Marshall Devor

A putative flip–flop switch for control of REM sleep

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (γ-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy.

Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats

Abstract Single units were recorded in dorsal roots or in the sciatic nerve of anaesthetised rats. It was shown by making sections, by stimulation and by collision that some ongoing nerve impulses were originating from the dorsal root ganglia and not from the central or peripheral ends of the axons. In a sample of 2731 intact or acutely sectioned myelinated sensory fibres, 4.75% ± 3.7% contained impulses generated within the dorsal root ganglia. In 2555 axons sectioned in the periphery 2–109 days before, this percentage rose to 8.6% ± 4.8%. There was a considerable variation between animals; 0–14% in intact and acutely sectioned nerves and 1–21% in chronically sectioned nerves. The conduction velocity of the active fibres did not differ significantly from the conduction velocity of unselected fibres. The common pattern of ongoing activity from the ganglion was irregular and with a low frequency (about 4 Hz) in contrast to the pattern of impulses originating in a neuroma which usually have a higher frequency with regular intervals. Slight mechanical pressure on the dorsal root ganglion increased the frequency of impulses. Unmyelinated fibres were also found to contain impulses originating in the dorsal root ganglion. In intact or acutely sectioned unmyelinated axons, the percentage of active fibres 4.4% ± 3.5% was approximately the same as in myelinated fibres but there were no signs of an increase following chronic section. Fine filament dissection of dorsal roots and of peripheral nerves and collision experiments showed that impulses originating in dorsal root ganglia were propagated both orthodromically into the root and antidromically into the peripheral nerve. It was also shown that the same axon could contain two different alternating sites of origin of nerve impulses: one in the neuroma or sensory ending and one in the ganglion. These observations suggest that the dorsal root ganglion with its ongoing activity and mechanical sensitivity could be a source of pain producing impulses and could particularly contribute to pain in those conditions of peripheral nerve damage where pain persists after peripheral anaesthesia or where vertebral manipulation is painful.

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

&NA; 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.

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

&NA; 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.

Corticosteroids suppress ectopic neural discharge originating in experimental neuromas

&NA; 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.

Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat

The sciatic nerve in rats was cut and ligated, and 5-18 days later pathophysiological properties of the resulting neuroma were studied. We found that afferent fibers ending in the neuroma produced prolonged discharges following repetitive stimulation of the lumbar sympathetic trunk (LST) or i.v. adrenaline. Mean latencies of activation of afferent fibers were 10 +/- 2.1 sec and 12 +/- 3.4 sec (mean +/- S.D.) to LST stimulation and to adrenaline injection, respectively. The alpha-adrenergic antagonist phentolamine blocked responses to LST stimulation and adrenaline. The beta-adrenergic antagonist propranolol had no effect.

The effect of peripheral nerve injury on dorsal root potentials and on transmission of afferent signals into the spinal cord

The sciatic nerve of adult rats was either cut and ligated or was crushed on one side. The response of the spinal cord to stimulation of the proximal part of the injured nerve was examined at various times after the lesion and compared to the effects of stimulating the intact nerve on the other side. During the first 10 days after nerve section the following measures were not affected: (i) the size of the input volley (compound action potential, CAP, measured on a dorsal root that carried sciatic nerve afferents (L5); (ii) the volley running in the dorsal columns; (iii) the dorsal root potential (DRP) evoked on neighbouring dorsal roots which do not contain sciatic afferents (L2 and L3); (iv) the post-synaptic volleys ascending in the spinal cord. However, by the fourth day after nerve section, there was a decrease of the DRP evoked on the ipsilateral L5 dorsal root by stimulation of the cut nerve. By 10 days this DRP had decreased by 50%. There was also a decrease in the DRP on the L5 root evoked by stimulation of the contralateral intact nerve. Crush lesions of the sciatic nerve did not produce DRP change. Beginning 10--20 days after nerve cut, there was a decrease in the amplitude of the afferent CAP and of all the measures of central response to the afferent volley. We discuss the possibility that the loss of the DRP may be associated with a disinhibition which results in novel receptive fields which we observe in cord cells deafferented by the peripheral nerve section. The decrease of DRP and the appearance of novel receptive fields do not occur if the peripheral nerve is crushed rather than cut.

Nerve pathophysiology and mechanisms of pain in causalgia

In contrast to sensory endings in skin, muscle, etc., afferents in the mid-course of intact nerves are normally incapable of generating impulses upon slow or prolonged depolarization. However, after various types of nerve injury, including complete nerve section and local demyelination, an ectopic pacemaker capability develops. One peculiarity of such abnormal differentiated sites is chemosensitivity to alpha-adrenergic agonists and to sympathetic efferents discharge. Such ectopic chemosensitivity may well be involved in the etiology of paraesthesias and pain in reflex sympathetic dystrophies including causalgia. Specifically, it is proposed that the fundamental cause of these conditions is the development of abnormal electrogenic membrane properties in the region of demyelination and sprout outgrowth. These abnormal properties presumably include the appearance of excess inward current conductances and ectopic alpha-adrenergic receptors. Catecholamines released from sympathetic efferents in the area of injury locally depolarize damaged sensory fibers, and because of the abnormal electrogenic properties of these fibers, an abnormal afferent discharge is generated.

Ephaptic transmission in chronically damaged peripheral nerves

Several weeks after damage of the sciatic nerve in adult rats, a stable electrical (ephaptic) interaction forms between pairs of injured sensory and motor axons. Fiber-fiber interaction occurs when the nerve ends in a neuroma, after end-to-end nerve suture and after nerve crush injury. Unlike the transient “artificial synapse” created acutely on section of a nerve, this form of crosstalk is long-lasting. Its existence lends support to the hypothesis that ephaptic interaction is an important factor in neurologic pathophysiology.

Ectopic discharge in Aβ afferents as a source of neuropathic pain

Ectopic discharge in axotomized dorsal root ganglion neurons is a key driver of neuropathic pain. However, the bulk of this activity is generated and carried centrally in large diameter myelinated Aβ afferents, a cell type that normally signals touch and vibration sense. Evidence is considered suggesting that following axotomy, Aβ afferents undergo a change in their electrical characteristics and also in the neurotransmitter complement that they express. This dual phenotypic switching renders them capable of (1) directly driving postsynaptic pain signaling pathways in the spinal cord, and (2) triggering and maintaining central sensitization.