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Peripheral nerve fascicles are deliberately impaled during microneurography experiments. We have assessed conduction block under these circumstances. First we recorded compound action potentials (CAP) in the sural nerve following stimulation of the sciatic nerve. The insertion of injection and microneurography electrodes between stimulation and recording sites produced a 20% decrease in the size of the CAP, which was maintained for the 10 min duration of impalement. After withdrawal, the conduction block partially resolved. In other experiments, single-unit action potentials were recorded from L4 and L5 dorsal roots following peripheral nerve stimulation. Microneurography electrodes inserted into the sciatic nerve produced conduction block in 50% of these axons. When axons were blocked, anodal stimulation through the tungsten electrode became more effective than cathodal stimulation. These results suggest that a temporary conduction block occurs in a significant number of myelinated fibers near the site of an inserted electrode.

A satisfactory explanation of neuropathic pain must include mechanisms capable of generating three types of pain: ongoing, episodic and allodynic. It must explain why many such pains develop very soon after injury while others occur after long delays. It must take into account the many painless neuropathies and the unpredictable relationship of the pain to the pathology in the painful neuropathies. While these diseases clearly start in the periphery and peripheral changes must contribute to the pain, there are also three types of central change. First changes in the afferent impulse barrage can induce long term shifts of central synaptic excitability. Second, changes of the chemical substances transported from the periphery to the cord produce alterations of cord cell excitability. Third, central control mechanisms can change into a pathological state permitting hyperexcitability. The combined peripheral and central pathology offers more than explanation since each factor could be a target for prevention as well as cure.

(1) Capsaicin solution was applied for 15 min around a 1 cm length of sciatic nerve in the mid upper leg of adult rats. (2) Electron microscopic examinations of the nerve in the treated region after 14 days shows no signs of degeneration of either myelinated or unmyelinated fibres attributable to the capsaicin. (3) Fluoride resistant acid phosphatase FRAP disappears from the central terminals of the treated nerve by 7 days. (4) 1.5 mM capsaicin is sufficient to product a complete reduction of FRAP in the spinal cord. (5) The peptides substance P and cholecystokinin (CCK) are markedly depleted in the region of spinal cord terminations of the treated nerve at 14 days. (6) Substance P and CCk are not affected in spinal cord regions other than in the unmyelinated afferent terminal zone. Similarly neurotensin and neurophysin which are not present in afferent fibres are not influenced by capsaicin treatment of the sciatic. (7) It is concluded that there are chemical changes in the spinal cord terminals of fine afferents after local peripheral capsaicin.

Activation of cutaneous chemosensitive afferents results in the release of substances which increase the permeability of the microcirculation, producing inflammation. That this inflammation is neurogenic is readily demonstrated by antidromic electrical stimulation of afferent fibres. In the present study we have used the technique of dye extravasation to compare both qualitatively and quantitatively neurogenic extravasation skin and skeletal muscle. Plasma extravasation has been found to occur in skeletal muscle after stimulation but only at less than 10% of the levels seen in skin. We have also found that the levels of the C-fibre markers substance P and fluoride-resistant acid phosphatase are greatly reduced in muscle compared with skin nerves. These results show that there are substantial differences in the population of C-fibres supplying muscle compared with those supplying skin.

This paper reviews the central consequences of local application of capsaicin to one nerve in adult animals. 1) Marked chemical changes occur in the central terminals of C fibres. These include depletion of the enzyme FRAP and the peptides SP, CCK, somatostatin, CGRP and an increase of VIP. Maximal depletions occur if the nerve is soaked with capsaicin solutions with a concentration higher than 3 mM. The depletion begins by 7 days and is complete by 11. Recovery begins at about 110 days and is largely complete by 200. Our studies have concentrated on the effects of 40 mM capsaicin examined 14 days after the application. 2) Capsaicin treatment of a peripheral nerve decreased the ability of C fibres in that nerve to excite or to inhibit spinal cord cells. It produces a marked expansion of receptive fields of some cells in the dorsal horn which respond to A fibre stimulation. It is proposed that this change is not due to anatomical changes but to disinhibition. A further example of receptive field expansion is seen after treatment of the mouse infraorbital nerve which defocuses the normally precise projection of individual whiskers onto single cells in the barrel field of the somatosensory cortex. 3) Behavioural consequences follow the treatment of one adult nerve with capsaicin. In the area subserved by the treated nerve, there is a raised threshold to response to chemical and thermal stimuli, no change in the response to mechanical stimuli and an increase of autotomy following nerve section. 4) The aim of the experiments was to determine the role of C fibres in producing the changes seen in spinal cord following peripheral nerve section. Capsaicin treatment of nerve imitates the central effect of complete nerve section in certain important ways. Both result in a marked expansion of the receptive field of some cells. The effect is produced by a change of chemical transport. The results show that C fibres influence the connection of A fibres onto spinal cord cells.

The medial part of the L4 and 5 dorsal horn in adult rats is dominated by afferents from the toes and foot. After transection of the sciatic and saphenous nerves, virtually all cells in this region are left without any peripheral receptive field. Beginning 4 to 5 days after nerve section, however, many peripherally deafferented cells take on a novel receptive field on the thigh, lower back, or perineum. The new receptive fields are served by intact nerves ending in proximal skin rather than by misdirected sprouts of cut toe-foot nerves. Thus, peripheral axotomy results in synaptic reorganization in the spinal cord proper. Receptive field reorganization occurs after nerve transection, ligation, or ligation with distal transection but does not occur if the nerve is crushed. If a cut nerve is sutured and regeneration is permitted, spinal reorganization is reversed and the toe-foot afferents regain exclusive dominance of the medial dorsal horn.

(1) Lamina I contains large numbers of nociceptive specific cells and wide-dynamic-range (WDR) cells which respond to both noxious and innocuous stimuli. Many of the cells project to the brain. 82% of the projecting axons travel by way of the contralateral dorsolateral funiculus (DLF). (2) Section of the contralateral DLF produced no change in behavioural response to brief mechanical or thermal or chemical stimuli. However, section of the contralateral DLF greatly accelerated the slow onset autotomy in response to section of the sciatic and saphenous nerves. (3) Section of the ipsilateral DLF or bilateral section produce the same acceleration of onset of autotomy as is produced by contralateral DLF section. Section of dorsal columns does not change the long-term onset of autotomy. (4) Destruction of cells with ibotenic acid in the contralateral parabrachial area where many lamina I cells are known to terminate produced the same acceleration of autotomy as was observed after DLF lesions. Contralateral cortical lesions were without effect on autotomy. (5) It is proposed that the lamina I projection system is more concerned with long-latency long-duration reactions to prolonged events than to abrupt reactions to brief stimuli. The behavioural results reported here are consistent with McMahon and Wall's physiological hypothesis that a contralateral DLF projecting pathway excites cells in the parabrachial area which in turn excite descending control systems running mainly in the ipsilateral DLF to affect spinal dorsal horn cells.

The inhibitory effect of A-primary afferent activity on A- and C-evoked activity in dorsal horn convergent neurones has been investigated in the decerebrate spinal rat. A-afferent conditioning stimuli produce a powerful inhibition of the C-evoked activity in the majority of units recorded in lamina 5 but were almost without effect on the C-evoked activity in units recorded within the substantia gelatinosa (laminae 1 and 2). The ability of an A-volley to inhibit the response to a C-volley begins immediately after the arrival of the A-volley and lasts for 50-70 ms. Conditioning A-stimuli also inhibit the A-evoked activity of dorsal horn neurones, the inhibition lasting up to 125 ms. Unlike the effect of A-conditioning stimuli on C-responses, which was restricted to units in lamina 5, the A-volleys inhibited the response of both substantia gelatinosa and lamina 5 units. In rats with chronically sectioned sciatic nerves (7-14 days) both A on A and A on C inhibitions were significantly diminished in spite of intact afferent volleys and postsynaptic activity. In neurones activated by stimulation of the sectioned nerve, the A-conditioning stimuli either failed to produce an inhibition or produced a weak and shorter effect. These results are discussed in terms of the possible functional significance of A-afferent mediated inhibition.

In adult rats, the sciatic and saphenous nerves on one side were treated topically with capsaicin. The capsaicin treatment had the effect of increasing the latency for withdrawal of the foot from hot water; 11-22 days later, the animals were decerebrated, and cells in the superficial dorsal horn of the lumbar cord with axons projecting in the contralateral dorsolateral funiculus (DLF) were examined electrophysiologically on the treated and untreated sides of the cord. HRP was applied to cut axons of the DLF at C4, in other rats, and retrograde labelling of cells in the lumbar cord indicated that most or all of the recordings in the capsaicin-treated animals were likely to originate from lamina 1. The dorsal horn cells, with receptive fields on the foot, showed decreased responses to electrically evoked afferent impulses in C fibres and grossly altered receptive fields. After capsaicin treatment, the proportion of cells responding to C afferents fell from 83% to 14%. The proportion responding only to C afferents and not to A afferents fell from 9% to 0%. The receptive fields (RFs) of these cells showed two gross abnormalities; 32% of the cells on the treated side had no apparent RF or an ill-defined, intermittent RF, whereas such cells were rare on the untreated side or in intact animals. By contrast 49% of the cells had grossly expanded RFs with an average area of 430 mm2 against the normal average size of 130 mm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Single unmyelinated sensory afferent nerve fibers were recorded in dorsal root filaments in urethane-anesthetized or in decerebrate-spinal rats. The peripheral branch of these axons ran in the sural nerve where they were stimulated by tungsten microelectrodes. All action potentials showed the characteristics of single fiber responses with a fixed all or none shape and a fixed latency at a given stimulus strength. In all units, the action potential evoked from a proximal stimulus site collided with the action potential evoked from a distal stimulus site. Of the 44 single units isolated, 17 showed the expected small progressive decrease of latency of the recorded impulse as the stimulus strength at a fixed point on the sural nerve was progressively raised above threshold. However, in 27 units there was an abrupt jump decrease of latency as the stimulus rose above the threshold. The average size of this latency shortening was 2.2 msec, which occurred as the stimulus strength rose a mean 21% above threshold. As the stimulus rose above threshold, 7 fibers showed 3 different fixed latencies and 2 fibers showed 4 fixed latencies. In order to test the possibility that the peripheral nerve contained 2 branches of the same axon with one conducting slower than the other, the peripheral nerve was stimulated at progressively longer conduction distances. As predicted, the difference between the 2 fixed latencies became larger as the conduction distance increased. We discuss 6 possible explanations for the results and conclude they are consistent with the proposals that some fibers branch distal to the dorsal root ganglion and some branches do not establish a functional sensory ending in the periphery.

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.

(1) Systemic capsaicin treatment of neonatal and adult rats is known to affect unmyelinated afferents. However, the systemic route of administration presents several disadvantages and in order to overcome these a method was explored where a single nerve in adult rats was locally treated. (2) Sciatic nerves were exposed and a 10 mm length was soaked for 15 min in 1.5% capsaicin in vehicle or in the vehicle alone (10% Tween 80, 10% ethyl alcohol in saline). (3) Both the capsaicin solution and the vehicle caused acute block of the C compound action potential while in contact with the nerve. Removal of the solutions, however, resulted in substantial recovery of C fibre conduction. The A fibre volley was totally unaffected. (4) 13-21 days after treatment, the size of the myelinated and unmyelinated volleys evoked by maximal stimulation of the capsaicin treated nerve were unchanged but there was a 20% decrease of conduction velocity in the C fibres. (5) The ability of the maximal C volley from the treated nerve to excite cells in the spinal cord was substantially decreased (by 50%) 13-21 days after local capsaicin.

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.