltage-dependent, tetrodotoxin-sensitive Na(+) conductance and passive, voltage-independent K(+) leak. In drug-free media, voltage-sensitive K(+) channels act to suppress oscillations and increase their frequency. Numerical simulations support this model and account for the effects of gK(+) block. Oscillations in dorsal root ganglia neurones appear to be based on the simplest possible configuration of ionic conductances compatible with sustained high frequency oscillatory behaviour. The oscillatory mechanism might be exploited in the search for novel analgesic drugs.

Animals↗
PubMed2002

Subthreshold oscillations induced by spinal nerve injury in dissociated muscle and cutaneous afferents of mouse DRG.

Whole cell patch-clamp recordings were obtained from dissociated mouse lumbar dorsal root ganglion (DRG) neurons. Recordings were made from control neurons and neurons axotomized by transection of the corresponding spinal nerve 1-2 days prior to dissociation. Medium to large muscle and cutaneous afferent neurons were identified by retrograde transport of True Blue or Fluoro-Gold injected into the corresponding peripheral tissue. Action potentials were classified as non-inflected spikes (A(0)) and inflected spikes (A(inf)). High-frequency, low-amplitude subthreshold membrane potential oscillations were observed in 8% of control A(0) neurons, but their incidence increased to 31% in the nerve injury group. Fifty percent of axotomized muscle afferent A(0) cells displayed oscillations, while 26% of axotomized cutaneous afferents exhibited oscillations. Lower-frequency oscillations were also observed in a small fraction (4%) of A(inf) neurons on strong depolarization. Their numbers were increased after the nerve injury, but the difference was not statistically significant. The oscillations often triggered burst firing in distinct patterns of action potential activity. These results indicate that injury-induced membrane oscillations of DRG neurons, previously observed in whole DRG of rats, are present in dissociated DRG neurons of the adult mouse. Moreover, these observations indicate that both muscle and cutaneous afferents in the A(beta) size range give rise to injury-induced membrane oscillations, with muscle afferents being more prone to develop oscillations.

Action Potentials↗
PubMed2002

Mechanism of trigeminal neuralgia: an ultrastructural analysis of trigeminal root specimens obtained during microvascular decompression surgery.

OBJECT: Recent progress in the understanding of abnormal electrical behavior in injured sensory neurons motivated an examination, at the ultrastructural level, of trigeminal roots of patients with trigeminal neuralgia (TN). METHODS: In 12 patients biopsy specimens of trigeminal root were obtained during surgery for microvascular decompression. Pathological changes in tissue included axonopathy and axonal loss, demyelination, a range of less severe myelin abnormalities (dysmyelination), residual myelin debris, and the presence of excess collagen, including condensed collagen masses in two cases. Within zones of demyelination, groups of axons were often closely apposed without an intervening glial process. Pathological characteristics of nerve fibers were clearly graded with the degrees of root compression noted at operation. Pain also occurred, however, in some patients who did not appear to have a severe compressive injury. CONCLUSIONS: Findings were consistent with the ignition hypothesis of TN. This model can be used to explain the major positive and negative symptoms of TN by axonopathy-induced changes in the electrical excitability of afferent axons in the trigeminal root and of neuronal somata in the trigeminal ganglion. The key pathophysiological changes include ectopic impulse discharge, spontaneous and triggered afterdischarge, and crossexcitation among neighboring afferents.

Adult↗
PubMed2002

Cranial root injury in glossopharyngeal neuralgia: electron microscopic observations. Case report.

Optical and electron microscopic examinations were made of a biopsy sample of the ninth and 10th cranial nerves obtained during posterior fossa surgery for the relief of pain in a patient suffering from glossopharyngeal neuralgia (GN). Pathological findings, which were restricted to a small fraction of fascicles in the nerves, included large patches of demyelinated axons in close membrane-to-membrane apposition to one another and zones of less severe myelin damage (dysmyelination). These observations, in the light of similar morphological changes observed in biopsy samples excised from patients with trigeminal neuralgia, and new information on the pathophysiological characteristics of injured peripheral nerve axons, can account for much of the symptomatology of GN.

Adult↗
PubMed2001

Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital.

Concussion, asphyxia, and systemically administered general anesthetics all induce reversible depression of the organism's response to noxious stimuli as one of the elements of loss of consciousness. This is so even for barbiturate anesthetics, which have only modest analgesic efficacy at subanesthetic doses. Little is known about the neural circuits involved in this form of antinociception, although for anesthetic agents, at least, it is usually presumed that the drugs act in widely distributed regions of the nervous system. We now report the discovery of a focal zone in the brainstem mesopontine tegmentum in rats at which microinjection of minute quantities of pentobarbital induces a transient, reversible anesthetic-like state with non-responsiveness to noxious stimuli, flaccid atonia, and absence of the righting reflex. The behavioral suppression is accompanied by slow-wave EEG and, presumably, loss of consciousness. This zone, which we refer to as the mesopontine tegmental anesthesia locus (MPTA), apparently contains a barbiturate-sensitive 'switch' for both cortical and spinal activity. The very existence of the MPTA locus has implications for an understanding of the neural circuits that control motor functions and pain sensation, and for the cerebral representation of consciousness.

Adjuvants, Anesthesia↗
PubMed2000

Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury.

We examined the relation between ectopic afferent firing and tactile allodynia in the Chung model of neuropathic pain. Transection of the L5 spinal nerve in rats triggered a sharp, four- to six-fold increase in the spontaneous ectopic discharge recorded in vivo in sensory axons in the ipsilateral L5 dorsal root (DR). The increase, which was not yet apparent 16 h postoperatively, was complete by 24 h. This indicates rapid modification of the electrical properties of the neurons. Only A-neurons, primarily rapidly conducting A-neurons, contributed to the discharge. No spontaneously active C-neurons were encountered. Tactile allodynia in hindlimb skin emerged during precisely the same time window after spinal nerve section as the ectopia, suggesting that ectopic activity in injured myelinated afferents can trigger central sensitization, the mechanism believed to be responsible for tactile allodynia in the Chung model. Most of the spike activity originated in the somata of axotomized DRG neurons; the spinal nerve end neuroma accounted for only a quarter of the overall ectopic barrage. Intracellular recordings from afferent neuron somata in excised DRGs in vitro revealed changes in excitability that closely paralleled those seen in the DR axon recordings in vivo. Corresponding changes in biophysical characteristics of the axotomized neurons were catalogued. Axotomy carried out at a distance from the DRG, in the mid-portion of the sciatic nerve, also triggered increased afferent excitability. However, this increase occurred at a later time following axotomy, and the relative contribution of DRG neuronal somata, as opposed to neuroma endings, was smaller. Axotomy triggers a wide variety of changes in the neurochemistry and physiology of primary afferent neurons. Investigators studying DRG neurons in culture need to be alert to the rapidity with which axotomy, an inevitable consequence of DRG excision and dissociation, alters key properties of these neurons. Our identification of a specific population of neurons whose firing properties change suddenly and synchronously following axotomy, and whose activity is associated with tactile allodynia, provides a powerful vehicle for defining the specific cascade of cellular and molecular events that underlie neuropathic pain.

Animals↗
PubMed1999

Unexplained peculiarities of the dorsal root ganglion.

The cell soma of primary afferent neurons in the dorsal root ganglion (DRG) is assigned by classical neurophysiology the role of a metabolic depot, charged with supporting the peripheral sensory ending, the conducting axon, and the central synaptic terminals. However, certain peculiarities of DRG morphology and physiology do not sit well with this being its only role. For example, why are DRG cell somata electrically excitable, why are some able to fire repetitively on sustained depolarization, and why does the DRG lack a blood-nerve barrier? Consideration of these and related questions leads to several intriguing hypotheses: (1) Electrical excitability of the soma may be required to insure the reliable propagation of impulses past the DRG T-junction and into the spinal cord. (2) Invasion of the afferent spike into the cell soma may provide an essential feedback signal necessary for the cell soma to regulate the excitability of the sensory ending. 3) The subpopulation of DRG neurons that have repetitive firing capability may be responsible for generating the background sensation that we feel as our body schema. Moreover, these neurons may be chemical sensors that provide essential information about our body's internal milieu.

Animals↗
PubMed1994

Trigeminal neuralgia: the role of self-sustaining discharge in the trigeminal ganglion.

Idiosyncrasies of trigeminal neuralgia provide both clues and constraints on candidate hypotheses concerning the underlying neural mechanism. After reviewing the key clinical aspects of the disease, we propose here a novel hypothesis based on recent findings from experimental nerve-injury preparations. The hypothesis states that trigger stimuli set off bursts of activity in a small cluster of trigeminal ganglion (TRG) neurons that have been rendered hyperexcitable as a result of TRG or trigeminal root damage. Activity then spreads from this "TRG ignition focus" to encompass more widespread portions of the ganglion. After a brief period of autonomous firing (seconds to minutes), activity is quenched and a refractory period is initiated by an intrinsic suppressive (hyperpolarizing) process engaged as a result of the rapid firing. The primary abnormality resides in the TRG and trigeminal root, rather than in the skin or the CNS. Because of this, sensation is essentially normal between periods of ectopic paroxysmal TRG discharge.

Electrophysiology↗
PubMed1992

Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction.

Systemic application of lidocaine in rats suppressed ectopic impulse discharge generated both at sites of experimental nerve injury and in axotomized dorsal root ganglion (DRG) cells. ED50 for DRGs was significantly lower than for the injury site. Lidocaine doses effective at blocking ectopic discharge failed to block the initiation or propagation of impulses by electrical stimulation, and only minimally affected normal sensory receptors. This selectivity may account for the effectiveness of systemic local anesthetics and other drugs that share the same mechanism of action (notably certain anticonvulsants and antiarrhythmics), in the management of neuropathic paresthesias and pain. In addition, it may account for the prolonged analgesia sometimes obtained using regional local anesthetic block.

Action Potentials↗
PubMed1987

Contrasting thermal sensitivity of spontaneously active A- and C-fibers in experimental nerve-end neuromas.

Injured afferent A- and C-fibers ending in experimental neuromas in the rat sciatic nerve generate a substantial spontaneous discharge. We show that for individual axons the rate and percent incidence of spontaneous discharge are sensitive to neuroma temperature. Within the range of 14-43 degrees C, firing rate of all of the myelinated fibers examined increased as temperature rose, and decreased as temperature fell. For fibers with a tonic rhythmic discharge pattern, Q10 averaged 1.64 at 34-42 degrees C. Some fibers that were initially silent began to fire as the neuroma was warmed, and some fibers active at baseline temperature fell silent when the neuroma was cooled. Unmyelinated fibers behaved quite differently, showing either no response to temperature changes (44% of fibers sampled), or an increase in discharge rate upon cooling (56%). These effects are probably not secondary to vascular changes, but rather reflect thermal sensitivity of the ectopic neuroma impulse generator sites. This thermal sensitivity may account for the aggravation of phantom limb pain and other neuralgias during cold weather (i.e., post-traumatic cold intolerance).

Animals↗
PubMed1987

Behavioural effects of receptor-specific substance P agonists.

Septide and senktide are synthetic substance P (SP) agonists with extremely high selectivity for 1 of the 3 known SP receptor subtypes. When injected intrathecally, they produced dramatically different behavioural effects. Septide, the selective SP-P receptor agonist, evoked intense, compulsive scratching, biting and licking of the hind limb, with no sign of motor flaccidity, and without measurable effect on responses to noxious thermal or mechanical stimulation of the foot or tail. In contrast, senktide, the selective SP-N receptor agonist, produced profound, but transient, motor flaccidity, reduced response to noxious stimuli and, at low doses, 'wet-dog shakes.' These various symptoms, all previously associated with SP and/or synthetic SP analogues, appear therefore to derive from activation of distinct SP receptor subtypes.

Animals↗
PubMed1987

Collateral sprouting in skin and sensory recovery after nerve injury in man.

Two different modes of cutaneous sensory reinnervation are thought to be engaged following nerve injury: regenerative growth of the injured nerve and 'collateral sprouting' of neighboring intact nerves. Although both processes are well known from experimental preparations, there is little unequivocal documentation of collateral sprouting in human skin. We report here on 5 patients in whom at least partial recovery of sensation in the hand following traumatic or surgical nerve section was apparently based on collateral sprouting from nerves that had not themselves been injured. Two types of evidence are brought. In three of the cases a totally anesthetic region of skin at a distance from the site of injury was shown to recover sensitivity long before regenerating nerve fibers could have arrived, given the known rates of fiber outgrowth. In the remaining two cases, nerve blocks using local anesthetics were used to establish that the reinnervated skin was served by a nerve other than the injured one. Thus, collateral sprouting appears to contribute to cutaneous sensory recovery in man as well as in animals.

Adult↗
PubMed1985

Corticosteroids suppress ectopic neural discharge originating in experimental neuromas.

Some injured sensory fibers ending in an experimental neuroma in the rat sciatic nerve discharge spontaneously. Furthermore, many become sensitive to a range of physical and chemical stimuli. The resulting afferent barrage is thought to contribute to paresthesias and pain associated with peripheral nerve injury. We report that the development of such ectopic neuroma discharge is largely prevented when the freshly cut nerve end is treated with any of 3 commercially available corticosteroid preparations including two in depot form, triamcinolone hexacetonide (Lederspan) and triamcinolone diacetate (Ledercort), and one in soluble form, dexamethasone (Dexacort). These corticosteroids also produce a rapid and prolonged suppression of ongoing discharge in chronic neuromas that have already become active. The kinetics of corticosteroid suppression of neuroma discharge suggest a direct membrane action rather than an anti-inflammatory action.

Action Potentials↗