Pain, Dryness, and Itch Sensations in Eye Surface Disorders Are Defined By a Balance Between Inflammation and Sensory Nerve Injury.

Patients with corneal and conjunctival disorders report an array of ocular surface symptoms including stinging, foreign body sensation, and itching. The intensity and perceptual quality of these sensations and their duration, from brief intervals to long-term symptoms, also vary. We hypothesize that symptomatic differences across disorders reflect differences in the balance between ocular inflammation and nerve injury, with different conditions resulting from predominant effects of one of these, or a combined effect. This article provides an overview of corneal and conjunctival nerve cells, such as nociceptors and thermoreceptors, with descriptions of their morphological and molecular characteristics and their nerve-firing patterns and evoked sensations, as determined by earlier studies in animals and humans. Detailed descriptions of the changes in neuronal responses (such as abnormal responsiveness and spontaneous firing) due to local inflammation and nerve injury are provided, and assorted ocular surface disorders are discussed. Eye conditions in which inflammation is predominant include allergic conjunctivitis and photokeratitis, whereas nerve injury is the primary factor underlying complaints of dry eye after photorefractive keratectomy and in elderly patients. Both factors contribute substantially to dry eye disease and varicella-zoster infections. This model of the combined effects of inflammation and nerve injury serves to explain the different sensations reported in various eye surface disorders, including short-term versus chronic pain and dysesthesias, and may help to improve diagnoses and treatment methods.

Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: A behavioural and electrophysiological study.

BACKGROUND: Ocular surface diseases are among the most frequent ocular pathologies. Ocular pain following corneal injury is frequently observed in clinic. Corneal sensory innervation is supplied by ciliary nerves derived from ophthalmic division of the trigeminal ganglion. METHODS & RESULTS: Extracellular activity of the mouse ciliary nerve was first used to investigate the corneal responsiveness to chemical, mechanical and thermal stimulations in order to specifically study the responses of polymodal nociceptors, mechano-nociceptors and cold thermoreceptor in a control cornea. Then, in two models of corneal injury (repeated instillations of 0.02% benzalkonium chloride and corneal scraping), we first measured the corneal sensitivity to chemical (eye-wiping test) and mechanical (von Frey filaments) stimulation. Thereafter, we evaluated whether these corneal injuries modified the spontaneous and chemical stimulation-evoked activity of the ciliary nerve. Both models of injury induced a significant corneal chemical hypersensitivity correlated with an increase of the spontaneous activity of the ciliary nerve and a faster response of the ciliary nerve after a chemical stimulation. CONCLUSIONS: Overall, this study provides new insights into the functional aspects of corneal nerve fibre activity in mice after corneal injury. The increase in ciliary nerve activity may thus contribute to the development of ocular pain after corneal damage. SIGNIFICANCE: This study highlights the parallel increase in ciliary nerve activity and corneal sensitivity after corneal injury in mice. The strategy of combining ex vivo electrophysiological recordings of the ciliary nerve in mice and corneal sensitivity measurements therefore helps to uncover the functional aspects of corneal pain.

Impaired Nociception in the Diabetic Ins2+/Akita Mouse.

The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2+/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2+/Akita mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in Ins2+/Akita dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplantation also restored Ins2+/Akita intraepidermal nerve fiber density to the same level as wild-type mice, indicating that restored insulin production can reverse both sensory and anatomical abnormalities of diabetic neuropathy in mice. The reduced rate of action potential discharge in nociceptive fibers and the impaired heat responsiveness of Ins2+/Akita DRG neurons suggest that ionic sensory transduction and transmission mechanisms are modified by diabetes.

Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy.

Purpose: To define the characteristics and time course of the morphologic and functional changes experienced by corneal sensory nerves after photorefractive keratectomy (PRK). Methods: Unilateral corneal excimer laser photoablation was performed in 54 anesthetized 3- to 6-month-old mice; 11 naïve animals served as control. Mice were killed 0, 3, 7, 15, and 30 days after PRK. Excised eyes were placed in a recording chamber superfused at 34°C. Electrical nerve impulse activity of single sensory terminals was recorded with a micropipette applied onto the corneal surface. Spontaneous and stimulus-evoked (cold, heat, mechanical, and chemical stimuli) nerve terminal impulse (NTI) activity was analyzed. Corneas were fixed and stained with anti-ß-Tubulin III antibody to measure nerve density and number of epithelial nerve penetration points of regenerating subbasal leashes. Results: Nerve fibers and NTI activity were absent in the injured area between 0 and 7 days after PRK, when sparse regenerating nerve sprouts appear. On day 15, subbasal nerve density reached half the control value and abnormally responding cold-sensitive terminals were recorded inside the lesion. Thirty days after PRK, nerve density was almost restored, active cold thermoreceptors were abundant, and polymodal nociceptor activity first reappeared. Conclusions: Morphologic regeneration of subbasal corneal nerves started shortly after PRK ablation and was substantially completed 30 days later. Functional recovery appears faster in cold terminals than polymodal terminals, possibly reflecting an incomplete damage of the more extensively branched cold-sensitive axon terminals. Evolution of postsurgical discomfort sensations quality may be associated with the variable regeneration pattern of each fiber type.

Assessment of thermotactile and vibrotactile thresholds for detecting sensorineural components of the hand-arm vibration syndrome (HAVS).

BACKGROUND: Thermotactile thresholds and vibrotactile thresholds are measured to assist the diagnosis of the sensorineural component of the hand-arm vibration syndrome (HAVS). OBJECTIVES: This study investigates whether thermotactile and vibrotactile thresholds distinguish between fingers with and without numbness and tingling. METHODS: In 60 males reporting symptoms of the hand-arm vibration syndrome, thermotactile thresholds for detecting hot and cold temperatures and vibrotactile thresholds at 31.5 and 125 Hz were measured on the index and little fingers of both hands. RESULTS: In fingers reported to suffer numbness or tingling, hot thresholds increased, cold thresholds decreased, and vibrotactile thresholds at both 31.5 and 125 Hz increased. With sensorineural symptoms on all three phalanges (i.e. numbness or tingling scores of 6), both thermotactile thresholds and both vibrotactile thresholds had sensitivities greater than 80% and specificities around 90%, with areas under the receiver operating characteristic curves around 0.9. There were correlations between all four thresholds, but cold thresholds had greater sensitivity and greater specificity on fingers with numbness or tingling on only the distal phalanx (i.e. numbness or tingling scores of 1) suggesting cold thresholds provide better indications of early sensorineural disorder. CONCLUSIONS: Thermotactile thresholds and vibrotactile thresholds can provide useful indications of sensorineural function in patients reporting symptoms of the sensorineural component of HAVS.

Pathophysiology of empty nose syndrome.

OBJECTIVES/HYPOTHESIS: To review current knowledge on nasal airflow sensation in relation to empty nose syndrome (ENS). STUDY DESIGN: PubMed searches. METHODS: Current literature pertaining to measurement of nasal patency, mechanism of sensory perception of nasal airflow, and ENS. RESULTS: A reliance on pure anatomical analysis of the anatomy in ENS falls short of explaining the disorder. Our understanding of subjective nasal sensation has advanced, as has our understanding of the flow of air through the nose. Neural healing following a surgical insult may not result in a return to a normal physiologic state. Aberrations in neurosensory systems from improper healing may play a major role in the abnormal sensations ENS patients experience. CONCLUSIONS: An evidence-based hypothesis for the development and symptoms of ENS is offered.

Corneal sensory nerve activity in an experimental model of UV keratitis.

PURPOSE: To produce in guinea pigs a UV-induced keratitis, to analyze the effects of this pathology on corneal nerve activity. METHODS: In anesthetized animals, one eye was exposed to 254 nm UV-C radiation (500-1000 mJ/cm(2)), excised 24 to 48 hours later and superfused in vitro. Nerve impulse activity was recorded in ciliary nerve filaments or in corneal sensory terminals of intact and UV-irradiated eyes. Impulse activity in response to mechanical (von Frey hairs), chemical (98.5% CO2 gas jets), and thermal stimulation (cooling from 34°C to 20°C; heating to 50°C) was analyzed. Duration of eyelid closure and blinking and tearing rates were evaluated in control and in UV-irradiated eyes, before and after application of TRPV1, TRPA1, and TRPM8 agonists (100 µM capsaicin; 10 mM AITC, and 200 µM menthol, respectively). RESULTS: After irradiation, mechanical threshold of mechano-nociceptor corneo-scleral fibers was reduced (0.59 ± 0.4 vs. 0.27 ± 0.07 mN; P < 0.05) while polymodal nociceptors increased their response to chemical stimulation (1.7 ± 0.2 vs. 3.4 ± 0.5 imps/s; P < 0.05). In contrast, cold thermoreceptors showed a significantly lower ongoing activity at 34°C (8.6 ± 0.5 vs. 6.1 ± 0.9 imp/s; P < 0.05) and a reduced responsiveness to cooling pulses (peak frequency = 29.8 ± 1.3 vs. 18.9 ± 1.8 imp/s; P < 0.001). Blinking but not tearing rate was significantly higher; behavioral responses to topical capsaicin and AITC, but not to menthol were enhanced in UV-irradiated animals. CONCLUSIONS: Sensitization of nociceptor and depression of cold thermoreceptor activity following UV radiation appear to result from an action of inflammatory mediators on TRP channels selectively expressed by sensory nerve terminals. Changes in nerve activity possibly underlie discomfort sensations associated with corneo-conjunctival inflammation induced by UV exposure.

[Antipyretic effect of moxibustion at different temperatures and its relationship with the activity of temperature sensitive neurons in thermotaxic center].

OBJECTIVE: To discover the central mechanisms of antipyretic effect of moxibustion and its relationship with the acupoint sensor so as to provide the scientific evidence for "the treatment of heat syndrome with moxibustion". METHODS: Eighteen New Zealand Rabbits were randomly assigned into three groups, named group A (modeling with intravenous injection of Endotoxin), group B (moxibustion at 40 degrees C after Endotoxin injection) and group C (moxibustion at 48 degrees C after Endotoxin injection), 6 rabbits in each one. The experiment was undergoing in the condition of muscular relaxation and artificial respiration for the animals. The spotlight moxibustion at constant temperature was applied to "Zhiyang" (GV 9). The discharge of heat sensitive neurons (HSNs) at the preoptic region and anterior hypothalamus (POAH) was taken as the index. The impacts of the treatment on HSNs were observed in each group. RESULTS AND CONCLUSION: Moxibustion had significant antagonism to the pyrogen on its inhibition to the activity of HSNs in the thermotaxic center. As a result, the antipyretic effect was obtained. It is concluded that the effective result of moxibustion is achieved by stimulating polymodal receptors of acupoints.

Central circuitries for body temperature regulation and fever.

Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E(2) produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia.

Warm immersion recovery test in assessment of diabetic neuropathy--a proof of concept study.

The aim of this article was to present results of warm immersion recovery test in the diabetic foot with neuropathy using a liquid crystal-based contact thermography system. It is intended to provide a 'proof of concept' for promoting the role of supplementary thermal assessment techniques and evidence-based diagnosis of diabetic neuropathy. A total of 81 subjects from the outpatient department of MV Hospital for Diabetes, India, were assessed using a liquid crystal thermography system. Each subject was assigned to one of three study groups, that is diabetic neuropathy, diabetic non neuropathy and non diabetic healthy. The room temperature and humidity were consistently maintained at 24 degrees C and less than 50%, respectively, with air conditioning. The right foot for each subject was located on the measurement platform after warm immersion in water at 37 degrees C. Whole-field thermal images of the plantar foot were recorded for 10 minutes. Local measurements at the most prevalent sites of ulceration, that is metatarsal heads, great toe and heel, show highest temperature deficit after recovery for diabetic neuropathy group. The findings of the current study support the ones of a previous study by the authors, which used cold immersion recovery test for the neuropathic assessment of the diabetic foot. A temperature deficit between the recovery and the baseline temperature for the neuropathic group suggests degeneration of thermoreceptors. Thermal stimulus tests can be useful to validate the nutritional deficits' (during plantar loading and thermal stimulus) contribution in foot ulceration.

Background pain in fibromyalgia patients affecting clinical examination of the skin.

The purpose of this study was to investigate the relationship between on-going pain and acute thermal pain in patients suffering from chronic pain. This experimental study in cold and heat sensitivity was performed in order to test the following hypothesis: that fibromyalgia patients scoring high in current background pain tolerate less experimental thermal pain in the skin than patients with low scores. Ethical aspects of the study are discussed. The level of tolerable experimental thermal stimuli was tested and compared between the 'low-score' and the 'high-score' patients. Background pain seemed to affect the intensity of experimental cold pain. Clinical routine examinations and bodily care of the skin that might interfere with background pain in the fibromyalgia patients are discussed. Clinical practice should be carefully planned in order to assist fibromyalgia patients in understanding and coping with thermal conditions that might influence background pain.

Ice-water test in the urodynamic evaluation of spinal cord injured patients.

The purpose of this study was to determine the clinical utility of the ice-water test (IWT) during urodynamic evaluation in spinal cord injured (SCI) patients. Thirty-two suprasacral SCI patients with documented detrusor hyperreflexia (DH) underwent urodynamic study and IWT. Fifteen patients had repeated testing 2 weeks later. The IWT was performed with the patient in the supine position; 100 mL of sterile saline water at 4-8 degrees C was injected manually. If cystometric capacity was <200 mL, a volume of about 50% of the individual cystometric bladder capacity was used. The cold fluid was left within the bladder for 3 minutes. The test was considered positive if an involuntary bladder contraction > or =15 cm H2O was registered. All patients with cervical or thoracic level SCI had DH, which had 100% test-retest reproducibility on urodynamics. Seventy-two percent of patients with DH had a positive IWT and 28% had a negative IWT. IWT (same volume, 2 weeks later) in 4 (27%) of the 15 repeated tests gave different responses. Autonomic hyperreflexia, manifested as systolic blood pressure increase > or =50 mm Hg within 3 minutes of ice-water instillation, occurred in 16 (57%) of 28 patients with lesions above T7. In SCI patients, the IWT did not contribute to their management because of the insensitivity and nonspecificity. Autonomic hyperreflexia can occur during evaluation. The IWT did not influence clinical management in this group of SCI patients.

Thermoregulatory dysfunction in neuroleptic malignant syndrome.

Hyperthermia is the central feature of neuroleptic malignant syndrome (NMS), but its etiology remains elusive. Two competing hypotheses implicate either hypothalamic dysfunction (inappropriate "set point") or direct myotoxicity (excessive peripheral heat production). These two models have distinct implications for thermoregulatory activity in NMS. The first predicts that the individual should respond as to a hypothermic threat or infection (the hypothalamus signals the body to raise its temperature). The second implies that an excessive heat load is perceived by the hypothalamus, which responds to this hyperthermic threat (it signals the body to lower its temperature). To assess the validity of these two hypotheses the thermoregulatory responses of a series of NMS patients (36 patients, 46 episodes) were examined using standard statistical methods. In contrast to normal mammalian thermoregulatory behavior, thermoeffector responses were not organized into either mode, but appeared to function somewhat independently and paradoxically. We conclude that neither hypothesis is sufficient to explain altered thermoregulation in NMS, and that the loss of integrated thermoeffector activity may be unique to this disorder.

Thermal threshold determination in alcoholic polyneuropathy: an improvement of diagnosis.

Reports on the incidence of alcoholic polyneuropathies are variable depending on diagnostic tools. In this study, 50 chronic alcoholics with positive MALT (Munich Alcoholism Test) and greater than seven years history of excessive alcohol abuse were examined neurologically. Tibial and peroneal motor and sural nerve conduction velocities (NCV) were studied. Warm and cold perception was evaluated in the area behind the internal malleolus using a Somedic-Thermotest. Thresholds were determined by the method of limits. The effect of a slow, medium and fast temperature change rate on thermal perception was tested. Thirty-eight patients (76%) showed signs of neuropathy. Thermal perception was more often abnormal (62%) than NCV (42%) and clinical examination (56%). A medium temperature change rate of 2.0-2.5 degrees C/s was the most sensitive index of small fiber neuropathy. Thermal threshold measurement proved to be a reliable, sensitive and easy to perform method that should become standard in the examination of polyneuropathies.

Pain responsivity in major depression and bipolar disorder.

Signal detection theory measures of thermal pain responsivity were examined in patients with major depression and bipolar disorder and in control subjects. Patients with major depression had significantly poorer sensory discrimination of painful thermal stimuli than control subjects, but they did not differ from the control subjects in their sensory discrimination of warm thermal stimuli of lower intensity. Patients with bipolar disorder did not differ significantly in sensory discrimination from either the patients with major depression or the control subjects. Patients with major depression had significantly higher (i.e., more stoical) response criteria than the control subjects for the painful thermal stimuli and also for the lower intensity stimuli; patients with bipolar disorder had significantly higher criteria than control subjects for only the lower intensity stimuli. The results suggest that reduced responsivity to pain in major depression may reflect sensory as well as affective abnormalities. Complaints of pain are very common in mood disorders, and continued examination of experimental pain in individuals with these disorders has the potential to enhance our understanding of this phenomenon.

The influence of heat and cold on the pain threshold in rheumatoid arthritis.

Superficial heat and cold are commonly used therapeutic methods in patients with rheumatoid arthritis. Both procedures have analgesic effect. In 30 inpatients with rheumatoid arthritis the pain threshold was measured before and after warm bath and ice massage. Rheumatoid patients had significantly lower pain threshold compared to the healthy subjects in normal circumstances. Heat and cold remarkably raise the pain threshold right after the application. The pain threshold is also raised 10 and 30 min after cryotherapy, but not after the warm bath. Between investigated groups there were no statistically significant differences in the pain threshold values in any observed time. We consider that both methods have a reasonable place in the therapy of rheumatoid arthritis.

Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus.

1. We have studied the sensations evoked by threshold microstimulation (TMS) in the area of the human principal sensory nucleus of the thalamus [ventralis caudalis (Vc)] in patients (n = 11) undergoing stereotactic surgery for the treatment of movement disorders and pain. Preoperatively, patients were trained to describe somatic sensory stimuli using a standard list of descriptors. This same list was used to describe sensations evoked intraoperatively by thalamic microstimulation. Stimulation sites (n = 216) were defined by location within the area where the majority of cells had a reproducible response to innocuous cutaneous stimulation (core region) or in the cellular area posterior and inferior to the core region (posteroinferior region). 2. TMS-evoked sensations were categorized as paresthetic if the descriptors "tingle," "vibration," or "electric current" were chosen by the patient to describe the sensation and as thermal/pain if the descriptors "cool," "warm," "warm and cool," or "pain" were chosen. Thermal/pain sensations were evoked by stimulation in 82% (9/11) of patients and at 19% of sites studied. These results suggest that thalamic microstimulation can evoke thermal/pain sensations reproducibly across patients. 3. Thermal/pain sensations were evoked more frequently by stimulation at sites in the posteroinferior region (30%) than by stimulation at sites in the core region (5%). Nonpainful thermal sensations composed the majority of thermal/pain sensations evoked by stimulation in both the core (80%) and posteroinferior regions (86%). Sites where stimulation evoked pain and nonpainful cool sensations were found anterior to the area where nonpainful warm sensations were evoked. Thermal/pain sensations were evoked at sites located medially near the border between the core and posteroinferior regions. 4. Radiologic techniques were used to determine the presumed nuclear location of stimulation sites. Thermal/pain sensations were evoked less frequently by stimulation in the part of Vc included in the core region than by stimulation in any of the following: the part of Vc included in the posteroinferior region, ventralis caudalis portae nucleus, ventralis caudalis parvocellularis nucleus, or the white matter underlying the ventral nuclear group. 5. The location of the sensation evoked by stimulation [projected field (PF)] varied widely in size. PFs were categorized as large if they involved more than one part of the body (e.g., face and arm) or if they crossed at least one joint proximal to the metacarpophalangeal joint or to the metatarsophalangeal joint. PFs were more frequently large at sites where thermal/pain sensations were evoked by TMS (33%) than at those where paresthesia were evoked (6%).(ABSTRACT TRUNCATED AT 400 WORDS)

Vibratory and thermal thresholds in diabetics with and without clinical neuropathy.

Vibration and thermal detection threshold and heat pain threshold were determined in 34 diabetics scrutinized for clinical neuropathy using a standardized questionnaire and examination form. On the basis of the clinical grading patients were classified as having either no neuropathy or a neuropathy of increasing severity. As expected thermal and vibratory detection threshold increased with increasing severity of neuropathy. Comparison between diabetics without symptoms and signs of neuropathy and a corresponding non-diabetic control group showed that a warm sensibility index (WSI = the range in which non-noxious heat is perceived) was significantly lower on feet in diabetics than in their matched non-diabetic controls. The findings show that quantitative assessment of thermal sensitivity may be of value to detect early small nerve fiber dysfunction even in patients without symptoms or signs of a clinical neuropathy.

[Raynaud's phenomenon]. / Fenomenologiia Reino.

Raynaud's phenomenon is a pathological condition with a multicomponent pathogenesis characterizing the community of mechanisms of the reactivity of the terminal microvessels of the extremities in response to standard stimulation. Raynaud's phenomenon is not a nosological form. In discovering Raynaud's phenomenon, however, differential diagnosis must be conducted to recognize the disease which caused the phenomenon. The diagnosis of Raynaud's disease, which is a nosological form, can be established by the method of exclusion of all such diseases. Raynaud's syndrome in the existence of diseases which are the primary cause is merely a precise diagnostic formulation.