Fernando Cervero

The representation of prolonged and intense, noxious somatic and visceral stimuli in the ventrolateral orbital cortex of the cat

&NA; The responses of single neurones in the ventrolateral orbital (VLO) cortex to noxious pinch, heating of the skin, twisting of the joints and distension of the gall bladder were studied in cats anaesthetized with halothane. Of 60 neurones studied, 44 responded to prolonged ( > 10 sec) stimuli that were well within the noxious range. Neurones were relatively unresponsive to innocuous stimuli or to the transient application of noxious stimuli. Many single neurones responded to a variety of modalities of noxious stimuli (e.g., skin heating and gall bladder distension). Many neurones studied showed a fluctuating level (5–15 Hz) of ongoing spontaneous activity. Neurones responded with either an increased frequency of spikes (excitation) or an inhibition of spontaneous discharge, irrespective of the source of noxious stimulation. Noxious stimuli delivered simultaneously to two different tissues (e.g., skin and visceral) sometimes produced excitation of the neurone under study, to levels above that produced by the application a noxious stimulus to only one of the tissues. Receptive fields were often large involving both contralateral and ipsilateral areas of the body, as well as both fore and hind limbs. No evidence of somatotopic organization was obtained. The responses of some neurones outlasted the application of the stimuli by many minutes. It is concluded that single neurones in the ventrolateral orbital cortex respond to the prolonged application of intensely noxious stimuli to a variety of body tissues, in a manner that is in keeping with the involvement of this cortical area in both the physiological, autonomic and experiential components of the affective‐motivational aspect of pain. Furthermore, from the consequences of lesion studies in man and animals, it is proposed that the activation of cells in the orbital cortex by a variety of noxious stimuli reflects its more general role in the development and maintenance of behaviour in response to negative reinforcement of both social and physical origins.

SELECTIVE CHANGES OF RECEPTIVE FIELD PROPERTIES OF SPINAL NOCICEPTIVE NEURONES INDUCED BY NOXIOUS VISCERAL STIMULATION IN THE CAT

&NA; This study was designed to examine the central changes in the receptive field properties of dorsal horn neurones induced by a period of visceral noxious stimulation. The aim of this investigation was to establish whether noxious stimulation of the visceral input to the spinal cord could influence transmission of cutaneous information through dorsal horn neurones. Single‐unit electrical activity was recorded in the lower thoracic spinal cord of anaesthetized cats from dorsal horn neurones with a somatic receptive field in the ipsilateral flank. Changes in the properties of these receptive fields induced by reversible spinalization (by means of a cold block 4 or 5 segments rostral to the recording electrodes) and by a conditioning noxious stimulation of the biliary system (3 successive distensions of the gall bladder for 30 sec at 65–80 mm Hg at 1‐min intervals) were analysed. Nineteen neurones have been studied, 10 of which could be driven by stimulation of the gall bladder. All of these 10 cells showed increases in the size of their cutaneous receptive fields following conditioning noxious stimulation of the biliary system. The increases were large and lasted for at least 20 min. None of the 9 spinal cord neurones without an input from the gall bladder were affected by the conditioning visceral stimulus even though 7 showed changes in receptive field size when the animals were spinalised. These results show that noxious stimulation of viscera can evoke increases in the somatic receptive fields of spinal cord neurones but only of those neurones which are also driven by the visceral stimulus.

Development of secondary hyperalgesia following non-painful thermal stimulation of the skin: a psychophysical study in man.

&NA; A psychophysical study has been carried out in 10 normal human subjects to examine whether conscious perception of pain is necessary for the development of secondary hyperalgesia. Prolonged thermal stimulation of the skin was applied to the subjects at intensities known to evoke discharges in polymodal nociceptors but insufficient to evoke pain sensations. During this stimulation the development of punctate and of stroking hyperalgesia was examined as was the presence of a skin flare indicative of nociceptor activation. All subjects developed a flare and an area of hyperalgesia following the application of the non‐painful heat stimulus. The first change observed in the subjects was the appearance of an area of hyperalgesia to punctate stimuli, followed by flare and by stroking hyperalgesia. The onset of pain was always reported sometime after these events. Statistical analysis of these data for all subjects showed a highly significant difference between the time of onset of pain and the time of onset of any of the other 3 phenomena. Significant differences were also observed between the onset of punctate hyperalgesia and the onsets of flare and of stroking hyperalgesia. No difference was observed between the onset of flare and of stroking hyperalgesia. These results show that cutaneous hyperalgesia can be evoked in normal human subjects by prolonged thermal stimulation of the skin at temperatures that are not perceived as painful. The development of a flare in all subjects simultaneously with stroking hyperalgesia but before the perception of pain suggests that activation of nociceptors is necessary for the hyperalgesia to occur. Since the perception of a pain sensation is not the triggering factor for the development of cutaneous hyperalgesia the CNS mechanisms responsible for secondary hyperalgesia must involve alterations of sensory processing at sub‐cortical levels.

Dorsal Horn Neurons and Their Sensory Inputs

The mammalian skin is innervated by a variety of afferent nerve fibers connected to highly specialized sensory detectors whose adequate stimulation leads to the experience of tactile, thermal, or painful sensations. Microneurographic studies of human sensory nerves have demonstrated a direct correlation between the functional properties of a given sensory detector and the elementary sensory experience evoked by its stimulation (Ochoa and Torebjork, 1983). Under normal circumstances, this elementary specificity of cutaneous sensory receptors (see Winkelmann, Chapter 2, and Campbell and Meyer, Chapter 3) is subjected to the integrative and modulatory influences of the central nervous system. Therefore, complex sensory perceptions are the consequence of the activation of specific sensory channels whose output can be profoundly modified by the activity of other pathways within the central nervous system.

More than just gut feelings about visceral sensation

Abstract New and detailed information is currently being obtained on the mechanisms of visceral sensation. Precise correlations have been made between the nature and intensity of visceral stimulation and the type of sensory receptor activated by these stimuli 1,2 . Non-specific sensory receptors have been described in the colon and bladder whereas specific visceral nociceptors have been found in other internal organs. The mode of termination of visceral afferent fibres within the spinal cord follows a consistent and regular pattern 3–7 with main areas of projection in laminae I and V of the dorsal horn. Extensive viscero-somatic convergence in the thoracic spinal cord has been described as the basis for referred visceral pain from the gallbladder and the heart 8–12 . Research on the neurochemistry of visceral afferents 13–17 has thrown new light on the role of neuropeptides in the regulation of visceral function by suggesting that some peptides contained in visceral afferents can be released peripherally by a mechanism akin to the cutaneous axon reflex 17 . These new observations challenge some of the traditional views on visceral and cutaneous sensation.

An in vitro method for recording single unit afferent activity from mesenteric nerves innervating isolated segments of rat ileum

A technique has been developed for recording single unit afferent activity from mesenteric nerves in isolated segments of rat distal ileum in vitro. The preparation consists of a 3-cm segment of ileum, containing a single neurovascular bundle, held horizontally in an organ bath. One end of the segment is attached to a tension transducer to record changes in longitudinal tension of the gut muscle and the other is connected to a pressure transducer to record changes in intra-luminal pressure. Electromyographic activity of the smooth muscle is recorded using glass-insulated tungsten microelectrodes inserted in the wall of the gut. Afferent nerve activity is recorded with a monopolar platinum wire electrode from filaments of the mesenteric nerves that run between the artery and vein supplying the segment. This preparation permits the detailed analysis of the electrical activity of intestinal afferent nerve fibres correlated with mechanical and chemical events occurring naturally in the gut or imposed experimentally on it.

The Superficial Dorsal Horn

The superficial dorsal horn is a morphologically distinct region of the grey matter of the spinal cord that has been recognized as a separate anatomical entity for over 150 years. It contains the first synaptic relay of fine afferent fibres from skin, muscle and viscera and for this reason has been regarded as an important site for the initial processing of signals directly related to the transmission and modulation of pain. Every neurobiological technique (light microscopy, immunohistochemistry, single unit electrophysiology, electron microscopy) has shown more and more distinct features of this region of the dorsal horn which make it clearly different from the rest of the spinal grey matter. Moreover, some of these peculiarities point to fundamental differences — functional as well as anatomical — in the processing of the sensory information mediated by fine afferent fibres as opposed to the processing of the signals carried by large myelinated afferents.

A Comparison of the Receptive Field Plasticity of Nocireceptive and Multireceptive Dorsal Horn Neurones Following Noxious Mechanical Stimulation

We have previously shown that the ability of both Multireceptive (Class 2) and Nocireceptive (Class 3) dorsal horn neurones to encode the intensity of noxious mechanical stimuli is altered after a series of noxious pinches applied to their receptive field (RF) (Cervero et al, 1988). Further, the RF size of some dorsal horn neurones is known to increase following a brief period of electrical stimulation at C-fibre intensity (Cervero et al, 1984; Cook et al, 1987). We have now investigated the effect of a series of 2 minute noxious pinches upon the excitatory RF and mechanical threshold of Class 3 cells, predominantly recorded in the superficial dorsal horn. However, since only very small changes in RF size were observed in this population the responses of a sample of Class 2 neurones were also examined and the results included in this study to provide a comparison under the same experimental conditions.

Capsaicin-Sensitive Vagal Afferent Fibers and Gastric Motility: Evidence for an “Axon Reflex” Mechanism

The role of capsaicin‐sensitive afferent fibers in gastric motility has been studied in normal rats and in rats treated at birth with the sensory neurotoxin capsaicin, a procedure known to destroy up to 90% of unmyelinated afferent fibers. Gastric motility was measured as intragastric pressure changes evoked by the distention of the stomach with 8 to 10 ml of normal (154 mM) or 1 M saline solution. No differences were observed between the motility patterns evoked by gastric distention with these two solutions. Distention of the stomach evoked a significantly lower basal tone and a reduced number and amplitude of phasic contractions in capsaicin‐treated rats compared to control rats. Intravenous administration of the ganglionic blocker hexamethonium substantially reduced phasic motility in both groups of animals. Subsequent bilateral vagotomy had little extra effect. After bilateral vagotomy, electrical stimulation at supramaximal intensities of the peripheral end of the cut right vagus in the presence of hexamethonium produced an inhibition of the gastric basal tone in both groups of rats and, on cessation of stimulation, a series of rebound contractions in most control animals, but not in those treated at birth with capsaicin. These results provide evidence for an efferent role of vagal afferent fibers in the control of gastric motility, possibly via an axon reflex mechanism.