Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats.

Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia.

Zebrafish locomotor capacity and brain acetylcholinesterase activity is altered by Aphanizomenon flos-aquae DC-1 aphantoxins.

Aphanizomenon flos-aquae (A. flos-aquae) is a source of neurotoxins known as aphantoxins or paralytic shellfish poisons (PSPs) that present a major threat to the environment and to human health. Generally, altered neurological function is reflected in behavior. Although the molecular mechanism of action of PSPs is well known, its neurobehavioral effects on adult zebrafish and its relationship with altered neurological functions are poorly understood. Aphantoxins purified from a natural isolate of A. flos-aquae DC-1 were analyzed by HPLC. The major analogs found in the toxins were the gonyautoxins 1 and 5 (GTX1 and GTX5; 34.04% and 21.28%, respectively) and the neosaxitoxin (neoSTX, 12.77%). Zebrafish (Danio rerio) were intraperitoneally injected with 5.3 and 7.61 µg STXeq/kg (low and high dose, respectively) of A. flos-aquae DC-1 aphantoxins. The swimming activity was investigated by observation combined with video at 6 timepoints from 1 to 24 h post-exposure. Both aphantoxin doses were associated with delayed touch responses, reduced head-tail locomotory abilities, inflexible turning of head, and a tailward-shifted center of gravity. The normal S-pattern (or undulating) locomotor trajectory was replaced by a mechanical motor pattern of swinging the head after wagging the tail. Finally, these fish principally distributed at the top and/or bottom water of the aquarium, and showed a clear polarized distribution pattern at 12 h post-exposure. Further analysis of neurological function demonstrated that both aphantoxin doses inhibited brain acetylcholinesterase activity. All these changes were dose- and time-dependent. These results demonstrate that aphantoxins can alter locomotor capacity, touch responses and distribution patterns by damaging the cholinergic system of zebrafish, and suggest that zebrafish locomotor behavior and acetylcholinesterase can be used as indicators for investigating aphantoxins and blooms in nature.

Tactile sensibility of single-tooth implants and natural teeth under local anesthesia of the natural antagonistic teeth.

INTRODUCTION AND AIM: The term osseoperception describes the capability of developing a subtle tactile sensibility over dental implants. The present clinical study aims at clarifying the question of how far tactile sensibility is to be attributed to the periodontium of the natural opposing tooth of the implant. MATERIAL AND METHOD: Thirty-two subjects with single-tooth implants with natural opposing teeth were included in this clinical, single-blind, split-mouth study. The natural antagonistic tooth of the implant and the corresponding natural contralateral tooth were anesthetized with a locally infiltrated articaine anesthetic. In a computer-assisted and randomized way, copper foils of varying thickness (0-100 µm) were placed interocclusally between the single-tooth implant and the natural opposing tooth, and between the contralateral pair of natural opposing teeth in order to investigate the active tactile sensibility according to the psychophysical method of constant stimuli and evaluate it statistically by the Weibull distribution. RESULTS: The average tactile sensibility of the implants with anesthetized antagonists at the 50% value calculated by means of the Weibull distribution was 20 ± 11 µm with a support area (90%-10% value) of 77 ± 89 µm. For the pair of natural teeth, the tactile sensibility at the 50% value was 16 ± 9 µm with a support area of 48.4 ± 93 µm. This resulted in an average intraindividual difference of 3.5 ± 7 µm at the 50% value and 29 ± 93 µm in the support area. The statistical calculations demonstrated an equivalent tactile sensibility (50% value) of the single-tooth implant and the contralateral natural control tooth with the natural antagonists being anesthetized in each case (double t-test, equivalence limit ± 8 µm, P < 0.01, power >80%). CONCLUSION: Apparently, the active tactile sensibility of single-tooth implants with natural opposing teeth is not only to be attributed to the periodontium of the opposing tooth but also to a perception over the implant itself. This could support the hypothesis according to which the implant may have a tactile sensibility of its own.

Late sensory function after intraoperative capsaicin wound instillation.

BACKGROUND: Intense capsaicin-induced C-fiber stimulation results in reversible lysis of the nerve soma, thereby making capsaicin wound instillation of potential interest for the treatment of post-operative pain. Clinical histological and short-term sensory studies suggest that the C-fiber function is partly re-established after skin injection of capsaicin. However, no study has evaluated the long-term effects of wound instillation of purified capsaicin on sensory functions. METHODS: Patients included in a double-blind placebo-controlled randomized study of the analgesic effect of capsaicin after groin hernia repair were examined by quantitative sensory testing before, 1 week and 2 years post-operatively. The primary endpoint was occurrence of hyperalgesia/allodynia. The secondary endpoints were acute and late sensory changes between the two patient groups. Patients were blinded to the allocated treatment. RESULTS: Twenty (100%) capsaicin and 16 (76%) placebo-treated patients were seen at the 2 1/2 year follow-up. Hyperalgesia was seen in five capsaicin- vs. one placebo-treated patient (P=0.2). The mechanical detection threshold was significantly increased on the operated side in the capsaicin vs. placebo group at the 1-week follow-up (P<0.05), but was not different at the 2 1/2 year follow-up (P=0.3). There were no other significant differences in sensory function on the operated side between groups at the pre-operative, 1-week or 2 1/2 year post-operative follow-up (P>0.05). The sensory function on the contralateral side was comparable between groups throughout the study (P>0.1). CONCLUSION: This small-volume study calls for further long-term safety studies of wound capsaicin instillation.

Intraseptal vs. periodontal ligament anaesthesia for maxillary tooth extraction: quality of local anaesthesia and haemodynamic response.

There is no data concerning the use of the intraseptal anaesthesia (ISA) for single tooth extraction. The aims of this study were to compare the clinical efficacy and haemodynamic responses of the ISA with the periodontal ligament anaesthesia (PLA) for single tooth extraction. Thirty-five randomly selected healthy patients (ASA I) undergoing maxillary lateral incisors extraction entered the study. Onset of anaesthesia, the width of the anaesthetic field and duration of anaesthesia were recorded by pinprick testing. Intensity of anaesthesia was evaluated on a visual analogue scale. Haemodynamic parameters were recorded simultaneously at different time points after anaesthesia injection. The two techniques of local anaesthesia did not show statistically significant differences regarding the success rate and onset of anaesthesia, while the duration of the ISA on the buccal site was significantly longer in comparison with the PLA. The intensity of the achieved anaesthesia, estimated by the experienced pain during procedure, pointed out that pain was recorded in 24% of cases in the ISA group, and in 19% in the PLA group without significant differences. Postoperative pain was found to be smaller in the ISA group (70.9% of treated sites) than in the PLA group (81.3% of treated sites); however, this difference was not significant. Although the heart rate increased in both groups, there were no significant differences in the patients' haemodynamic response between the ISA and the PLA. The results of the present study indicate that both techniques are useful and suitable for the routine tooth extraction.

Perception of simulated local shapes using active and passive touch.

This study reexamined the perceptual equivalence of active and passive touch using a computer-controlled force-feedback device. Nine subjects explored a 6 x 10-cm workspace, with the index finger resting on a mobile flat plate, and experienced simulated Gaussian ridges and troughs (width, 15 mm; amplitude, 0.5 to 4.5 mm). The device simulated shapes by modulating either lateral resistance with no vertical movement or by vertical movement with no lateral forces, as a function of the digit position in the horizontal workspace. The force profiles and displacements recorded during active touch were played back to the stationary finger in the passive condition, ensuring that stimulation conditions were identical. For the passive condition, shapes simulated by vertical displacements of the finger had lower categorization thresholds and higher magnitude estimates compared with those of active touch. In contrast, the results with the lateral force fields showed that with passive touch, subjects recognized that a stimulus was present but were unable to correctly categorize its shape as convex or concave. This result suggests that feedback from the motor command can play an important role in processing sensory inputs during tactile exploration. Finally, subjects were administered a ring-block anesthesia of the digital nerves of the index finger and subsequently retested. Removing skin sensation significantly increased the categorization threshold for the perception of shapes generated by lateral force fields, but not for those generated by displacement fields.

B vitamins alleviate indices of neuropathic pain in diabetic rats.

There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

Developmental lead exposure induces tactile defensiveness in rhesus monkeys (Macaca mulatta).

BACKGROUND: Tactile defensiveness in children is associated with difficult social relations, emotional dysregulation, and inattention. However, there are no studies of lead exposure and tactile defensiveness in children or animals in spite of the fact that lead exposure is also associated with inattention and emotional dysregulation. OBJECTIVES: In this study we tested whether lead exposure induces tactile defensiveness in rhesus monkeys. METHODS: We tested 61 monkeys from a 3 (no lead, 1-year lead, 2-year lead) x 2 (succimer chelation or not) factorial experiment for tactile defensiveness at 4 years of age. Lead-treated monkeys had been orally administered lead in a daily milk solution from 8 days of life to either 1 or 2 years of age to produce blood lead levels of 35-40 mg/dL. Succimer chelation therapy or placebo was administered at 1 year of age. We measured tactile defensiveness using six repeated trials of each of three textures as a swipe to the cheek and neck. RESULTS: Lead-exposed monkeys showed higher negative responses to repeated tactile stimulation compared with controls. Blood lead during the first 3 months of life was positively correlated with the negative response on the tactile defensiveness test. There was an interaction of lead exposure x succimer chelation x trials, but it is not clear that succimer chelation was beneficial with respect to tactile defensiveness. CONCLUSIONS: This is the first report to implicate lead as a potential cause of tactile defensiveness. Research should examine whether lead exposure is associated with tactile defensiveness in children.

Tactile-induced ultrasonic vocalization in the rat: a novel assay to assess anti-migraine therapies in vivo.

A pharmacological model of migraine is described using ultrasound vocalization (USV) of rats following central inflammation-induced sensitization to tactile stimulation. Central inflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS) increased USV induced by an air current focused on the head and this was abolished by morphine and ketorolac, suggesting a nociceptive component. USV in naive rats were unaffected. Diazepam reduced USV in both inflamed and naive rats. The triptans, zolmitriptan and sumatriptan, both reduced USV in inflamed but not in naive rats, as did dihydroergotamine, and the calcitonin gene-related peptide (CGRP) antagonists alphaCGRP(8-37) and BIBN4096BS. The neurokinin-1 antagonist L-733-060 had no effect in either inflamed or naive rats when given after induction of inflammation, but when given with the LPS it prevented the augmentation of USV. This profile of activity of agents proven to be effective in the clinic suggests this model can be used to predict novel therapeutic agents for migraine.

Analgesic and antinociceptive effects of peripheral nerve neurostimulation in an advanced human experimental model.

Electrical peripheral nerve neurostimulation (PNS) is reported to be an effective pain treatment. An objective proof of antinociceptive effect is lacking. The human experimental study addressed PNS effects on nociception and pain by electrophysiology and psychophysics. In 23 healthy volunteers, 39 sessions were conducted. Three experiments (PNS ipsilateral, PNS contralateral, Control) consisted of 13 sessions each. Conditioning PNS (100 Hz) of left (PNS ipsilateral) or right (PNS contralateral) superficial radial nerve trunk evoked non-painful, tingling sensations on the hand dorsum. Local cutaneous anesthesia at PNS site provided for preferential nerve trunk stimulation. Cortical laser-evoked potentials (LEP) after painful stimulation at left hand dorsum were recorded together with mechanical and thermal perception thresholds at the same site before (T1), during (T2), and after (T3) PNS or a no stimulation period (Control). Mechanical and thermal perception decreased in the anesthetized area. Late LEP amplitude decreased independently of PNS site. Exclusively under ipsilateral PNS, N2 latency increased and laser ratings decreased. Mechanical detection threshold transiently increased during ipsilateral PNS at hand dorsum. PNS induced strong reduction of mechanical perception due to peripheral collision of orthodromic (test stimulus) and antidromic (PNS) selective Abeta fiber excitation. Delay of N2 component and reduction of laser pain were specific to ipsilateral PNS. Divergent and common effects of ipsilateral and contralateral PNS suggest a combination of peripheral and central antinociceptive mechanisms. The study in man documents inhibition of nociception and pain by PNS and provides with an experimental model for future objectives in neuromodulation.

Effect of systemic and intrathecal gabapentin on allodynia in a new rat model of postherpetic neuralgia.

Patients with postherpetic neuralgia often have an increased sensitivity to a tactile stimulus but impaired thermal sensitivity in the same affected dermatomes. We recently found that depletion of capsaicin-sensitive afferents by systemic treatment with a potent TRPV1 agonist, resiniferotoxin, in adult rats produces long-lasting paradoxical changes in mechanical and thermal sensitivities, which resemble the unique clinical features of postherpetic neuralgia. The anticonvulsant gabapentin is effective in reducing the subjective pain score in patients with postherpetic neuralgia. In this study, we quantified the potential effect of systemic and intrathecal gabapentin on tactile allodynia induced by resiniferotoxin in rats. Intraperitoneal injection of 200 microg/kg resiniferotoxin produced a rapid and sustained increase in the paw withdrawal latency to a radiant heat stimulus. Profound tactile allodynia developed in all the resiniferotoxin-treated rats within 3 weeks. Intraperitoneal injection of 30-60 mg/kg of gabapentin in resiniferotoxin-treated rats significantly increased the withdrawal threshold in response to von Frey filaments. Furthermore, intrathecal administration of 10-30 microg of gabapentin also produced a significant effect on the mechanical withdrawal threshold in all resiniferotoxin-treated rats. These data provide complementary new information that gabapentin administered systemically and spinally can effectively relieve tactile allodynia in this animal model of postherpetic neuralgia.

Psychophysical sensory examination in individuals with a history of methylmercury exposure.

Paresthesias are the first symptom that people report following toxic doses of methylmercury. The authors conducted a psychophysical study of tactile sensation to evaluate the somatosensory abilities of subjects living in a methylmercury-polluted area around Minamata City, Japan. The authors examined control subjects and methylmercury-exposed subjects with and without numbness. A history of methylmercury exposure was taken and a neurological examination performed. Aluminum-oxide abrasive papers were used as stimuli in a psychophysical sensory examination of fine-surface-texture discrimination. Difference thresholds from 3 microm were calculated by the two-alternative, forced-choice technique. Difference thresholds in control subjects were also calculated for comparison. The difference threshold was 6.3 microm in exposed subjects with sensory symptoms, 4.9 microm in exposed subjects without sensory symptoms, and 2.7 microm in control subjects. Acuity of fine-surface-texture discrimination was disturbed not only in subjects with clinical complaints of hand numbness, but also in subjects without hand numbness who lived in the district where methylmercury exposure occurred. Sensory testing using a psychophysical test of fine-surface-texture discrimination in this population suggests that the number of individuals affected by methylmercury exposure in the polluted area was greater than previously reported.

Neurons in the primate orbitofrontal cortex respond to fat texture independently of viscosity.

The primate orbitofrontal cortex (OFC) is a site of convergence from primary taste, olfactory, and somatosensory cortical areas. We describe the responses of a population of single neurons in the OFC that respond to orally applied fat (e.g., safflower oil) and to substances with a similar texture but different chemical composition, such as mineral oil (hydrocarbon) and silicone oil [(Si(CH3)2O)n]. These findings provide evidence that the neurons respond to the oral texture of fat, sensed by the somatosensory system. Use of an oral viscosity stimulus consisting of carboxymethyl-cellulose in the range 1-10,000 centipoise (cP) showed that the responses of these fat-sensitive neurons are not related to stimulus viscosity. Thus a textural component independent of viscosity and related to the slick or oily property is being used to activate these oral fat-sensitive neurons. Moreover, a separate population of neurons responds to viscosity (produced, e.g., by the carboxymethyl-cellulose series), but not to fat with the same viscosity. Thus there is a dissociation between texture channels used to sense fat viscosity and non-fat-produced viscosity. Further, free fatty acids such as linoleic acid do not activate these neurons, providing further evidence that the oral fat-sensing mechanism through which these OFC neurons are activated is not gustatory but textural. Most of this population of fat-sensitive neurons receive convergent taste inputs. These results provide evidence about how oral fat is sensed and are relevant to understanding the physiological and pathophysiological processes related to fat intake.

The role of cutaneous feedback for anticipatory grip force adjustments during object movements and externally imposed variation of the direction of gravity.

Grip force adjustments to changes of object loading induced by external changes of the direction of gravity during discrete arm movements with a grasped object were analyzed during normal and anesthetized finger sensibility. Two subjects were seated upright in a rotatable chair and rotated backwards into a horizontal position during discrete movements with a hand-held instrumented object. The movement direction varied from vertical to horizontal inducing corresponding changes in the direction of gravity, but the orientation of the movement in relation to the body remained unaffected. During discrete vertical movements a maximum of load force occurs early in upward and late in downward movements; during horizontal movements two load force peaks result from both acceleratory and deceleratory phases of the movement. During performance with normal finger sensibility grip force was modulated in parallel with fluctuations of load force during vertical and horizontal movements. The grip force profile adopted to the varying load force profile during the transition from the vertical to the horizontal position. The maximum grip force occurred at the same time of maximum load force irrespective of the movement plane. During both subjects' first experience of digital anesthesia the object slipped from the grasp during rotation to the horizontal plane. During the following trials with anesthetized fingers subjects substantially increased their grip forces, resulting in elevated force ratios between maximum grip and load force. However, grip force was still modulated with the movement-induced load fluctuations and maximum grip force coincided with maximum load force during vertical and horizontal movements. This implies that the elevated force ratio between maximum grip and load force does not alter the feedforward system of grip force control. Cutaneous afferent information from the grasping digits seems to be important for the economic scaling of the grip force magnitude according to the actual loading conditions and for reactive grip force adjustments in response to load perturbations. However, it plays a subordinate role for the precise anticipatory temporal coupling between grip and load forces during voluntary object manipulation.

A new model of visceral pain and referred hyperalgesia in the mouse.

The generation of transgenic mice that lack or overexpress genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is widely used in mice. Here we describe a novel model, chemical stimulation of the colon, which we have developed in mice. Mice of either sex were injected i.v. with 30 mg/kg Evan's Blue for subsequent determination of plasma extravasation. For behavioural testing, they were placed on a raised grid and 50 microl of saline, mustard oil (0.25-2.5%) or capsaicin (0.03-0.3%) was administered by inserting a fine cannula into the colon via the anus. Visceral pain-related behaviours (licking abdomen, stretching, contractions of abdomen etc) were counted for 20 min. Before intracolonic administration, and 20 min after, the frequency of withdrawal responses to the application of von Frey probes to the abdomen was tested. The colon was removed post-mortem and the Evan's Blue content measured. Mustard oil and capsaicin administration evoked dose-dependent visceral pain behaviours, referred hyperalgesia (significant increase in responses to von Frey hairs) and colon plasma extravasation. The peak behavioural responses were evoked by 0.1% capsaicin and by 1% mustard oil respectively. The nociceptive behavioural responses were dose-dependently reversed by morphine (ED50 = 1.9 +/- 1 mg/kg s.c.). We conclude that this model represents a useful tool both for phenotyping mutant mice and for classical pharmacology since information on visceral pain, referred hyperalgesia and colon inflammation can all obtained from the same animal.

Large cortical lesions produce enduring forelimb placing deficits in un-treated rats and treatment with NMDA antagonists or anti-oxidant drugs induces behavioral recovery.

Previous studies have utilized a lesion model of cortical injury that produces transient behavioral impairments to investigate the recovery of function process. To better understand the recovery process, it would be beneficial to use a lesion model that produces more severe, enduring, behavioral impairments. The purpose of experiment 1 was to validate whether large lesions of the sensorimotor cortex (SMC), which included the rostral forelimb and caudal forelimb regions, produced enduring behavioral deficits. Rats were given large unilateral electrolytic lesions of the SMC, administered either the N-methyl-D-aspartate (NMDA) antagonist, MK-801 or saline 16 h after injury, and tested on a battery of behavioral tests. Enduring behavioral deficits were observed, for at least 6 months, on two tests of forelimb placing while transient deficits were observed on the foot-fault and somatosensory neutralization tests. Administration of MK-801 facilitated recovery on the somatosensory neutralization test; however, it did not induce recovery on either forelimb placing test. A second experiment was performed to determine if earlier administration of MK-801, the NMDA antagonist magnesium chloride (MgCl(2)), or the anti-oxidant N-tert-butyl-alpha-phenylnitrone (PBN) could induce behavioral recovery in this chronic model. Treatment with these drugs induced behavioral recovery on the forelimb placing tests, whereas, the saline-treated rats did not show any signs of behavioral recovery for at least 3 months. Anatomical analysis of the striatum showed that MK-801 and MgCl(2) but not PBN reduced the extent of lesion-induced striatal atrophy. These results suggest that administration of MK-801, MgCl(2), or PBN shortly after cortical injury can induce recovery of function when recovery is otherwise not expected in un-treated rats.

Comparison of sedative effects of romifidine following intravenous, intramuscular, and sublingual administration to horses.

OBJECTIVE: To compare sedative effects of romifidine following IV, IM, or sublingual (SL) administration in horses. ANIMALS: 30 horses that required sedation for routine tooth rasping. PROCEDURE: Horses (n = 10/group) were given romifidine (120 microg/kg) IV, IM, or SL. Heart rate, respiratory rate, head height, distance between the ear tips, thickness of the upper lip, response to auditory stimulation, response to tactile stimulation, and degree of ataxia were recorded every 15 minutes for 180 minutes. Tooth rasping was performed 60 minutes after administration of romifidine, and overall adequacy of sedation was assessed. RESULTS: IV and IM administration of romifidine induced significant sedation, but SL administration did not induce significant sedative effects. Scores for overall adequacy of sedation after IV and IM sedation were not significantly different from each other but were significantly different from scores for horses given romifidine SL. Sedative and other effects varied among groups during the first 60 minutes after drug administration; thereafter, effects of IV and IM administration were similar. CONCLUSIONS AND CLINICAL RELEVANCE: Onset of action was fastest and degree of sedation was greater after IV, compared with IM, administration of romifidine, but duration of action was longer after IM administration. Sublingual administration did not result in clinically important sedative effects.

Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection.

BACKGROUND AND OBJECTIVES: We observed clinically that tramadol and metoclopramide appear to have local anesthetic action. Tramadol is a central-acting analgesic. Metoclopramide is a commonly used antiemetic. The local anesthetic effect of tramadol in reducing propofol injection pain has never been mentioned, although it was speculated with metoclopramide. METHODS: We conducted a double-blind, placebo-controlled study by injecting tramadol or metoclopramide intradermally in 10 healthy volunteers (5 men, 5 women; age 25-56 years). Each subject received 0.5 mL of four solutions in random order on the volar side of the forearm. These solutions were 25 mg tramadol, 5 mg metoclopramide, 5 mg lidocaine, and 0.5 mL normal saline. Pain on injections and the degree of local anesthesia (tested by pinprick, light touch, and cold) at each site was reported on a 0-3 scale at designed time intervals. RESULTS: Like 1% lidocaine, tramadol and metoclopramide demonstrated loss of sensation for pinprick, light touch, and cold for 15 minutes after intradermal injection (P < .01 ). CONCLUSIONS: Intradermal tramadol or metoclopramide can produce local anesthetic effect.

Tactual discrimination of softness.

1. We investigated the ability of humans to tactually discriminate the softness of objects, using novel elastic objects with deformable and rigid surfaces. For objects with deformable surfaces, we cast transparent rubber specimens with variable compliances. For objects with rigid surfaces ("spring cells") we fabricated telescoping hollow cylinders with the inner cylinder supported by several springs. To measure the human discriminability and to isolate the associated information-processing mechanisms, we performed psychophysical experiments under three conditions: 1) active touch with the normal finger, where both tactile and kinesthetic information was available to the subject: 2) active touch with local cutaneous anesthesia, so that only kinesthetic information was available; and 3) passive touch, where a computer-controlled mechanical stimulator brought down the compliant specimens onto the passive fingerpad of the subject, who therefore had only tactile information. 2. We first characterized the mechanical behavior of the human fingerpad and the test objects by determining the relationship between the depth and force of indentation during constant-velocity indentations by a rigid probe. The fingerpad exhibited a pronounced nonlinear behavior in the indentation depth versus force trace such that compliance, as indicated by the local slope of the trace, decreased with increases in indentation depth. The traces for all the rubber specimens were approximately linear, indicating a constant but distinct value of compliance for each specimen. The fingerpad was more compliant than each of the rubber specimens. 3. All the human subjects showed excellent softness discriminability in ranking the rubber specimens by active touch, and the subjective perception of softness correlated one-to-one with the objectively measured compliance. The ability of subjects to discriminate the compliance of spring cells was consistently poorer compared with that of the rubber specimens. 4. For pairwise discrimination of a selected set of rubber specimens, kinesthetic information alone was insufficient. However, tactile information alone was sufficient, even when the velocities and forces of specimen application were randomized. In contrast, for discriminating pairs of spring cells, tactile information alone was insufficient, and both tactile and kinesthetic information were found to be necessary. 5. The differences in the sufficiency of tactile information for the discrimination of the two types of objects can be explained by the mechanics of contact of the fingerpad and its effect on tactile information. For objects with deformable surfaces, the spatial pressure distribution within the contact region depends on both the force applied and the specimen compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of iontophoresis of lidocaine with a eutectic mixture of lidocaine and prilocaine (EMLA) for topically administered local anesthesia.

BACKGROUND: Almost all dermatologic surgery is accomplished using local anesthesia. To make our patients more comfortable, there is a constant search for less painful methods of administering anesthetic agents. Topical EMLA as well as iontophoresis are both useful in this regard. OBJECTIVE: In this study we compared topical EMLA with lidocaine delivered by iontophoresis in a double-blind placebo-controlled trial. Our goal was to assess the degree of anesthesia obtained as well as the relative rapidity of onset. METHODS: A double-blind controlled study was performed on 10 healthy volunteers between 26 and 37 years of age. Three test sites were placed on each forearm. EMLA or a moisturizer control was placed on two of the three test sites on each arm. Each site was wiped free of cream and tested for sensitivity to pinprick 30 and 60 minutes after cream placement. One iontophoretic unit was placed on each forearm. Both units were saturated with anesthesia with the control unit being turned off. Sensitivity to pinprick was evaluated at the iontophoretic sites and one of the EMLA sites 30 minutes after site placement on the subject. The additional EMLA-treated site was tested in the same manner 60 minutes after placement. RESULTS: Both EMLA cream and the iontophoretic unit delivered topical anesthesia greater than the control. Significantly more anesthesia was acquired 1 hour after application of EMLA than was seen 30 minutes earlier. The iontophoretic patch-treated area provided greater anesthesia than the EMLA-treated sites evaluated 30 and 60 minutes after placement. Both modalities provided significant anesthesia when left in place for 60 minutes. CONCLUSION: Both iontophoresis of lidocaine and topical EMLA delivered significant, and sometimes complete, local anesthesia. A greater degree of anesthesia is delivered via iontophoresis after 30 minutes as compared with EMLA left on the skin for 30 or 60 minutes. Both modalities have important and unique advantages and disadvantages. Topical EMLA and iontophoretically delivered lidocaine are both valuable tools for the dermatologic surgeon.