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Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.

Nylon monofilaments may substitute for German Research Network on Neuropathic Pain standards in tactile but not pinprick testing. Ramped stimuli are faster but underestimate thresholds due to reaction time artefacts., Introduction: Quantitative sensory testing is used to assess somatosensory function in humans. The protocol of the German Research Network on Neuropathic Pain (DFNS) provides comprehensive normative values using defined tools; however, some of these may not be feasible in low-resource settings. Objectives: To compare the standard DFNS devices for assessment of mechanosensory function to a low resource tool, the Sorri-Bauru-monofilaments. Methods: Mechanical detection thresholds (MDT), pain thresholds (MPT), and suprathreshold pinprick ratings (pain sensitivity: MPS) were measured over cheek, hand dorsum, and fingertip in 13 healthy subjects (7 female, aged 21–44 years). Mechanical detection threshold was assessed with DFNS standard glass monofilaments (0.25–512 mN, 0.5 mm tip) and nylon monofilaments (Sorri-Bauru; 0.5–3000 mN). MPT was assessed with DFNS standard cylindrical probes (8–512 mN, 0.25 mm tip), Sorri-Bauru monofilaments, and with ramped stimuli using an electronic von Frey aesthesiometer (10 mN/s or 100 mN/s, 0.20 mm tip). MPS was measured in response to stepped and ramped pinpricks (128 and 256 mN). Results: Mechanical detection thresholds were the same for DFNS and Sorri-Bauru monofilaments. For MPT, Sorri-Bauru filaments yielded lower values than PinPricks over face but not hand. Pain thresholds were higher at all test sites for ramped than stepped pinpricks (P < 0.01). Suprathreshold ratings were lower for ramped than stepped pinpricks (P < 0.05). Conclusion: Sorri-Bauru filaments are acceptable substitutes for DFNS standards in estimating tactile sensitivity, but are not consistent with standard probes for pinprick sensitivity because of their nonstandardized tips. Ramped stimuli overestimated MPT and underestimated MPS due to reaction time artefacts and therefore need their own normative values.

Background: Acupuncture therapy is frequently used to treat Knee Osteoarthritis (KOA) in clinic, and usually used local acupoints near the diseased knees as therapeutic targets. Some local acupoints appeared sensitization phenomenon which was called sensitized acupoints, which were regarded as important therapeutic targets to get better therapeutic effect on clinic. Therefore, it is necessary to explore the biological basis of acupoint sensitization. Meanwhile, there is a lack of an analysis of the metabolism for sensitized acupoints in KOA patients. Considering that acupuncture effect could be multi-targeted, omics (such as metabolomics) may be a useful method to reveal the relationship between sensitized acupoints and clinical efficacy of acupuncture. Methods and analysis: This study is a parallel design trial. Thirty KOA patients and 30 healthy volunteers will be recruited in this study. Mechanical pain threshold will be measured by Electron Von frey in order to confirm the highest sensitized acupoints. Then collect tissue fluid from the highest sensitized acupoints by micro dialysis technical, then apply electro-acupuncture method on the highest sensitized acupoints to treat KOA patients, after 20 sessions treatments, measure and collect again. Liquid chromatography-tandem mass spectrometry method will be used to analyze the metabonomics of dialysate. Results: This study will provide a high-quality evidence to reveal the local molecular mechanism of acupuncture sensitized acupoints for patient with KOA. Conclusion: This study will provide up-date evidence of whether acupuncture sensitized acupoints have local molecular mechanism for KOA. Trial registration number: NCT03599180 (24 Jul. 2018)

Improvement of impaired neurological function(s) is a primary endpoint in experimental stroke recovery studies, making the choice and nature of the functional tests crucial for proper execution and interpretation of such studies. Currently, there are a limited number of neurological tests which reliably evaluate functional deficit in mice over a long period of time after stroke. In this study, we evaluated the applicability of forepaw grip strength and automated von Frey tactile sensitivity tests to assess forelimb dysfunction following stroke in the mouse photothrombotic model and compared them with two widely-used tests, grid-walking and cylinder, for up to 21 days after stroke. Three month-old, CD-1 male mice were randomly subjected to photothrombotic stroke or sham surgery in the sensorimotor cortex (n = 10/group). Neurological assessments were conducted 3 days before and 1, 7, 14 and 21 days after stroke in a blinded manner. Grip strength was measured using Mark-10 digital force gauge at peak tension operation mode and performance of each forepaw to hold a grasped wire was evaluated. In the automated von Frey test, the forelimb withdrawal threshold was measured using the same force gauge, attached to a plastic tip, at peak compression operation mode. The cylinder test was used to determine forelimb symmetry in exploratory rearing in a clear cylinder, whereas the grid-walking test was used to measure the number of forelimb footfaults of mice walking on a metallic grid. Our results indicate that while the length of time required to conduct the two new tests is comparable to that of the grid-walking and cylinder tests, the data from the new tests is obtained and ready for analysis upon completion of the testing session. In addition, our observations indicate that the automated von Frey test detected substantial and sustained deficit in the withdrawal threshold of the mice on all evaluation days after stroke, whereas the forepaw grip strength test was only marginally sensitive to document functional impairment. Our data demonstrate that the automated von Frey tactile sensitivity test is a time efficient and sensitive method which can be used together with other established tests to evaluate long-term functional outcome in the mouse photothrombotic stroke model.

Objective The aim of this study was to use the Face, Legs, Activity, Cry, Consolability Scale; salivary cortisol levels; and withdrawal reflex thresholds to assess pain, stress, and pain sensitivity in young children with cerebral palsy during early developmental intervention programs. Design A total of 40 children with cerebral palsy (age range, 1-4 yrs) participated in the early intervention programs, which included neurodevelopmental treatment, neuromuscular electrical stimulation, occupational therapy, head acupuncture, and Chinese traditional manipulation five times per week for 3 wks. The Face, Legs, Activity, Cry, Consolability Scale was applied during the course of each treatment, and salivary cortisol samples were obtained from each child 10 mins before and 10 mins after each treatment. Withdrawal reflex thresholds were assessed via mechanical stimulation of the foot with von Frey hairs. Results All treatment programs caused some degree of pain. In descending order, the extents of the pain caused by each treatment were head acupuncture, neurodevelopmental treatment, neuromuscular electrical stimulation, Chinese traditional manipulation, and occupational therapy. There were statistically significant increases in salivary cortisol levels after the head acupuncture (P 0.05). Conclusions The results of this study demonstrate that early developmental intervention programs cause pain and stress in young children with cerebral palsy.

Previous research on multisensory integration has demonstrated that viewing the stimulated body part enhances discrimination ability. Participants in this experiment watched a video showing a hand being touched by a stick and a second video showing the stick touching the space beneath the hand. Sensory thresholds of the index fingers were tested with von Frey filaments. We found significant enhancements of the sensory threshold after showing the video with the touched hand but not after showing the video with no touch of the hand. This enhancement was specific for the index finger shown in the video. The results link the visuotactile enhancement of this study to the observation of touch rather than to the simple depiction of the body part.

Postoperative sensitivity to tactile stimuli differs as a function of age. In this study, we hypothesized that preoperative sciatic nerve block (SNB), by providing preemptive analgesia, would result in better analgesia than postoperative SNB in the young rat. With the paw incision model of postoperative pain, male Sprague-Dawley rats, aged 2 or 4 wk, underwent general anesthesia and then received a left SNB with 5 microL/g of 0.5% bupivacaine or normal saline. SNB was performed either before or after surgery. Mechanical allodynia was assessed by using von Frey filaments before and at various times after SNB and surgery. In the 2-wk-old rats, preoperative SNB produced a significant reduction in mechanical allodynia, as reflected by a higher threshold at 2, 5, and 24 h when compared with saline control (P < 0.03). At 24 h, the threshold was 4.0 +/- 0.7 g in the preoperative SNB group compared with 1.6 +/- 0.3 g in the postoperative SNB group (P = 0.004). There was no difference at any time point between the preoperative and the postoperative SNB in the 4-wk-old animals. These results suggest that preoperative SNB in young animals provides a preemptive analgesic effect on mechanical allodynia that is age or developmentally dependent.

The traditional concept that pain is poorly localized has been challenged by recent studies, where subjects were able to point to the stimulated spot on the skin with an accuracy of 10-20 mm. Pointing movements themselves, however, have errors of about 15 mm. To determine the limits of sensory performance of the nociceptive system independent of motor performance, point localization of heat pain (540 mJ punctate laser stimuli, 5 mm diameter), mechanical pain (256 mN punctate probe, 200 microm diameter), and touch (16 mN von Frey probe, 1.1 mm diameter) were tested in a two-alternative forced-choice paradigm in 12 healthy subjects. Stimuli were applied in randomized order to two parallel lines on the back of the hand (4-32 mm distance). The cumulative distribution functions for correct localization were of similar sigmoid shape for all test stimuli, indicating logarithmic normal distributions. The 75% correct localization threshold for painful heat was 8.6 mm (3.1 +/- 0.1 log2 units) and did not differ significantly from that of non-painful touch (9.0 mm, 3.2+/-0.2 log2 units). Localization of mechanically-induced pain (5.1 mm, 2.4 +/- 0.2 log2 units) was significantly more accurate than both heat pain and touch, possibly due to a synergism of two different sensory channels, the tactile channel and the nociceptive channel, which were activated simultaneously. For all three stimuli, discrimination was significantly better in radial-ulnar compared to proximal-distal direction, which might be related to oval receptive field shapes. Sequential spatial discrimination for touch was significantly better than simultaneous spatial discrimination tested with a grating orientation task (18.9 mm), but both were one order of magnitude worse than at the finger tip (1.3 mm, 0.4 +/- 0.1 log2 units). In conclusion, pain evoked by radiant heat pulses and touch evoked by von Frey probes were localized with similar precision on the back of the hand. These findings indicate that outside the tactile fovea at finger tips or lips the spatial discrimination capacities of the nociceptive and tactile systems are about equal.

The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia to punctate stimuli was assessed with a rigid von Frey hair (462 mN). The heat pain responses to 45 degrees C in 5 s (3.75 cm2) were tested in the area just outside the burn, where the subjects developed secondary hyperalgesia, and on the lateral crus where no subject developed secondary hyperalgesia (control area). The burns decreased pain thresholds and increased pain responses to both thermal and mechanical stimuli within the burn (P < 10(-5)). Further, the burns induced secondary hyperalgesia (mean 89 cm2) to punctate mechanical stimuli (P < 10(-5)), and increased the pain response to mechanical stimuli in the areas of secondary hyperalgesia (P < 10(-5)). The pain response to heat stimuli increased over time in the area of secondary hyperalgesia (P < 10(-5)), and so did the pain response to heat on the lateral part of the crus (P < 10(-3)). However, the heat pain response increased more (P = 0.006) and was more intense (P = 0.001) within the zone of secondary hyperalgesia than on the lateral part of the crus. Further, the heat pain response was more intense in the zone of primary hyperalgesia than in the zone of secondary hyperalgesia (P = 0.004), in contrast to the mechanical pain response, which was not significantly different between the two zones of hyperalgesia. In conclusion, secondary hyperalgesia in man is not restricted to mechanical stimuli, as significant hyperalgesia to heat developed within the zone of secondary hyperalgesia to punctate mechanical stimuli. The data, combined with other evidence, suggest differences in the mechanisms accounting for primary hyperalgesia to heat and mechanical stimuli, whereas secondary hyperalgesia to heat and mechanical stimuli may be explained by a common central mechanism.

An experimental mononeuropathy was produced in rats by unilateral loose ligation of the sciatic nerve, with a contralateral sham surgery. Repeated bilateral sensory testing was performed over time to investigate any threshold differences between the loose ligature side and the contralateral control side. A prolonged reduction in the mean withdrawal threshold to heat was observed on the loose ligature side over the medial dorsum of the hindpaw (MDH), and over the plantar surface of the hindpaw (PSH). Following loose ligature there was also a significant reduction in the von Frey fiber withdrawal thresholds over the lateral dorsum of the hindpaw (LDH) and the medial dorsum of the hindpaw (MDH). In a second experiment the saphenous nerves were transected bilaterally in rats who had an earlier unilateral loose sciatic ligation. The heat hyperalgesia that had been previously observed over the MDH was abolished, and no withdrawal response could be elicited with the largest von Frey fiber over the MDH, indicating that the MDH hyperalgesia induced by sciatic loose ligature was mediated by the saphenous nerve. This adjacent neuropathic hyperalgesia (ANH) resembles the saphenous mediated ANH observed over the MDH following sciatic transection, follows the same temporal course of onset, and may share a similar pathogenesis. The heat threshold over the PSH and the pressure threshold over the LDH were unaffected by the bilateral saphenous transection, demonstrating that following loose sciatic ligation both of these thresholds are mediated by the sciatic nerve.

Objective: The purpose of this study is to learn if participants with Parkinson9s (PD) over estimate the magnitude of weak tactile stimuli. Perhaps in PD the perceived magnitudes of sensory events are increased, leading to the hypometric response. Alternatively, people with PD may have frontal dysfunction with impaired ability to disengage attention, producing a perceptual "grasp" such that the perception of stimuli with high or low intensity will be perceived as having a reduced range of magnitudes (regression to the mean). Background People with Parkinson9s disease (PD) have motor and cognitive hypometria that cannot be fully explained by alterations of efferent motor signals. Design/Methods: To determine if magnitude estimation of tactile stimuli is altered in PD, we used "von Frey hairs" made of nylon monofilaments. For each trial a standard monofilament was applied to the skin on the palm and the participant was told its magnitude was "50". Then, a second monofilament was applied and the participant was asked to provide a numerical estimate of the magnitude of the second stimulus relative to the first. We tested 13 people with PD and 7 control participants. Steven9s Power Law applied to responses made for stimuli lower in intensity than the standard. Results: When compared to controls, participants with PD over-estimated the magnitudes of stimulus intensities below the standard stimulus. Conclusions: Our results indicate that participants with PD overestimate the magnitudes of weak stimuli, the direction consistent with hypometric responses. These findings do not rule out perceptual "grasp". Further studies assessing estimated magnitudes for stimuli having greater intensities than the standard will reveal whether consistent overestimation or reduced range of estimates account for this change. Disclosure: Dr. Kesayan has nothing to disclose. Dr. Falchook has nothing to disclose. Dr. Williamson has nothing to disclose. Dr. White has received (royalty or license fee or contractual rights) payments from patents. Dr. White has received research support from Neuromuscular Engineering, Inc. Dr. Skidmore has nothing to disclose. Dr. Heilman has received personal compensation for activities with law firms as a consultant.Dr. Heilman has received personal compensation in an editorial capacity for Journal Watch.

To the Editor: Bara-Jimenez et al. recently reported1 that patients with idiopathic focal dystonia of the hand are impaired in localizing finger contact with nylon monofilaments (Semmes-Weinstein, von Frey type). They also showed that these patients performed worse in a grating orientation task (GOT) compared to control subjects. Threshold values for GOT were not similar to those for monofilament localization. These results for the two tasks point to different neural mechanisms. Understanding the neural basis for performance in tactile tasks used in a study of dystonia seems essential if one hopes to develop a …

Two cross-sectional studies were made of the recovery of tactile and pain sensitivity in subjects having skin flaps in the region of the chest and neck as a result of tumor excision. In experiment 1, stimuli ranging from 2.46 to 17.10 gm of force were delivered by von Frey hairs to the flaps and comparable normal sites in 35 subjects at times ranging from 1 month to 10 years after surgery. No subjects perceived stimuli of less than 11.80 gm, thermal, or moving touch applied to flaps, whereas 21 percent perceived 11.80 gm or greater force (judged as painful applied to normal skin). The results of experiment 2 showed that these findings were not due to visual information available to subjects. Possible explanations for the fact that these results are radically different from those reported in the literature are discussed.