A new tactile skin sensor for measuring skin hardness in patients with systemic sclerosis and autoimmune Raynaud's phenomenon

We used a new tactile sensor to measure the elastic properties of skin in patients with systemic sclerosis or Raynaud's phenomenon. The sensor consists of a piezoelectric vibrator with vibration pickup to measure frequency changes when the sensor is placed on the skin. The mean frequency change at the skin surface of the proximol third phalanx in patients with systemic sclerosis was significantly lower than in age- and sex-matched controls. The results in systemic sclerosis patients were statistically correlated to the Modified Rodnan Skin Thickness Score. This technique was also used to measure the therapeutic efficacy of salpogrelate, a new specific serotonin receptor antagonist. A greater mean frequency change was seen after treatment. We conclude that this new tactile sensor is useful for quantitatively measuring skin sclerosis and may help determine the efficacy of therapeutic treatments.     

Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P < 0.05) and greater increases in sympathetic activity than breath holds (P < 0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.     

Facilitation of the responses of primate spinothalamic cells to cold and to tactile stimuli by noxious heating of the skin

Spinothalamic tract cells in anesthetized monkeys were found to respond to noxious cold stimuli ($\text{18}\text{19}$ cells tested), as well as to noxious heat and noxious mechanical stimuli. Responses to repetition of the noxious cold stimuli after a series of noxious heat stimuli were enhanced. However, subtraction of the enhanced background activity that resulted from damage of the skin revealed that the enhanced responses to noxious cold stimuli were due to superposition of the original responses upon an enhanced background activity, rather than to sensitization of the responses to noxious cold stimuli per se. Furthermore, the responses to innocuous mechanical stimuli applied either within the area that was damaged or outside this area were enhanced, provided the noxious heat was applied for a long enough time. Thus, damage to a region of skin can result in enhanced responsiveness of spinothalamic cells to stimuli applied in an undamaged region of the receptive field. The possible relationship between these observations and cutaneous hyperalgesia is discussed.     

Diphenhydramine produces local cutaneous analgesia in response to dorsal skin noxious stimuli in the rat

Although diphenhydramine has been shown to produce longer duration of spinal block than lidocaine, few studies disclose its skin infiltrative anesthesia when compared with a long‐lasting local anesthetic, bupivacaine. The purpose of this study was to investigate whether diphenhydramine elicited cutaneous analgesia in comparison with bupivacaine. After inhibition of cutaneous trunci muscle reflex via subcutaneous injection of drugs in rats, we examined the local anesthetic effect of diphenhydramine and bupivacaine as infiltrative cutaneous analgesia in a dose‐dependent fashion. We showed that diphenhydramine, as well as bupivacaine displayed a dose‐dependent cutaneous analgesia in response to dorsal cutaneous noxious stimuli. The relative potency (50% effective dose) was bupivacaine (0.023 [0.013–0.035]%) > diphenhydramine (0.078 [0.068–0.091]%; P < 0.001). On an equipotent basis, diphenhydramine had a similar duration of action to bupivacaine. Neither local injection of saline nor intraperitoneal administration of a large dose of diphenhydramine or bupivacaine produced cutaneous analgesia (data not shown). We conclude that diphenhydramine is less potent than bupivacaine at producing cutaneous analgesia. At equipotent doses for infiltrative cutaneous analgesia, the duration of action of diphenhydramine is equal to that of bupivacaine.     

Anomalous anticipatory skin conductance response to acoustic stimuli: experimental results and speculation about a mechanism

OBJECTIVES: The primary aim of this study was to conduct a replication, simplification, and extension of similar previous studies that claimed anomalous anticipatory skin conductance responses prior to various stimuli and to provide sufficient protocol and analysis details in order to foster additional replications. A secondary aim was to provide a testable model in order to understand the observed results. DESIGN: We used standard skin conductance measures and techniques to search within 50 participants for responses prior to 1-second duration, 97-dB acoustic stimuli, compared to prior to silent controls. We used an interstimulus interval randomly and uniformly distributed between 30 and 50 seconds. OUTCOME MEASURES: The dependent variable was the difference between proportions of 3.5-second prestimulus intervals prior to acoustic stimuli and prior to silent controls that contained a fully formed, nonspecific skin conductance response (ns-SCR). The null hypothesis was that the proportion difference should be zero. RESULTS: We found a significant proportion difference of 0.032 (Z = 2.08; effect size = 0.077 +/- 0.037; p(1t) = 0.0018), which is a replication of earlier similar studies. CONCLUSIONS: We examined and ruled out a number of potential artifacts that might have accounted for this finding. To understand these results, we demonstrated, by Monte Carlo techniques, that a possible explanation is that experimenters may have used their own intuition to initiate experiment runs to somehow sort otherwise random nonspecific skin conductance responses into appropriate bins in order to mimic physiological responses. We found experimental evidence to support this idea as an operational mechanism. If this speculation is confirmed in prospective studies, then this intuition-based mimicking of effects may profoundly impact the interpretation of results from complementary and alternative medical studies that use statistical inference to assess outcomes.     

Differential fMRI activation to noxious heat and tactile stimuli in parasylvian areas of new world monkeys

Emerging evidence supports an important role of posterior parasylvian areas in both pain and touch processing. Whether there are separate or shared networks for these sensations remains controversial. The present study compared spatial patterns of brain activation in response to unilateral nociceptive heat (47.5°C) or innocuous tactile stimulation (8-Hz vibration) to digits through high-resolution functional magnetic resonance imaging (fMRI) in squirrel monkeys. In addition, the temporal profile of heat-stimulus-evoked fMRI Blood Oxygenation Level Dependent (BOLD) signal changes was characterized. By examining high-resolution fMRI and histological measures at both the individual and the group levels, we found that both nociceptive heat and tactile stimuli elicited activation in bilateral secondary somatosensory and ventral parietal areas (S2/PV) and in ipsilateral ventral somatosensory areas (VS) and retroinsula (Ri). Bilateral posterior insular cortex (pIns) and area 7b responded preferentially to nociceptive heat stimulation. Single voxels within each activation cluster showed robust BOLD signal changes during each block of nociceptive stimulation. Across animals (n = 11), nociceptive response magnitudes of contralateral VS and pIns and ipsilateral Ri were significantly greater than corresponding areas in the opposite hemisphere. In sum, both distinct and shared areas in regions surrounding the posterior sylvian fissure were activated in response to nociceptive and tactile inputs in nonhuman primates.     

Nociceptor sensitization to mechanical and thermal stimuli in pig skin in vivo

Primary hyperalgesia to mechanical and thermal stimuli are major clinical symptoms of inflammatory pain and can be induced experimentally by ultraviolet‐B (UV‐B) irradiation in humans. We set‐up a pig model in order to have more options for pharmacological intervention on primary hyperalgesia. Pig skin was irradiated with a dose one‐ to threefold higher than the minimum erythema dose (MED) and investigated for mechanical and heat responsiveness 24 and 48h post UV‐B treatment. C‐fiber activation upon mechanical and thermal stimulation was assessed indirectly by extent of the axon reflex erythema (flare) measured by laser Doppler imaging. Mechanical stimulation with von Frey filaments (100mN) induced flare responses in UV‐B treated skin at 24 and 48h, but no effect was measured in normal untreated skin. Increased mechanical stimulation (600mN) elicited a small flare response in normal skin in an area of 1.8cm² on average that was extending about 2.5cm² in the UV‐B irradiated sites. Thermal stimuli provoked in normal pig skin flare areas of approximately 2cm² (45°C, 10s) and 4.5cm² (47°C, 10s) which increased to about 3.5cm² (45°C) and 5.5cm² (47°C) following UV‐B irradiation at 24 and 48h. No significant differences of mechanically or thermally induced hypersensitivity were seen between 24 and 48h after irradiation. We conclude that UV‐B induced mechanical and heat sensitization of primary afferent nociceptors can be assessed in pig skin, providing a new human‐like model of primary hyperalgesia. Sensitization of primarily mechano‐insensitive (silent) nociceptors, which are underlying the flare response in humans, most probably contributes to the observation presented here.     

Hypothalamus and amygdala response to acupuncture stimuli in Carpal Tunnel Syndrome

Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI-4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short-term brain response to acupuncture stimulation, as well as the influence of longer-term acupuncture therapy effects on this short-term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non-specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala – the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter-digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.     

Characteristic renal excretion patterns in response to physiological,pathological and pharmacological stimuli

• 1.1. The effect of several factors on the renal output of water, sodium, potassium and creatinine, and, in some patients, also of protein and other substances was studied in consecutive 3-h periods under standard conditions. Since the diurnal rhythm cannot be eliminated, the effect of all other factors was evaluated against the background of the large but regular variations of the diurnal excretory rhythm found on control days. It was demonstrated that this elaborate method is indispensable for the study of phenomena of short duration.
• 2.2. The three principal types of physiological diuresis and antidiuresis associated with diurnal rhythm, osmoregulation and circulatory homoeostasis (“volume regulation”) appeared to be characteristic and could be distinguished from each other and from the effect of external agents.
• 3.3. The possible mechanism of the diurnal excretory rhythm is discussed on the basis of differences and similarities in the excretion pattern of several substances. The large parallel variations in sodium and potassium excretion were similarly found in patients with and without significant fluctuations in creatinine output.
• 4.4. A tendency to nycturia could be demonstrated in many patients in spite of continuous bedrest. Nycturia could be attributed to an excessive influence of circulatory homoeostasis overruling the diurnal rhythm. Normal excretory rhythm was always re-established by strict recumbency and inactivity. Patients in whom factors were present favouring an insufficient or an excessive circulation appeared to be prone to nycturia.
• 5.5. The effect of pharmacological doses of hormones was compared with excretion patterns found in endocrine diseases. The excretion pattern was found to be characteristic in Cushing's disease and in glucocorticoid deficiency unaccompanied by miner-alocorticoid deficiency. In the latter condition a non-postural type of nycturia concerning only water output was found.
• 6.6. The effect of ACTH on the renal excretion pattern was shown to be a relatively simple and reliable test for adrenocortical insufficiency.
• 7.7. The characteristic excretion patterns induced by different diuretics are shown. The influence of hyperaldosteronism on the response to diuretics is demonstrated.
• 8.8. Protein excretion varies considerably under the influence of the diurnal rhythm even when the creatinine output shows no appreciable fluctuations. Variations in water and sodium excretion resulting from circulatory homoeostasis or induced by diuretics are only accompanied by changes in protein excretion when creatinine output is appreciably altered. Renal protein output is directly related to variations in the serum albumin concentration.
     

Withdrawal reflex,skin resistance reaction and pain ratings due to electrical stimuli in man

Simultaneous measurements of pain rating, withdrawal reflex, and skin resistance reaction with non-painful and painful electrical stimuli were performed on 15 healthy male volunteers. Eight different intensities were delivered in standardized randomized order. Each intensity appeared 10 times.There was no influence of the preceding stimulus on responses to the following stimulus. Neither skin resistance reaction nor withdrawal reflex were specific for pain in the sense that they appeared solely when pain was reported; the two reaction threshold currents were significantly smaller than the pain threshold. The reaction amplitudes, however, showed a close correlation to the intensity of sensation. The relations between all reactions measured and stimulus strength could be described best by power functions, with an exponent ? 1 if least square fits in linear scales were performed. Graphical evaluation in double logarithmic scales led to systematic errors causing higher exponents. Compound relations, like skin resistance reaction or withdrawal reflex amplitude as function of subjective estimation, could also be approximated by power functions, with parameters predictable from stimulus-reaction functions. No change in exponent was observed when subjective estimation turned from pre-pain to pain.     

多频稳态诱发电位在豚鼠中的检测分析

目的:探讨同步多频听觉稳态诱发电位在豚鼠听力检测中的应用。方法:健康杂色豚鼠20只(雌性12只,雄性8只),分别进行同步多频听觉稳态诱发电位测试。同步多频听觉稳态诱发电位刺激声信号的载波频率为0.5kHz、1kHz、2kHz及4kHz。双耳上述各个频率分别以77～103Hz不同的调制频率进行调幅调制。测试时,双耳8个(每耳4个)声信号经插入式耳机同步给出。测试状态为戊巴比妥钠镇静睡眠。所有数据以SPSS统计软件分析。结果:同步多频听觉稳态诱发反应阈,在0.5kHz、1kHz、2kHz及4kHz的平均值及标准差分别为左耳:(31.00±16.19)dBSPL,(25.50±12.34)dBSPL,(18.00±6.96)dBSPL,(18.50±6.71)dBSPL;右耳:(35.00±14.33)dBSPL,(25.50±12.37)dBSPL,(20.00±9.37)dBSPL,(20.00±9.18)dBSPL。左右耳同频率之间的差异无统计学意义。结论:同步多频听觉稳态诱发电位测试具有频率特异性、客观的特点,可以作为豚鼠听力测试的备选方法。     

Microvascular response in guinea pig skin to histamine challenge with and without application of skin window

We measured the microvascular response to histamine in guinea pig skin. Histamine (40 mg ml(-1)) was given either as a skin prick test or applied topically onto a skin window. The skin window was prepared by applying suction and gentle warming to the skin so that a blister was formed, and by removing the top of the blister. The microvascular response was measured as the accumulation of radiolabelled transferrin in the skin in vivo, reflecting a combination plasma exudation and vasodilatation. In the control (saline) challenge, the response was slightly greater in the skin window than after skin prick challenge and the scatter was larger. Histamine challenge resulted in a significant microvascular response with respect to the control situation when measured immediately after provocation for both challenge techniques. Ten minutes after challenge, a smaller response was measured, which was still significantly greater than control for the skin prick challenge, but not for topical provocation using the skin window technique. We conclude that the microvascular response to histamine after provocation with the skin prick technique is similar to that after topical provocation using the skin window technique. The skin window technique may have a lower sensitivity than the skin prick technique owing to a higher scatter in the control situation. This difference should be considered when performing and interpreting studies of the microvascular reaction in the skin.     

A human skin explant model to study molecular changes in response to fractional photothermolysis: Spatio-temporal expression of HSP70

Background and objectivesAblative fractional photothermolysis (AFP) is a new concept to treat aged skin. Despite growing clinical experience, little is known about the molecular changes induced over time by AFP in the targeted skin compartments. This is due, in part, to difficulties in obtaining multiple skin biopsies from AFP-treated individuals. In an attempt to circumvent these limitations, a human skin explant model was designed. In order to test its suitability as a model to study molecular changes induced by AFP, the spatio-temporal expression of heat shock protein 70 (HSP70) has been investigated in response to AFP at different pulse energies.Materials and methodsAFP was performed using a scanned 250 μm CO₂-laser beam. The ablative single pulse energies were set to 50, 64 and 300 mJ at 150 ablation zones per cm². The immediate response to AFP, as well as a response 1, 3 or 7 days after AFP, was studied; untreated skin explants served as a control. Additionally, intradermal injections of transforming growth factor β (TGF-β) on day 0 served as a positive control for HSP70 induction in non-laser-treated samples, cultivated over 7 days. A routine pathology workup and immunohistochemistry (HSP70) was performed in all untreated (control group and positive control samples) and AFP-treated samples. In summary, a total of 245 samples were investigated.ResultsIn this explant model, HSP70 showed a clear time-dependent induction by AFP with expression profile being most prominent in the epidermis, a marked up-regulation at 1 h following AFP, peaking between 1 and 24 h post-treatment, only then to decline significantly within the following 7 days.ConclusionThe human skin explant model can be used to bridge the gap between in vitro cell culture experiments and in vivo investigations to study the spatio-temporal effects of AFP on human skin. Specifically, CO₂-laser AFP of skin explants resulted in an energy-dependent, short-lived up-regulation of HSP70 expression predominantly in the epidermal compartment.     

Different neural systems adjust motor behavior in response to reward and punishment

Individuals use the outcomes of their actions to adjust future behavior. However, it remains unclear whether the same neural circuits are used to adjust behavior due to rewarding and punishing outcomes. Here we used functional magnetic resonance imaging (fMRI) and a reward-providing reaction time task to investigate the adaptation of a simple motor response following four different outcomes (delivery versus omission and monetary gain versus loss). We found that activation in the thalamus and insula predicted adjustments of motor responses due to outcomes that were cued and delivered, whereas activation in the ventral striatum predicted such adjustments when outcomes were cued but omitted. Further, activation of OFC predicted improvement after all punishing outcomes, independent of whether they were omitted rewards or delivered punishments. Finally, we found that activity in anterior cingulate predicted adjustment after delivered punishments and activity in dorsal striatum predicted adaptation after delivered rewards. Our results provide evidence that different but somewhat overlapping circuits mediate the same behavioral adaptation when it is driven by different incentive outcomes.     

Immune cells in the melanoma microenvironment hold information for prediction of the risk of recurrence and response to treatment

Melanoma is an immunogenic tumor and immunotherapy treatment has established an increase in disease-free and overall survival in melanoma patients. However, a complex network of immunosuppressive mechanisms has been demonstrated to occur at the tumor site and in locoregional immune districts, such as sentinel lymph nodes (SLNs). The interplay between tumor cells and the local microenvironment leads to a tumor-driven shaping of the immune response that results in a heterogeneous cellular and molecular composition of tumor infiltrating lymphocytes (TILs). Several studies have reported the potential prognostic value of TILs infiltrating primary tumors and the association of ‘immune signature’ in SLNs and in melanoma metastases with prognosis and responsiveness to immunotherapeutic approaches. However, a systematic and deeper characterization of the local immunological status of TILs and SLNs is still required to refine melanoma stage classification.     

Cortical activation in response to pure taste stimuli during the physiological states of hunger and satiety

This event-related functional magnetic resonance imaging (er-fMRI) study investigated BOLD signal change in response to a series of pure gustatory stimuli that varied in stimulus quality when subjects were hungry and sated with a nutritional pre-load. Group analyses showed significant differences in activation in the hunger minus satiety condition in response to sucrose, caffeine, saccharin, and citric acid within the thalamus, hippocampus, and parahippocampus. When examining the hunger and satiety conditions, activation varied as a function of stimulus, with the majority of the stimuli exhibiting significantly greater activation in the hunger state within the insula, thalamus, and substantia nigra, in contrast to decreased activation in the satiated state within the parahippocampus, hippocampus, amygdala, and anterior cingulate. Region of interest (ROI) analysis revealed two significant interactions, ROI by physiology and ROI by physiology by stimulus. In the satiety condition, the primary (inferior and superior insulae) and secondary (OFC 11 and OFC 47) taste regions exhibited significantly greater brain activation in response to all stimuli than regions involved in processing eating behavior (hypothalamus), affect (amygdala), and memory (hippocampus, parahippocampus and entorhinal cortex). These same regions demonstrated significantly greater activation within the hunger condition than the satiety condition, with the exception of the superior insula. Furthermore, the patterns of activation differed as a function taste stimulus, with greater activation in response to sucrose than to the other stimuli. These differential patterns of activation suggest that the physiological states of hunger and satiety produce divergent activation in multiple brain areas in response to different pure gustatory stimuli.     

Chronic smoking and the BOLD response to a visual activation task and a breath hold task in patients with schizophrenia and healthy controls

Many psychiatric patient groups smoke heavily, but little is known regarding the effects of this habit on functional brain imaging results. The present report assesses the effect of chronic smoking on the blood oxygen level-dependent (BOLD) response to a simple visual activation (VA) task and a breath hold (BH) task in patients with schizophrenia. Eight healthy controls and twelve patients with schizophrenia were studied. Half of each group had never smoked and the other half of each group had smoked for more than 10 pack years. Responses to the VA task were assessed in the visual cortex and responses to the BH task were assessed in gray matter generally. There were four fMRI-dependent measures: (1) median percent signal change; (2) activation volume (in voxels); (3) time-to-peak of the impulse response function (IRF); and (4) time-to-trough of the IRF. All measures were tested as dependent variables in an ANCOVA with diagnosis and smoking status as crossed factors and age as a covariate. Heavy smokers had 22% larger percent signal change for the VA task and 50% larger percent signal change for the BH task. Patients had a 40% larger percent signal change for the breath hold task. Other statistically significant effects of smoking history on activation volume and the timing of the brain responses were noted. If replicated, the results may have important implications for fMRI studies comparing groups with markedly different smoking habits, such as studies comparing patients with schizophrenia, 60-90% of whom smoke, and healthy controls, who smoke with a much lower frequency.     

Muscle afferent and central command contributions to the cardiovascular response to isometric exercise of postural muscle in patients with mild chronic heart failure

The roles of muscle afferent activity and central drive in controlling the compromised cardiovascular system of patients with mild chronic heart failure (CHF) during isometric exercise were examined. Blood pressure and heart rate responses were recorded in eight stable CHF patients (ejection fraction 20-40%; age 62+/-11 years) and in nine healthy age-matched controls during voluntary and electrically evoked isometric plantar flexion and subsequent post-exercise circulatory occlusion (PECO). During voluntary contraction, control subjects had a greater mean increase in systolic blood pressure than patients (42.4+/-19.2 and 23.0+/-10.9 mmHg respectively; P<0.01), but this was not the case during PECO. During electrically evoked contraction, but not during PECO, the CHF group had smaller (P<0.05) mean increases in both systolic and diastolic blood pressure than controls (13.0+/-5.3 compared with 25.4+/-14.0 mmHg and 7.6+/-3.0 compared with 12.9+/-7.2 mmHg respectively). Intra-group comparison between responses to voluntary and electrically evoked contractions revealed greater (P<0.05) mean increases in systolic and diastolic blood pressure during the voluntary contraction in both the patients and the control subjects. These data suggest that muscle afferent drive to the pressor response from the triceps surae is low in this age group, both in control subjects and in CHF patients. Additionally, the patients may have a relatively desensitized muscle mechanoreceptor reflex.     

Modulation of the inflammatory response to histamine by terbutaline and sodium nitroprusside in guinea-pig skin

We measured the microvascular response (vasodilatation and plasma exudation) to skin prick provocations with histamine, terbutaline, sodium nitroprusside (SNP) and the combinations of terbutaline and histamine as well as SNP and histamine in guinea-pig skin. The response was measured by external detection of beta radiation from transferrin labelled with (113m)In. Histamine induced a moderate microvascular response. Terbutaline alone induced a smaller response, probably reflecting vasodilatation. When added to histamine, terbutaline significantly reduced the microvascular response to histamine. The response to histamine, SNP and the combination of histamine and SNP were all similar. We conclude that the anti-inflammatory effect of terbutaline can be readily measured with this technique. We found no indication of a pro-inflammatory effect of SNP when combined with histamine. Rather, the lack of additive effect may suggest an anti-inflammatory effect of SNP on the response to histamine.     

Rimantadine and 2‐adamantanamine elicit local anesthesia to cutaneous nociceptive stimuli in a rat model

The aim of this study was to investigate infiltrative cutaneous anesthesia of 2‐adamantanamine and rimantadine. After subcutaneous injections of drugs in rats, the blockade of cutaneous trunci muscle reflex by 2‐adamantanamine and rimantadine was evaluated. Lidocaine, a common local anesthetic, was used as control. We showed that rimantadine and 2‐adamantanamine as well as the local anesthetic lidocaine produced infiltrative anesthesia of skin in a dose‐dependent fashion. Saline (vehicle) group displayed no cutaneous anesthesia. The relative potency of these drugs was rimantadine [23.8 (21.1–26.8)] = lidocaine [26.4 (22.7–30.6)] > 2‐adamantanamine [64.6 (55.0–75.9)] (P < 0.01). On an equianesthetic basis [25% effective dose (ED₂₅), ED₅₀, and ED₇₅], rimantadine and 2‐adamantanamine had longer duration of action than lidocaine (P < 0.05). Neither local injection of saline nor intraperitoneal administration of a large dose of drugs elicited cutaneous anesthesia (data not shown). These data demonstrated for the first time that rimantadine had a similar potent and longer duration of skin infiltrative anesthesia than did lidocaine, whereas 2‐adamantanamine had a less potency but longer duration of cutaneous anesthesia than did lidocaine.