Primary afferent input to and receptive field properties of cells in rat lumbar area X.

In this study we examined the primary afferent input to rat area X of Rexed, and characterized sensory receptive fields (RFs) of the cells therein. This poorly understood area contains primary afferent fibres, some of which are arranged into a compact bundle beneath the central canal. Anterograde transport of the B fragment of cholera toxin (CTB) from the sciatic nerve showed a strictly ipsilateral projection to segments in L4 and L5 but both ipsi- and contralateral projections in L6 and more caudal segments. The response of cells in area X to mechanical cutaneous stimuli was recorded through extracellular microelectrodes in decerebrate, decerebrate-spinal, and urethane-anaesthetised preparations. The lateral edge of area X was marked by an abrupt change in the RFs: Lateral to area X in the dorsal horn, they were strictly unilateral and relatively small. At a mean of 90 microm from the midline, there was an abrupt expansion of the RFs to cover at least the entire ipsilateral dermatome. Within area X, 70% of the cells' RFs extended across the midline to include contralateral skin. In 35% of cells recorded in rats with intact spinal cords, the RF extended rostrally onto the forelimb. In a small number of cells, the RF included ear pinnae and nose. The precise function of area X cells remains unknown; although they have been shown to be involved in visceral reflexes, the fact that they receive convergent input from a wide variety of tissues and from local and remote body parts implies a more generalized, integrative function.

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.

Brief and prolonged effects of Lissauer tract stimulation on dorsal horn cells.

Increased excitability of dorsal horn neurones may play a critical role in producing some pain states and there is evidence that the excitability of neurones lying throughout the dorsal horn is subject to regulation by cells in its most superficial laminae. This paper examines the effect on dorsal horn cell receptive fields and excitability of the specific activation of Lissauer's tract, a tract containing propriospinal axons which arise from cells in the substantia gelatinosa and which project to the substantia of neighbouring spinal segments. Experiments were carried out on anaesthetised spinal rats in the L3-4 spinal segments with microelectrode stimulation on the surface of the Lissauer tract (LT) and microelectrode recording of single cells or small groups of cells that responded to gentle brushing on the skin. Single shocks or brief trains of low-level stimuli to the LT produced a characteristic long-latency dorsal root potential (DRP) on the L3 dorsal root and a brief burst of firing in superficial cells with no stimulation of primary afferents. Generally, this was accompanied by no excitation of deeper dorsal horn cells but commonly by a period of inhibition, often followed by facilitation. We then turned to the effect of long periods (30-90min) of continual LT stimulation because we had seen hints of prolonged facilitation of the deeper cells after periods of such stimulation. Trains of 5 stimuli separated by 2ms and repeated every 200ms were used with individual pulses of 200 micros duration and less than 10 microA amplitude. This resulted in a shift of the effect on deep cells from primarily inhibition to mainly facilitation. We then examined in detail the effect of these long periods of LT stimulation on the size of receptive fields (RFs) of dorsal horn cells first on single units and then by repeated mapping of the RFs of small groups of cells. Control periods of 60min with no LT stimulation produced no significant RF changes but 30, 60 or 90min of LT stimulation produced successively greater expansions of RFs. When the LT stimulus was turned off after 1h, the RFs remained expanded for at least 2h. The spike height of these cells remained unchanged. The effect was not influenced by the NMDA antagonist MK801 but was imitated by the GABA(A) antagonist picrotoxin. It is concluded that the prolonged expansion of RFs could not be produced by modulation of descending control since the animals had spinal transections. Neither was it dependent on an NMDA-sensitive mechanism. With these data it is not possible to conclude whether the mechanism is pre-synaptic, post-synaptic or both. It is proposed that the most likely explanation is a decrease in the normal tonic inhibition operated in part by a GABA dependent mechanism. This phenomenon may play a role in prolonged pathological states of increased spinal cord excitability.

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.

Effect of the forebrain on flexion reflexes in rats with ankle joint urate arthritis.

Ankle joint urate arthritis in rats is associated with increased responses to ankle stimulation and decreased responses to stimulation of the distal foot. To determine the influence of the forebrain on flexion reflexes in this model, responses to ankle and foot stimulation were examined in chronic decerebrate rats, decerebrated either before or after the induction of the arthritis. The increased responsiveness to stimulation of the arthritic ankle which had been observed after 24 h of urate arthritis was equally apparent in animals decerebrated 24 h before the induction of the arthritis and in those decerebrated 24 h after the urate injection. However, the decreased responsiveness of the distal foot to pressure or temperature stimuli, which had been observed in arthritic animals with an intact forebrain, was still apparent in animals decerebrated 24 h after the induction of the arthritis but did not appear in animals who had been decerebrated before the arthritis induction. It is concluded that the forebrain is required for the production of the reduced responsiveness of the distal foot but is not required for its maintenance once the insensitive state has been acquired.

Ankle joint urate arthritis (AJUA) in rats: an alternative animal model of arthritis to that produced by Freund's adjuvant.

Injection of sodium urate crystals into one ankle joint in the rat produces arthritis which is fully developed within 24 h. The time-course and dose-response of associated inflammation and sensory abnormalities are described. Following intra-articular sodium urate rats reduce the weight placed on the paw of the treated hind limb and develop a limp in their gait. The ankle swells and becomes more sensitive to pressure and passive movements. Touch, pressure and thermal stimuli applied to the foot distal to the treatment produce decreased responses, presumably because active flexion movements are noxious. Joint pathology is reflected by tissue oedema and the infiltration of polymorphonuclear leucocytes. However, there is no destruction or decrease in density of bone. It is proposed that this model of arthritis may have ethical and scientific advantages over adjuvant arthritis in the study of some aspects of the neural mechanisms of arthritis.

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.

Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries.

Features of acute pain were examined in patients at an emergency clinic. Patients who had severe, life-threatening injuries or who were agitated, drunk, or 'in shock' were excluded from the study. Of 138 patients who were alert, rational and coherent, 51 (37%) stated that they did not feel pain at the time of injury. The majority of these patients reported onset of pain within an hour of injury, although the delays were as long as 9 h or more in some patients. The predominant emotions of the patients were embarrassment at appearing careless or worry about loss of wages. None expressed any pleasure or indicated any prospect of gain as a result of the injury. The occurrence of delays in pain onset was related to the nature of the injury. Of 46 patients whose injuries were limited to skin (lacerations, cuts, abrasions, burns), 53% had a pain-free period. Of 86 patients with deep-tissue injuries (fractures, sprains, bruises, amputation of a finger, stabs and crushes), only 28% had a pain-free period. The McGill Pain Questionnaire was administered to patients who felt pain immediately after injury or after a delay, and revealed a normal distribution of sensory scores but very low affective scores compared to patients with chronic pain. The results indicate that the relationship between injury and pain is highly variable and complex.

On the relation of injury to pain. The John J. Bonica lecture.

Pain is better classified as an awareness of a need-state than as a sensation. It serves more to promote healing than to avoid injury. It has more in common with the phenomena of hunger and thirst than it has with seeing or hearing. The period after injury is divided into the immediate, acute and chronic stages. In each stage it is shown that pain has only a weak connection to injury but a strong connection to the body state.