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The sensory-efferent function of capsaicin-sensitive sensory neurons.

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

Animals

The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons.

In acute spinal rats (C2-C3) the transvesical infusion of saline activates a vesico-vesical excitatory reflex (Brain Res., 380 (1986) 83-93). In bladders containing a subthreshold amount of fluid the topical application of capsaicin on the outer surface of the bladder dome activated this spinal reflex and also produced a transient rise in blood pressure and heart rate. The effects of systemic capsaicin desensitization (50 mg/kg s.c. 5 min, 60 days before) on the sensory (activation of the spinal vesico-vesical reflex) and 'efferent' (tetrodotoxin-insensitive capsaicin-induced contraction) functions mediated by the capsaicin-sensitive sensory fibers were correlated to changes in substance P-like immunoreactivity (SP-LI) content of the urinary bladder in adult rats. Blockade of both sensory and efferent functions was observed at a time (60 min from capsaicin administration) when the SP-LI content of the urinary bladder was unaffected. Four days after capsaicin desensitization the SP-LI levels of the bladder are almost depleted indicating that the neuropeptide(s) are entirely stored in sensory structures. At this time the sensory-efferent functions mediated by these fibers are still blocked. At 15-60 days from systemic capsaicin desensitization there was a progressive, time-related recovery of SP-LI levels in the bladder as well as of the sensory-efferent functions. These findings indicate a role of the capsaicin-sensitive innervation of the urinary bladder in activating the spinal vesico-vesical reflex. The present findings suggest that measurement of SP-LI levels in the rat bladder may be a useful biochemical index for monitoring the function(s) of the capsaicin-sensitive, peptidergic sensory neurons.

Animals

Sensory neglect after lesions of substantia nigra or lateral hypothalamus: differential severity and recovery of function.

Sensory neglect was studied in cats after unilateral lesions of: lateral hypothalamus (LH); internal capsule (IC) adjacent to the LH; substantia nigra (SN) or the ventromedial hypothalamus (VMH). Special behavioral tests were employed to yield quantifiable data and also to exclude any confounding due to simple movement deficits. Lesions of SN or IC produced severe and enduring contralateral visual and somesthetic deficits and a facilitation of ipsilateral visual responsiveness. In contrast, LH lesions sparing the adjacent IC produced only weak and transient deficits and VMH lesions had no effects on sensory function. This suggests that lesions of the SN or its forebrain connections are important for producing sensory neglect and that sensory deficits after LH lesions are due to infringement on fibers of passage to or from the SN. Lesions which produced neglect often suppressed the amplitude of flash evoked responses in the ipsilateral caudate nucleus and visual and association cortex. However, these evoked potential effects were transient. There was no effect on the spontaneous EEG and this fails to support the hypothesis of a lack of hemispheric arousal in sensory neglect. The results are discussed in relation to nigrotectal projections and the process of attention. This lesion-behavior model is suggested for studies of recovery of function.

Animals

Effects of chronic dietary restriction on sensory-motor function and susceptibility to stressor stimuli in the laboratory rat.

Two sets of experiments describing the effects of chronic undernutrition on sensory-motor function and susceptibility to environmental stressors are described. In the first, Fischer 344 rats between 10 and 12 months of age were placed on an every-other-day feeding regimen. Behavioral tests designed to assess sensory function (auditory and visual thresholds), somato-motor competence (hang time from a horizontal wire, balance on a narrow beam, descent of a wire mesh pole), and sensory-motor integrity (auditory startle) were then conducted every 3 to 6 months. Chronic undernutrition significantly increased life span and increased somato-motor competence but did not affect sensory function or sensory-motor integrity. In the second set of experiments both acute and chronic dietary restriction impaired the ability of young adult Sprague-Dawley rats to effectively thermoregulate in response to a cold environment. Body temperature dropped more rapidly and recovered at a slower rate in the dietarily restricted animals. Fischer 344 rats maintained on a restricted diet for 16 months were similarly impaired. The latter findings suggest that techniques for extending life span based on laboratory animal models may have little relevance to either animals or humans living in their natural habitats where a wide variety of environmental stressors are encountered.

Animals

New autonomic and sensory neuropathy with loss of adrenergic sympathetic function and sensory neuropeptides.

A 30-year-old woman with longstanding dizziness was found to have a severe postural fall in blood pressure and a reduced skin axon-reflex flare response. Autonomic tests indicated selective impairment of adrenergic sympathetic function. Plasma noradrenaline, adrenaline, dopamine, and dopamine beta hydroxylase were undetectable. Skin biopsy specimens showed loss of tyrosine hydroxylase and neuropeptide Y (markers of adrenergic sympathetic fibres) and of substance P and calcitonin gene-related peptide (sensory neuropeptides). A sural nerve biopsy specimen showed severe depletion of unmyelinated fibres. The constellation of losses were compatible with nerve growth factor (NGF) deprivation, which was confirmed on assay. This new syndrome may be explained by loss of trophic action of NGF.

Adrenergic Fibers

Autonomic and sensory nerve function in diabetic foot ulceration.

Peripheral sensory and autonomic nerve dysfunction are thought to be crucial factors in the pathogenesis of diabetic foot ulceration. However, their relative importance is not known. In this study we have compared peripheral sensory nerve function and cardiac autonomic reflexes in 51 diabetics with a history of foot ulceration and 480 diabetic control subjects. In the diabetics with ulceration ankle reflexes were absent or impaired and vibration perception threshold reduced in 96.1% and 82.4%, respectively, compared with 40.8% and 25.8%, respectively, in control subjects (P less than 0.001). Cardiac autonomic tests were abnormal more frequently in the diabetics with ulceration and an autonomic score derived from four tests was abnormal in 62.8% of those with ulceration compared with 13.5% of those without ulceration (P less than 0.001). Discriminant analysis of the two groups of diabetes showed that an abnormal autonomic score was the best predictor of foot ulceration in diabetic patients.

Diabetic Neuropathies

[Sensory sphere function in children with enuresis].

The kinesthetic and acoustic analyzers were investigated in 62 enuretic and 50 healthy children. In patients, the sensitivity thresholds of the analyzers were substantially increased. The fall in function of the sensory sphere is a major pathogenetic factor of the disease.

Adolescent

Factors in prostate cancer metastasis.

Death related to prostate cancer is invariably due to the tumor metastasis (to lungs, skeleton and lymph nodes). Tumor cell metastatic behaviour is still poorly understood. The R3327 prostate tumor model in the male Copenhagen rat offers an opportunity to investigate the different aspects of metastatic processes in vivo and to evaluate effects of current and new treatment approaches. Lymphatic spread of cancer cells can be measured by determining volume of local load in successive draining lymph node stations. Surgical removal of primary tumor and inguinal lymph node shows that lymphatic metastasis in the R3327-MATLyLu tumor variant is a continuous progressive phenomenon, which starts already in early stages of tumor growth after subcutaneous transplantation. Spread to the lungs can be quantified by enumeration of macroscopically visible pleural lung colonies. Metastatic spread to the lungs can be mimicked by intravenous injection of monodispersed tumor cell suspension. Within 10 days pleural tumor colonies become visible. Effects of different agents and treatments like chemotherapeutic drugs, heparin, surgery and high energy shock wave (HESW) treatment have been described using these methods. Recently, metastasis to the vertebral column was induced by temporal occlusion of venous blood flow through the caval veins while injecting tumor cells in the lateral tail vein. The resulting osteoblastic metastatic lesions in the lumbar vertebrae and the concomitant spinal cord compression led in time to the loss of motoric and sensory function of the hind legs. These observations permit investigation of the mechanisms of bone metastasis based on biological functions, i.e. sensory and motoric function of the hind legs. Finally, it can be said that the various variants of the R3327 rat prostate tumor offer an appropriate model to study various aspects of prostate cancer and metastasis.

Animals

Discrimination strategies in animal psychophysics and their role in understanding sensory receptor function.

Discrimination is defined in a restricted sense here as a precise and specifiable relation between stimuli and responses. Experimenter control of stimulation is one significant feature of this relation. It is suggested that there may be some important differences between discrimination of drugs and exteroceptive stimulation. However, a discussion of current strategies in animal psychophysics might uncover similarities between these two discrimination formats useful in formulating questions and designing future research. Traditionally animal psychophysics has focused on basic questions of acuity and sensitivity (threshold). Beyond their obvious value in the study of comparative sensory function and evolutionary development, these experiments have provided particularly important new insights into the understanding of peripheral sensory transduction and processing and their relation to perception. Our experiments have been carried out in animals whose hearing has been impaired by drugs and cryolesions, and relations have been sought between the subsequent hearing loss and the histopathological changes occurring in the auditory receptor cells of the inner ear. But threshold sensitivity is only one of many perceptual dimensions and tells us nothing of the discriminations that are made among stimuli which are clearly above minimum detectable levels. For example, discriminations occur along stimulus dimensions such as wavelength of light, sound pressure, acoustic frequency, and so on. Sensory systems also permit the accurate location of the source of stimulation at a distance, the selection of certain frequencies or wavelengths and the rejection of others, and finally the discrimination among very complex but biologically useful signals such as speech. Prototypical experiments are described; the results suggest significant and orderly relations with peripheral sensory processing mechanisms. The power of operant behavior to examine perception from a variety of perspectives is discussed.

Animals

Dorsal spinal cord stimulation in the treatment of multiple sclerosis.

Previously published work indicated significant improvement in the symptoms of multiple sclerosis with dorsal spinal cord stimulation. In this study 23 patients with multiple sclerosis documented by history, examination, laboratory studies, and clinical course were treated with dorsal spinal cord stimulation and followed for 19 to 45 months (mean, 32 months). Pre- and postoperative clinical assessment was carried out using the Kurtzke Scale. Walking velocity, upper limb coordination, sphincter function, and sensory function were also evaluated quantitatively. No statistically significant objective improvement in any of these measures was demonstrated. Fifty per cent of the patients initially reported subjective symptomatic improvement, but this declined to 30% at last follow-up. Fifteen of 23 patients experienced complications related mainly to the hardware used and required a total of 21 subsequent operative procedures for correction of these complications. These results do not support the continued clinical use of dorsal spinal cord stimulation in the symptomatic treatment of multiple sclerosis.

Electric Stimulation Therapy

[Axillary brachial plexus block with lidocaine HCl and carbonated lidocaine].

An accordance with the clinical examination recommended by Lanz and Theiss, we studied 26 patients undergoing a blockade of the axillary plexus with lidocaine-CO2 or lidocaine-HCl. Furthermore, we determined the blood concentrations of these local anaesthetics. The study showed no significant differences between the two groups of patients, except that the onset of the blockade was more reliable in one group. There was less impairment of motor function than sensory function. Blood lidocaine concentrations amounted to 2.46 mg/l (mean value) within 25 min. Slight cerebral intoxication could be seen in four patients, with no correlation with possibly high lidocaine concentrations. Lidocaine CO2 is recommended as a rapid blockade of short duration in outpatient regional anesthesia.

Adolescent

Hyperthermia-induced damage to rat sciatic nerve assessed in vivo with functional methods and with electrophysiology.

A 5-mm segment of the rat sciatic nerve was treated in vivo with hyperthermia (43-45 degrees C) for different times using a brass thermode. The effect of this local heat treatment on the nerve was assessed with electrophysiology and using two functional assays. Hyperthermia led to a dose-dependent decrease of motor and sensory function. Electrophysiological examination showed a decrease in amplitude of motor and reflex responses rather than a decrease in conduction velocities. Calculated ED50 values were not significantly different for the two functional and for the electrophysiological methods. Functional recovery from nerve damage took place in all cases. Measured at the same level of damage, i.e., 50% function loss, it took 14 days to recover from complete sensory function loss and 20 days from complete motor function loss. Although both motor and sensory functions were restored, 30 days after hyperthermia no responses could be detected with electrophysiology, this as a result of the thin myelin sheaths that occur upon recovery.

Animals

Capsaicin-sensitive bronchopulmonary receptors with dual sensory-efferent function: mode of action of capsaicin antagonists.

It has been suggested that capsaicin-sensitive interoceptors subserve dual sensory-efferent function in sense of being sites not only for initiating sensory impulses but also for release of mediators. The efferent response of smooth muscle contraction to capsaicin was analyzed in vitro on the trachea and main bronchi of the guinea-pig. Tetrodotoxin-resistant neurogenic contraction of the trachea evoked by capsaicin was inhibited by pretreatment of the tissue with the mast cell depleting agent of compound 48/80. Pretreatment of the preparation with indomethacin or with antagonists of histamine and 5-HT caused no changes in the responses. Electrical field stimulation of the nerve fibres in the main bronchi induced prolonged capsaicin-sensitive bronchoconstriction. Participation of mast cells and particularly leukotrienes in the responses is suggested. Sensory effect and site of action of capsaicin and its antagonists at the pulmonary receptors were tested in vivo by recording the Bezold-Jarisch reflex in the rat. Ruthenium red (0.5-2 mg/kg i.v.) and resiniferatoxin (0.1 micrograms/kg i.v.) did not evoke the vagal reflex triad of bradycardia, fall in blood pressure and apnoea, but antagonized the effect of capsaicin. The cardiorespiratory reflex triad evoked by stimulation of the regenerative region of the receptors by veratridine was not inhibited by ruthenium red. Furthermore, bradycardia evoked by electrical stimulation of the vagal nerve remained unchanged after pretreatment of the rat with either ruthenium red or resiniferatoxin. It is suggested that capsaicin excites the generator region of the receptors. Ruthenium red and resiniferatoxin antagonize its effect at different sites of the capsaicin receptor coupled cation channel.

Animals

Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions.

The results of recent investigations designed to elucidate the neuroeffector functions of sensory fibres, the cause of migraine headache and the mechanism of action of antimigraine drugs are reviewed and discussed. Neurogenic inflammation (vasodilatation and neurogenic plasma extravasation) is one explanation for the development of headaches and the blood flow changes which occur during migraine headache. Numerous studies have recently been carried out on rats and guinea-pigs into the effects of antimigraine agents, including ergot alkaloids, sumatriptan and non-steroidal anti-inflammatory drugs (NSAIDs), on neurogenic plasma protein extravasation in the dura mater induced by electrical stimulation of trigeminal ganglia or systemic administration of capsaicin. It is known that the dura mater is able to produce headaches in man. Ergot alkaloids have been shown to block neurogenic inflammation via a C-fibre dependent neuronal mechanism. Sumatriptan appears to act fairly similarly although, whereas the ergot alkaloids are non-selective for either 5-hydroxytryptamine (5-HT; serotonin) receptors or 5-HT1, sumatriptan is selective for 5-HT1 receptors. The antimigraine action of NSAIDs may be via either an effect on blood vessels or an effect on the nerve fibre. The antimigraine effects of ergot alkaloids, sumatriptan and NSAIDs are discussed in the light of the common vasoconstrictor actions of these agents and knowledge that vasodilatation is apparently not responsible for migraine headache pain in most cases.

Animals

Introduction to the symposium on functional amblyopia: sensory or motor disorder?

The theme of the symposium is identified by 2 questions: (1) is the mechanism that underlies functional amblyopia sensory or motor? and (2) How do sensory and motor factors contribute to the loss of acuity in amblyopic eyes? The answers to these questions as well as to several questions about clinical diagnosis and treatment of amblyopia are provided in the following 7 papers and panel discussion that comprise this symposium.

Amblyopia

Impairment and recovery profiles of sensory-motor function following stroke: single-case graphical analysis techniques.

Graphical analysis procedures have been developed to improve interpretation of sensory-motor tests from individual subjects following acute brain damage. The procedures have been applied to 11 unilateral stroke patients assessed serially over 12 months on a computerized quantitative sensory-motor test battery of which grip strength, arm speed, and tracking have been chosen for illustrative purposes. The results indicate that four graphs are necessary to fully demonstrate neurologic impairment and recovery of each sensory-motor function, although fewer graphs would be satisfactory in some applications. Such analyses have proven valuable in the display of serial performance of individual patients but demonstration of impairment and recovery is much more difficult than for group analyses.

Activities of Daily Living

Heart rate development and sensory-evoked cardiac responses in perinatal rats.

Sensory-evoked changes in heart rate (HR) are often used to assess sensory function in infants, but HR measures have not been applied in studies of perinatal sensory function. Normative HR data are needed to judge whether baseline characteristics and response properties of the late fetal and newborn heart are appropriate as a dependent measure in sensory studies. We compared parameters of HR development and phasic cardiac responses to stimulation across the perinatal period in Norway rats. EKG was measured in cesarean-delivered prenatal rats (embryonic day 20-day of birth; conception = E0) and compared to both cesarean and vaginally delivered neonates (day of birth-postnatal day 2; birth = P0). Resting heart rate increased monotonically across the perinatal period, except between E21 and DOB (Experiment 1). During an hour-long test, HR was strong and stable. Variations in HR across successive measurement intervals (10 sec) were uniformly low (less than 2%) in all age groups. In Experiment 2, fetuses and neonates responded with dramatic HR decelerations (20-80 bpm) to an intraoral infusion of lemon extract. HR responses did not appear to be reflexively mediated by changes in respiration. These findings suggest that parameters of resting HR and cardiac responses to stimulation are well suited to studies of perinatal sensory function.

Animals

Correlation between sensory loss, functional disability and short-latency somatosensory evoked potentials in strokes.

Short-latency somatosensory evoked potentials (SEPs) were reviewed for their correlation with the clinical features and functional deficit of 64 patients with supratentorial deep or superficial ischemic strokes. Abnormal SEPs correlated with lesions of proprioceptive pathways and with clinical sensory impairment. 87% of patients with abnormal SEPs had sensory loss and 88% of those with normal SEPs had normal sensation. The reliability of the SEPs made them useful in an objective demonstration of an abnormality in sensory system function. However, they are not sensitive enough to be used as a method of prognostication because 1) the SEPs abnormalities depend on the involvement of their generators and therefore may be normal in some thalamic or cortical lesions associated with severe disability, 2) 48.4% of the patients studied had normal sensation, and 3) in the group with absent SEPs, the functional disability was poorer than in the group with normal SEPs, not in relation to the type of the sensory loss but to the volume and location of the infarcted area.

Activities of Daily Living