Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Unit responses in the anterior and posterior hypothalamus to stimulation of the splanchnic and sciatic nerves and to photic stimulation

By extracellular recording of spike discharges the sensory properties of neurons of the anterior and posterior regions of the cat hypothalamus were studied during stimulation of the splanchnic and sciatic nerves and during photic stimulation. Hypothalamic neurons were shown to be characterized by wide convergence of heterosensory excitation: 68% of spontaneously active hypothalamic neurons responded to somatovisceral and photic stimulation. Some posterior hypothalamic neurons responded to somatovisceral stimulation but not to photic stimulation. Neurons responding only to photic stimulation were found in the anterior hypothalamus; no neurons responding only to visceral stimulation were found in the hypothalamus. Total convergence of somatic and visceral afferentation of neurons of the posterior and anterior hypothalamus was observed. Mostly responses of phasic type were obtained to stimulation of all modalities. The study of the quantitative ratio between responses of excitatory and inhibitory types showed that the former predominate. The principles governing the functional organization of hypothalamic afferent systems are discussed.Academician L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 8, No. 3, pp. 276–282, May–June, 1976.     

Monoaminergic Modulation of Spinal Viscero-Sympathetic Function in the Neonatal Mouse Thoracic Spinal Cord

Descending serotonergic, noradrenergic, and dopaminergic systems project diffusely to sensory, motor and autonomic spinal cord regions. Using neonatal mice, this study examined monoaminergic modulation of visceral sensory input and sympathetic preganglionic output. Whole-cell recordings from sympathetic preganglionic neurons (SPNs) in spinal cord slice demonstrated that serotonin, noradrenaline, and dopamine modulated SPN excitability. Serotonin depolarized all, while noradrenaline and dopamine depolarized most SPNs. Serotonin and noradrenaline also increased SPN current-evoked firing frequency, while both increases and decreases were seen with dopamine. In an in vitro thoracolumbar spinal cord/sympathetic chain preparation, stimulation of splanchnic nerve visceral afferents evoked reflexes and subthreshold population synaptic potentials in thoracic ventral roots that were dose-dependently depressed by the monoamines. Visceral afferent stimulation also evoked bicuculline-sensitive dorsal root potentials thought to reflect presynaptic inhibition via primary afferent depolarization. These dorsal root potentials were likewise dose-dependently depressed by the monoamines. Concomitant monoaminergic depression of population afferent synaptic transmission recorded as dorsal horn field potentials was also seen. Collectively, serotonin, norepinephrine and dopamine were shown to exert broad and comparable modulatory regulation of viscero-sympathetic function. The general facilitation of SPN efferent excitability with simultaneous depression of visceral afferent-evoked motor output suggests that descending monoaminergic systems reconfigure spinal cord autonomic function away from visceral sensory influence. Coincident monoaminergic reductions in dorsal horn responses support a multifaceted modulatory shift in the encoding of spinal visceral afferent activity. Similar monoamine-induced changes have been observed for somatic sensorimotor function, suggesting an integrative modulatory response on spinal autonomic and somatic function.     

Human cerebrocortical potentials evoked by stimulation of the dorsal nerve of the penis

Cortical evoked potentials resulting from stimulation of the dorsal nerve of the penis (DNP) provide a unique opportunity to document the cortical localization of sexual sensory representation in man. The DNP supplies sensory axons to the major portion of the human phallus, including the penile shaft and glans. Animal and human studies indicate that this nerve plays a crucial role in erection and ejaculation. Direct cortical evoked responses to DNP electrical stimulation were recorded in patients undergoing preoperative evaluation for resection of epileptic foci. These studies provided evidence that the primary sensory cortex contains a large area of cortex devoted to the afferent fibers of the DNP and that the sensory field is in a different location than previously described. The location and distribution of this response indicated the need for revision of the traditional concept of the sensory cortical homunculus.     

Functional organization of afferent inputs of neurons of the cat somatic cortex

Responses of cortical neurons in the posterior sigmoid gyrus to stimulation of two points of the ventro-posterolateral nucleus were investigated in cats immobilized with D-tubocurarine. Some neurons responding to stimulation of one point of this nucleus with a latent period of 2.5–4 msec, were activated by stimulation of the other point after 10 msec or longer. Conditioning stimulation of one point facilitated or inhibited the response to test stimulation of the other point. The facilitatory effect was usually exhibited if the response latency exceeded 5 msec. It is concluded that a cortical input neuron for some afferent fibers is activated by other similar afferent fibers only after intracortical relay. The system of "input" cortical neurons is thus not only a structural, but also to some extent a functional, concept; under certain conditions an incoming afferent volley activates them only polysynaptically.     

Interoception: the sense of the physiological condition of the body

Converging evidence indicates that primates have a distinct cortical image of homeostatic afferent activity that reflects all aspects of the physiological condition of all tissues of the body. This interoceptive system, associated with autonomic motor control, is distinct from the exteroceptive system (cutaneous mechanoreception and proprioception) that guides somatic motor activity. The primary interoceptive representation in the dorsal posterior insula engenders distinct highly resolved feelings from the body that include pain, temperature, itch, sensual touch, muscular and visceral sensations, vasomotor activity, hunger, thirst, and 'air hunger'. In humans, a meta-representation of the primary interoceptive activity is engendered in the right anterior insula, which seems to provide the basis for the subjective image of the material self as a feeling (sentient) entity, that is, emotional awareness.     

EEG patterns suggestive of shifted levels of excitation effected by hathayogic exercises

Concurrent with the performance of hathayogic exercises such as Nauli, Bhastrika and Suryabhedana, three characteristic EEG patterns were identified: a "wicket" rhythm at a frequency wave of 12 to 17 Hz, recordable from para-Rolandic areas, which we have called Xi rhythm; a 26-33 Hz sinusoidal activity, confined to the mid-sagittal parietooccipital region; and paroxysmal activity localized in the lateral boundaries of parieto-temporo-occipital regions, bilaterally. - The expectation that hathayogic exercises would affect the electrical activity of circumscribed, relatively well defined areas of the brain was based on the fact that these exercises imply a strong stimulation of somatic and splanchnic receptors, the afferent impulses of which are fed into specific cortical representation areas localized for the most part around central and anterior parietal areas.     

Cerebral potentials evoked by rectal distention in humans

The afferent pathways from the rectum can be stimulated and studied after mechanical distention of the rectum. We studied the rectum-brain axis in 24 healthy young adults. The rectum was stimulated with a rectal balloon using inflation volumes of 10 ml and 30 ml air at a stimulation frequency of 0.167 Hz. Additional studies were carried out with 20 ml distention volumes, random stimulation frequency, and stimulation rates of 0.08 Hz and 0.017 Hz. We found two different cortical EPs. An early onset EP was present in 21 of the 24 subjects. P1 latency shortened significantly with increasing distention volumes, but peak amplitudes did not change significantly with larger distention volumes. A late onset EP was present in all subjects with NI latency of 210 ± 15 msec, PI latency of 316 ± 24 msec, and NII latency of 444 ± 34 msec. The different EPs could be due to stimulation of two different visceral afferent pathways which are present in the same individual, due to stimulation of two different fiber populations or due to simultaneous stimulation of afferents in surrounding structures. EP recording after rectal stimulation might be useful in future studies of patients with abnormal rectal sensation.     

Restoration of contralateral representation in the mouse somatosensory cortex after crossing nerve transfer

Avulsion of spinal nerve roots in the brachial plexus (BP) can be repaired by crossing nerve transfer via a nerve graft to connect injured nerve ends to the BP contralateral to the lesioned side. Sensory recovery in these patients suggests that the contralateral primary somatosensory cortex (S1) is activated by afferent inputs that bypassed to the contralateral BP. To confirm this hypothesis, the present study visualized cortical activity after crossing nerve transfer in mice through the use of transcranial flavoprotein fluorescence imaging. In naïve mice, vibratory stimuli applied to the forepaw elicited localized fluorescence responses in the S1 contralateral to the stimulated side, with almost no activity in the ipsilateral S1. Four weeks after crossing nerve transfer, forepaw stimulation in the injured and repaired side resulted in cortical responses only in the S1 ipsilateral to the stimulated side. At eight weeks after crossing nerve transfer, forepaw stimulation resulted in S1 cortical responses of both hemispheres. These cortical responses were abolished by cutting the nerve graft used for repair. Exposure of the ipsilateral S1 to blue laser light suppressed cortical responses in the ipsilateral S1, as well as in the contralateral S1, suggesting that ipsilateral responses propagated to the contralateral S1 via cortico-cortical pathways. Direct high-frequency stimulation of the ipsilateral S1 in combination with forepaw stimulation acutely induced S1 bilateral cortical representation of the forepaw area in naïve mice. Cortical responses in the contralateral S1 after crossing nerve transfer were reduced in cortex-restricted heterotypic GluN1 (NMDAR1) knockout mice. Functional bilateral cortical representation was not clearly observed in genetically manipulated mice with impaired cortico-cortical pathways between S1 of both hemispheres. Taken together, these findings strongly suggest that activity-dependent potentiation of cortico-cortical pathways has a critical role for sensory recovery in patients after crossing nerve transfer.     

Comparative electrophysiological characteristics of afferent representation in the cortical and striatal divisions of the turtle forebrain

In experiments on immobilized, lightly anesthetized turtles the presence of visual and somatic representation was established in the subcortical striatal division of the forebrain — the pallial thickening, the dorsal ventricular ridge, and the putamen. In their physiological characteristics they are similar to the corresponding representation in the general cortex. The absence of significant differences between the latent periods of cortical and striatal evoked potentials to flashes and to stimulation of the dorsal thalamus indicates that visual projection fibers (from the lateral geniculate body) terminate at both cortical and striatal levels. Differences in the distribution of latent periods of unit responses in the cortex to visual and thalamic stimulation are due to the presence of a rotundo-telencephalic visual channel, with direct connections with the striatal and polysynaptic connections with the general cortex, as well as the geniculo-telencephalic tract. Considerable differences between the latent periods of the evoked potentials and also between unit responses to electrodermal stimulation in the cortical and striatal structures indicate that somatic projection fibers relay in the striatum on their path to the general cortex. Consequently, the somatosensory system of turtles is less corticalized than the visual system. Comparison of the results described with those obtained by workers studying other vertebrates suggests that the afferent supply of the striatum may be reorganized in the transition from premammals to mammals.I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 7, No. 2, pp. 184–193, March–April, 1973.     

Mechanisms of corticofugal control of the activity of “vagal” viscerosensory neurons in theNucleus tractus solitarii

In experiemnts on cats under chloralose-nembutal anesthesia, we studied viscerosensory neurons in thenucl. tractus solitarii identified by their responses to stimulation of then. vagus. The responses of these cells to stimulation of the secondary sensorimotor cortex (zoneS2) and dorsal regions of field 25 of the limbic cortex (DLC) were recorded. A substantial part of the “vagal” viscerosensory units demonstrated convergent properties and responded toS2 and DLC stimulations by phasic responses. The short latencies of these responses were indicative of oligosynaptic and, in some cases, even monosynaptic transmission of corticofugal influences on a considerable part of such neurons. Using paired stimulation allowed us to demonstrate that the effects of stimulation of the visceral afferent fiber undergo long-lasting suppression exerted by descending corticofugal volleys. The mechanisms of cortical control of the activity of bulbar viscerosensory neurons are discussed.     

Possible mechanisms of the anterior limbic cortex influence on the neuron activity of the vago-solitary complex

In ananesthetized cats, neurons of the nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNV) revealed phasic excitatory responses to separate single vagal and cortical stimuli. Stimulation of the anterior limbic cortex combined with vagal stimulation resulted in inhibitory or excitatory modification of the vagal induced responses of the NTS and DMNV neurons. The data obtained suggest that complete inhibitory effects are related to general cortical mechanisms of control of the functional state of the brain stem visceral neurons. Selective inhibition of the vagal induced responses by limbic cortex stimulation is due to particular cortical mechanisms of the visceral sensory transmission control via the NTS neurons.     

Neuronal responses of the rate somatosensory cortex transplanted into the vibrissae representation field of the neocortex to the electrical stimulation of the recipient brain

Neuronal responses of the rat somatosensory cortex grafted into damaged host barrel field to electrical stimulation of the host brain were investigated extracellularly in rats under light pentobarbital anaesthesia. The following structures of the host brain were stimulated: ventrobasal complex and posterior thalamic nuclei, ipsilateral area of vibrissae representation in the sensorimotor cortex and contralateral barrel field. Reactivity of the grafted neurones was lower, than in the intact barrel field, but the mean latencies of responses were not significantly different. Stimulation of the thalamic nuclei was more effective than that of the cortical areas both in grafted and intact barrel fields. Posttetanic depression after repetitive stimulation was often observed in the grafts, while posttetanic potentiation was more usual for the intact barrel field. The data show the sources of some functional afferent inputs to the grafts which may be responsible for neuronal reactions to somatosensory stimulation of the host animal.     

Neuronal and synaptic mechanisms of cortical inhibition

The latent periods, amplitude, and duration of IPSPs arising in neurons in different parts of the cat cortex in response to afferent stimuli, stimulation of thalamocortical fibers, and intracortical microstimulation are described. The duration of IPSPs evoked in cortical neurons in response to single afferent stimuli varied from 20 to 250 msec (most common frequency 30–60 msec). During intracortical microstimulation of the auditory cortex, IPSPs with a duration of 5–10 msec also appeared. Barbiturates and chloralose increased the duration of the IPSPs to 300–500 msec. The latent period of 73% of IPSPs arising in auditory cortical neurons in response to stimulation of thalamocortical fibers was 1.2 msec longer than the latent period of monosynaptic EPSPs evoked in the same way. It is concluded from these data that inhibition arising in most neurons of cortical projection areas as a result of the arrival of corresponding afferent impulsation is direct afferent inhibition involving the participation of cortical inhibitory interneurons. A mechanism of recurrent inhibition takes part in the development of inhibition in a certain proportion of neurons. IPSPs arise monosynaptically in 2% of cells. A study of responses of cortical neurons to intracortical microstimulation showed that synaptic delay of IPSPs in these cells is 0.3–0.4 msec. The length of axons of inhibitory neurons in layer IV of the auditory cortex reaches 1.5 mm. The velocity of spread of excitation along these axons is 1.6–2.8 msec (mean 2.2 msec).A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 16, No. 3, pp. 394–403, May–June, 1984.     

Absence of increasing cortical fMRI activity volume in response to increasing visceral stimulation in IBS patients

Cerebral cortical activity associated with perceived visceral sensation represents registration of afferent transduction and cognitive processes related to perception. Abnormalities of gut sensory function can involve either or both of these processes. Cortical registration of subliminal viscerosensory signals represents cerebral cortical activity induced by stimulation of intestinal sensory neurocircuitry without the influence of perception-related cortical activity, whereas those associated with perception represent both neural circuitry and cognitive processes. Our aims were to determine and compare quantitatively cerebral cortical functional magnetic resonance imaging (fMRI) activity in response to subliminal, liminal, and nonpainful supraliminal rectal distension between a group of irritable bowel syndrome (IBS) patients and age/gender-matched controls. Eight female IBS patients and eight age-matched healthy female control subjects were studied using brain fMRI techniques. Three barostat-controlled distension levels were tested: 1) 10 mmHg below perception (subliminal), 2) at perception (liminal), and 3) 10 mmHg above perception (supraliminal). In control subjects, there was a direct relationship between stimulus intensity and cortical activity volumes, ie., the volume of fMRI cortical activity in response to subliminal (3,226 +/- 335 microl), liminal (5,751 +/- 396 microl), and supraliminal nonpainful stimulation (8,246 +/- 624 microl) were significantly different (P < 0.05). In contrast, in IBS patients this relationship was absent and fMRI activity volumes for subliminal (2,985 +/- 332 microl), liminal (2,457 +/- 342 microl), and supraliminal nonpainful stimulation (2,493 +/- 351 microl) were similar. Additional recruitment of cortical fMRI activity volume in response to increasing stimulation from subliminal to liminal and supraliminal domains is absent in IBS patients, suggesting a difference in the processing of perceived stimulation compared with controls.     

Cortical localisation of magnetic fields evoked by oesophageal distension

Magnetoencephalographic source localisation techniques were used to measure oesophageal evoked magnetic fields from the cerebral cortex in 3 subjects. By using rapid balloon distension as a stimulus, a comparison of proximal and distal oesophageal cortical representation was made. The distal oesophagus was represented bilaterally in the insular cortex and SII as well as the inferior aspect of SI. The proximal oesophagus was represented unilaterally in superior and inferior SI, insular cortex and SII. Significantly, the superior portion of SI was consistently activated in subjects following stimulation of the proximal oesophagus, but similar activation was not found in response to distal stimulation. This may reflect the contribution from somatic afferent fibres in the striate muscle of the proximal segment. In conclusion, vagal afferents appear to contribute more to cortical activation following stimulation of the distal rather than the proximal oesophagus, while spinal afferents appear to be activated by both proximal and distal oesophageal stimulation.     

Subdiaphragmatic vagal afferent nerves modulate visceral pain

Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Adelta or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Adelta fibers (40 microA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 microA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Adelta fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.     

Viscero-cardiac reflexes in the edible snail]

Only two inhibitory neurons in the visceral ganglia provide the viscero-cardial and cardio-cardial reflexes of Helix pomatia. These neurons are connected in parallel and do not interact with each other. The cells have extensive receptive fields in all visceral organs which are considerably overlapped. These inhibitory neurons can provide the afferent function because of a high sensitivity to tactile stimulation of their endings. The analysis of the data showed that morphological and functional characteristics of the neurons in question corresponded completely to previously identified multifunctional interneuron V21.     

Evoked potentials in the rat neostriatum during local cooling of the cortex in the zone of primary response to the applied stimulus

The effect of local cooling of the surface of the somatosensory cortex was studied while recording primary response (PR) in the center of a cooled area and evoked potentials (EP) in the striatum to the forepaw stimulation. The cooling which served to arise the amplitude of the PR, served also to arise the amplitude of the EP in the striatum. EP to the stimulus, the sensory representation of which in the cortex was cooled, were facilitated only. Facilitation of the striatal EP was more intense than facilitation of the cortical PR in the cooled area. The level of facilitation of the EP was the same in the region of the striatum which receives corticofugal fibers from the cooled area of the cortex and in other regions of the striatum, receiving the corticofugal fibers from other parts of the cortex. The data show a possibility for the interactions in the striatum of the corticofugal signals from different cortical areas with each other and with the ascending afferent signals.     

Stress analgesia in experimental burn shock

Experiments with curarized and slightly anesthetised adult cats with burn shock have demonstrated pronounced depression of excitation transmission in associative and nonspecific afferent systems during somatic, sound and light stimulation. Effects controlling the activity of the cardiovascular system were facilitated in efferent systems. In white rats, burn shock led to an increase in the somatic and visceral pain threshold during the first 5 days. Rausedyl and naloxone reduced stress analgesia caused by burn shock in white rats. Burn shock enhanced opiate-like activity (beta-endorphine, beta-lipotropin) of the white rat forebrain as shown by radioimmunoassay. The data suggest that stress analgesia associated with experimental burn shock is likely to be accounted for by the increased production of endogenous opiates.