Patrick D. Wall

Temporary abolition of pain in man.

In eight patients with intense chronic cutaneous pain, sensory nerves or roots. supplying the painful area were stimulated. Square-wave 0.1-millisecond pulses at 100 cycles per second were applied, and the voltage was raised until the patient reported tingling in the area. During this stimulation, pressure on previously sensitive areas failed to evoke pain. Four patients, who had diseases of their peripheral nerves, experienced relief of their pain for more than half an hour after stimulation for 2 minutes.

Ongoing activity in peripheral nerves: The physiology and pharmacology of impulses originating from a neuroma ☆

Abstract In rats, the sciatic nerve was cut, drawn into a polythene tube with one end sealed, and a neuroma allowed to develop in the chamber. Activity in the dorsal and ventral roots terminating in the neuroma was examined between 9 days and 4 months after the section. A fraction of the small myelinated afferent fibers originating in the neuroma were carrying a steady ongoing barrage of nerve impulses. Many of the fine terminals were excited by slight mechanical distortion. The fine sprouts in the neuroma were electrically excitable. The ongoing afferent barrage was highly dependent on blood flow. It was abolished for long periods of time after a brief antidromic tetanus had invaded the active fibers. This suggests that some of the pain relief obtained from peripheral nerve stimulation may have a peripheral rather than a central mechanism. No signs of excitatory on inhibitory interaction were detected between volleys in one group of nerve fibers and the activity in other groups of fibers in the neuroma. Alpha active sympathetic amines, noradrenaline, excited the ongoing activity while beta agents, isoprenaline, had no excitatory effect. This suggests that alpha blocking agents might be useful to test if the sympathetic system is involved in particular pains.

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.

Autotomy following peripheral nerve lesions: experimental anesthesia dolorosa

&NA;When hindlimb peripheral nerves are cut across in rats and mice, there is a tendency for the animal to attack the anaesthetic limb. We have called this attack “autotomy”. In this paper we describe the time course and degree of autotomy following various types of nerve injury.Four different types of lesion were applied to the sciatic nerve of rats. The most serious autotomy was produced by section of the nerve and encapsulation of its cut end in a polythene tube. Section followed by immediate resuturing also produced serious autotomy. Simple ligation of the nerve end was followed by less autotomy than encapsulation or cut and resuture. A crush lesion caused only minimal attack.Section of the saphenous branch of the femoral nerve produced no autotomy. However, if the saphenous and sciatic nerves were ligated at the same time so that the entire foot became anaesthetic there was a great increase of autotomy over that seen when the sciatic nerve alone was ligated. This increase with the double lesion occured even if the saphenous nerve was ligated more than 100 days after the sciatic nerve had been cut.Mice showed autotomy very similar to that seen in rats but the onset was somewhat faster.Reasons are given to propose that autotomy is triggered by an abnormal afferent barrage generated in the cut end of the nerve. Autotomy from peripheral nerve lesions is a different phenomenon from that seen after dorsal root section. Autotomy occurs under conditions which produce anaesthesia dolorosa in man. This simple model may be suitable for studies of the prevention of irritations originating from chronic lesions of peripheral nerves.

The laminar organization of dorsal horn and effects of descending impulses

1. An examination of the physiological properties of cells in cat lumbar dorsal horn shows that there are three horizontal laminae which correspond approximately to Rexed (1952) laminae 4, 5, and 6.

Muscle but not cutaneous C‐afferent input produces prolonged increases in the excitability of the flexion reflex in the rat.

Stimulation of cutaneous afferent fibres in the sural nerve and muscle afferent fibres in the gastrocnemius‐soleus nerve at a strength that excites C axons produces a delayed and long‐lasting burst of activity in posterior biceps femoris/semitendinosus flexor motoneurones. Following a 20 s stimulation at 1 Hz to the sural nerve the flexor motoneurones continue to fire for 20 s while a similar stimulus to gastrocnemius‐soleus nerve results in an after‐discharge lasting three times longer. Using stimuli to the sural and gastrocnemius‐soleus nerves as conditioning stimuli (20 s, 1 Hz) changes in the excitability of the flexor reflex were measured by recording the discharge evoked by a test sural nerve stimulus or by a standard pinch to the ipsilateral and contralateral toes. Prior to any conditioning stimulus the flexor reflex remained stable for prolonged periods. Conditioning stimuli at strengths that activated large myelinated afferent fibres only, or large and small myelinated afferent fibres, failed to produce more than a very transient alteration in the reflex excitability. Conditioning stimuli at C‐fibre strength to the sural nerve produced a marked increase in the excitability of the reflex for 10 min. C‐fibre strength gastrocnemius‐soleus nerve conditioning stimuli resulted in a similar increase in excitability followed by a second phase of facilitation peaking at 20‐30 min and lasting for up to 90 min. The afferent barrage initiated by cutting the sural and gastrocnemius‐soleus nerves resulted in similar patterns of reflex excitability increases with the muscle nerve resulting in a more prolonged effect than the cutaneous nerve. The results show that a brief C‐afferent fibre input into the spinal cord can produce a prolonged increase in the excitability of the flexion reflex and that muscle C‐afferent fibres evoke longer‐lasting changes than cutaneous C fibres. The differences in the time course of the post‐conditioning effects may be related to the well‐described differences in the sensory consequences of injury to skin versus deep tissue.

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.

Central hyperexcitability triggered by noxious inputs

Repetitive activity in unmyelinated sensory afferent neurones, arising from electrical stimuli, tissue injury or nerve damage, can induce long-lasting sensitization in dorsal horn neurones. This process can be blocked by antagonists of the NMDA receptor. In the past year it has emerged that sensory neuropeptides and nitric oxide are also essential mediators of this phenomenon.

Nerve growth factor counteracts the neurophysiological and neurochemical effects of chronic sciatic nerve section

The sciatic nerve was sectioned unilaterally in rats and nerve growth factor (NGF) applied locally to the nerve stump for the following 10-14 days using an indwelling osmotic pump. The aim of the experiment was to test whether NGF had any effect on the previously reported neurophysiological and neurochemical events that occur central to a peripheral nerve lesion. The method of application allowed the sciatic nerve on the other side to be used as a control. Primary afferent depolarization fell, as expected, to 13% of its control value after chronic nerve section but if NGF was administered it fell to only 43.5% of control. Chronic nerve section is also known to result in expansion of the receptive fields of deafferented dorsal horn cells. NGF treatment reduced the number of such large receptive fields by 50%. The normal depletion of fluoride resistant acid phosphatase from the cut nerve terminals in the dorsal horn did not occur following NGF treatment. Radioimmunoassay of substance P revealed that the 30% reduction in dorsal horn levels that follows chronic sciatic nerve section did not occur when NGF was applied and that the accompanying 60% decrease in dorsal root ganglion levels was changed to a 64% increase by NGF. The results show that chronic NGF treatment of a cut sciatic nerve does partially reverse the central changes that normally follow deafferentation.