Dynamic Mechanical Allodynia Research Articles

Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area.

In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.

Assessment of somatosensory profiles by quantitative sensory testing in children and adolescents with and without cerebral palsy and chronic pain

ObjectiveWe investigated differences in somatosensory profiles (SSPs) assessed by quantitative sensory testing in children and adolescents with cerebral palsy (CCP) with and without chronic pain and compared these differences to those in a group of typically developed children and adolescents (TDC) with and without chronic pain. MethodAll included subjects were consecutively recruited from and tested at the same outpatient orthopedic clinic by the same investigator. The subjects had their reaction times tested. The SSP consisted of the following tests: warmth (WDT), cool (CDT), mechanical (MDT), and vibration (VDT) detection thresholds; heat (HPT), pressure (PPT), and mechanical (MPT) pain thresholds; wind-up ratio (WUR); dynamic mechanical allodynia (DMA) and cold pressor test (CPT) using a conditioned pain modulation (CPM) paradigm. ResultsWe included 25 CCP and 26 TDC. TDC without chronic pain served as controls. In TDC with chronic pain, WDT, HPT, HPT intensity, and PPT were higher than in controls. No differences in SSPs between CCP with and without chronic pain were observed. In CCP, the MDT, WDT, CDT, and HPT intensity were higher than in controls. CCP had longer reaction times than TDC. There were no differences regarding the remaining variables. DiscussionIn CCP, the SSPs were independent of pain status and findings on MR images. In all CCP the SSPs resembled TDC with chronic pain, compared to TDC without chronic pain. This suggests that CCP do not have the normal neuroplastic adaptive processes that activate and elicit functional changes in the central and peripheral nervous systems.

Healthy women show more experimentally induced central sensitization compared with men.

Women more often experience chronic pain conditions than men. Central sensitization (CS) is one key mechanism in chronic pain that can differ between the sexes. It is unknown whether CS processes are already more pronounced in healthy women than in men. In 66 subjects (33 women), a thermal CS induction protocol was applied to the dorsum of one foot and a sham protocol to the other. Spatial extent [cm 2 ] of secondary mechanical hyperalgesia (SMH) and dynamic mechanical allodynia were assessed as subjective CS proxy measures, relying on verbal feedback. Changes in nociceptive withdrawal reflex magnitude (NWR-M) and response rate (NWR-RR) recorded through surface electromyography at the biceps and rectus femoris muscles were used as objective CS proxies. The effect of the CS induction protocol on SMH was higher in women than in men (effect size 2.11 vs 1.68). Nociceptive withdrawal reflex magnitude results were statistically meaningful for women (effect size 0.31-0.36) but not for men (effect size 0.12-0.29). Differences between men and women were not meaningful. Nociceptive withdrawal reflex response rate at the rectus femoris increased in women after CS induction and was statistically different from NWR-RR in men (median differences of 13.7 and 8.4% for 120 and 140% reflex threshold current). The objective CS proxy differences indicate that dorsal horn CS processes are more pronounced in healthy women. The even larger sex differences in subjective CS proxies potentially reflect greater supraspinal influence in women. This study shows that sex differences are present in experimentally induced CS in healthy subjects, which might contribute to women's vulnerability for chronic pain.

5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT3 receptors and monoamines.

Vincristine is the drug of choice for Hodgkin's lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The available drugs used for vincristine-induced neuropathic pain (VINP) have a range of safety, efficacy, and tolerability issues prompting a search for new therapies. 5,7-Dimethoxycoumarin (5,7-DMC) also known as citropten, is a natural coumarin found in the essential oils of citrus plants such as lime, lemons, and bergamots, and it possesses both antidepressant and anti-inflammatory effects. This study was designed to investigate the possible analgesic and antiallodynic effects of 5,7-DMC in a murine model of VINP. Vincristine was administered to groups of BALB/c male mice (0.1mg/kg intraperitoneally) once daily for 14days to induce VINP. Thermal hyperalgesia and mechanical allodynia were quantified using the tail immersion test and von Frey filament application method. The levels of monoamine neurotransmitters and vitamin C in frontal cortical, striatal and hippocampal tissues, as well as the TNF-α level in plasma, were quantified using high performance liquid chromatography and ELISA respectively. On day 15 of the protocol, acute treatment with 5,7-DMC clearly reversed VINP thermal hyperalgesia, mechanical static allodynia, mechanical dynamic allodynia, and cold allodynia. The activity of 5,7-DMC against hyperalgesia and allodynia was inhibited by pretreatment with ondansetron but not naloxone, implicating a 5-HT3 receptor involvement. VINP vitamin C levels were restored by 5,7-DMC in the frontal cortex, and changes in serotonin, dopamine, adenosine, inosine and hypoxanthine levels caused by vincristine were reversed either fully or partially. Additionally, the vincristine-induced rise in hippocampal serotonin, dopamine, inosine and striatal serotonin was appreciably reversed by 5,7-DMC. 5,7-DMC also reversed the vincristine-induced increase in the plasma level of TNF-α. In negating the changes in the levels of some neurotransmitters in the brain caused by vincristine, 5,7-DMC showed stronger effects than gabapentin. It was concluded that, there is a potential role of 5-HT3 receptors and monoamines in the amelioration of VINP induced by 5,7-DMC, and the use of this compound warrants further investigation.

Quantitative Dynamic Allodynograph-A Standardized Measure for Testing Dynamic Mechanical Allodynia in Chronic Limb Pain.

Dynamic mechanical allodynia (DMA) is both a symptom and a central sensitization sign, yet no standardized method for quantifying the DMA area has been reported. This study aimed to establish psychometric properties for Quantitative Dynamic Allodynography (QDA), a newly developed protocol measuring the DMA area as a percentage of the body surface. Seventy-eight patients aged 18-65 diagnosed with chronic complex regional pain syndrome (CRPS) participated in this study. Test-retest reliability was conducted twice, one week apart (N = 20), and inter-rater (N = 3) reliability was conducted on 10 participants. Disease severity (CRPS Severity Score, CSS), pain intensity (VAS), and quality of life (SF-36) measures were utilized to test construct validity. High inter-rater reliability (intraclass correlation coefficient (ICC) = 0.96, p < 0.001) and test-retest reliability (r = 0.98, p < 0.001) were found. Furthermore, the QDA score was found to be correlated with the CSS (r = 0.47, p < 0.001), VAS (r = 0.37, p < 0.001), and the SF-36 physical health total (r = -0.47, p < 0.001) scores. The QDA is the first developed reliable and valid protocol for measuring DMA in a clinical setting and may be used as a diagnostic and prognostic measure in clinics and in research, advancing the pain precision medicine approach.

Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions

Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

BDNF-TrkB signaling pathway-mediated microglial activation induces neuronal KCC2 downregulation contributing to dynamic allodynia following spared nerve injury.

Mechanical allodynia can be evoked by punctate pressure contact with the skin (punctate mechanical allodynia) and dynamic contact stimulation induced by gentle touching of the skin (dynamic mechanical allodynia). Dynamic allodynia is insensitive to morphine treatment and is transmitted through the spinal dorsal horn by a specific neuronal pathway, which is different from that for punctate allodynia, leading to difficulties in clinical treatment. K+-Cl- cotransporter-2 (KCC2) is one of the major determinants of inhibitory efficiency, and the inhibitory system in the spinal cord is important in the regulation of neuropathic pain. The aim of the current study was to determine whether neuronal KCC2 is involved in the induction of dynamic allodynia and to identify underlying spinal mechanisms involved in this process. Dynamic and punctate allodynia were assessed using either von Frey filaments or a paint brush in a spared nerve injury (SNI) mouse model. Our study discovered that the downregulated neuronal membrane KCC2 (mKCC2) in the spinal dorsal horn of SNI mice is closely associated with SNI-induced dynamic allodynia, as the prevention of KCC2 downregulation significantly suppressed the induction of dynamic allodynia. The over activation of microglia in the spinal dorsal horn after SNI was at least one of the triggers in SNI-induced mKCC2 reduction and dynamic allodynia, as these effects were blocked by the inhibition of microglial activation. Finally, the BDNF-TrkB pathway mediated by activated microglial affected SNI-induced dynamic allodynia through neuronal KCC2 downregulation. Overall, our findings revealed that activation of microglia through the BDNF-TrkB pathway affected neuronal KCC2 downregulation, contributing to dynamic allodynia induction in an SNI mouse model.

Clinical Assessment of Mechanical Allodynia in Youth With Complex Regional Pain Syndrome: Development and Preliminary Validation of the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense)

Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The 6 Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = .956) and discharge (CR = .973), reasonably fit the hypothesized linear model of stimulus intensity (P < .0001), and significantly loaded onto a single latent factor, mechanical allodynia (P < .0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (rs = .40; P = .004) and pain catastrophizing (rs = .33; P = .017) at admission. The Pedi-Sense appeared responsive to intervention as participants’ total scores improved by 1.44 points (95% CI: .72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PerspectiveThis article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Trigeminal‐mediated headshaking: A diagnostic challenge

Trigeminal‐mediated headshaking: A diagnostic challenge

Sensitivity to movement-evoked pain, central sensitivity symptoms, and pro-nociceptive profiles in people with chronic shoulder pain: Aparallel-group cross-sectional investigation.

To investigate whether sensitivity to movement-evoked pain (SMEP), central sensitivity symptom burden, and quantitative sensory testing (QST) outcomes differ between healthy controls and people with chronic shoulder pain. People with chronic shoulder pain (n=39) and healthy controls (n=26) completed validated questionnaires measuring demographic, pain characteristics, psychological factors, social support, sleep quality, central sensitivity inventory (CSI), and physical activity levels. A blinded assessor administered QST measuring pressure pain threshold, temporal summation, conditioned pain modulation, and cold hyperalgesia. All participants performed repeated lifting of weighted canisters and reported severity of pain over successive lifts of the weighted canisters. Between-group differences in the QST, SMEP and CSI scores were investigated. Demographic and psychosocial variables were adjusted in the analyses. Dynamic mechanical allodynia, mechanical temporal summation, movement-evoked pain scores, SMEP index, and CSI scores were significantly (p ≤ 0.05) higher in the chronic shoulder pain group than in healthy controls. A significant proportion of people with chronic shoulder pain presented with pro-nociceptive profiles and experienced higher pain severity, interference, and disability. People with chronic shoulder pain displayed symptoms and signs of central sensitization. Future research should investigate the predictive role of central sensitization on clinical outcomes in shoulder pain.

Analgesic Characteristics of NanoBEO Released by an Airless Dispenser for the Control of Agitation in Severe Dementia.

Chronic pain is one of the most common causes of the need for clinical evaluation, acquiring more importance in the elderly with cognitive impairment. Reduced self-reporting capabilities cause unrelieved pain contributing to the development of agitation. Safe and effective pain treatment can afford the management of agitation without the serious increase in death risk associated with neuroleptics. To this aim, the essential oil of bergamot (BEO), proven by rigorous evidence to have strong preclinical anti-nociceptive and anti-allodynic properties, has been engineered (NanoBEO, patent EP 4003294) to allow randomized, double-blind, placebo-controlled trials (BRAINAID, NCT04321889). The present study: (1) assesses the analgesic effects of a single therapeutic dose of NanoBEO, as supplied by an airless dispenser for clinical translation, in models of inflammatory, neuropathic, and sensitization types of pain relevant to clinic; (2) provides a dose–response analysis of the efficacy of NanoBEO on scratching behavior, a typical behavioral disturbance occurring in dementia. A single therapeutic dose of NanoBEO confirms efficacy following thirty minutes pre-treatment with capsaicin and on the central sensitization phase induced by formalin. Moreover, it has an ID50 of 0.6312 mg and it is efficacious on static and dynamic mechanical allodynia. Altogether, the gathered results strengthen the potential of NanoBEO for clinical management of pain and agitation.

Pre-Synaptic GABAA in NaV1.8+ Primary Afferents Is Required for the Development of Punctate but Not Dynamic Mechanical Allodynia following CFA Inflammation.

Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABAA in NaV1.8-positive sensory neurons (Scn10aCre;Gabrb3fl/fl) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABAA. Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABAA and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8+ afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABAA in NaV1.8+ nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.

Naltrexone promotes mechanical allodynia in humans and rats

Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired static and dynamic mechanical allodynia, as measured by von Frey filament (vFf) and brush stimulations. Pregabalin and levodopa administrations in N.T.P. significantly reduced allodynic behaviour, albeit these molecules did not completely stop it. As evidenced by the deployment of the vFf, subchronic treatment with Naltrexone delivered peripherally or intrathecally induced allodynic behaviour in rats. Increased expressions of two pain markers, pERK1/2 and PKCγ, in the spinal dorsal horn laminae were associated with naltrexone-induced allodynic behaviour. After vFf stimulation, pERK1/2 expression was substantially higher (p < 0.001) in superficial spinal dorsal horn laminae than in non-stimulated or naive non-stimulated rats. In addition, when compared to control rats, N.T.R. showed a substantial (p < 0.001) increase in PKCγ expression. PKCγ expression was found to be strong in lamina IIi and laminae III-IV. A cellular mechanism is proposed for the naltrexone effect. In both people and rats, Naltrexone induces static mechanical allodynia, according to this study.

LB898 Validation of the paindetect questionnaire in hidradenitis suppurativa using quantitative sensory testing

Hidradenitis suppurativa (HS) is a painful, inflammatory skin condition that causes nociceptive, neuropathic, and nociplastic pain types. The PainDETECT Questionnaire (PD-Q) is a nine-item survey that has been used to assess the likelihood of neuropathic pain character. However, it has not been validated in HS. Quantitative Sensory Testing (QST) is a standardized series of sensory exams considered the gold standard for evaluation of sensory dysfunction including neuropathic pain. Evaluating the performance of the PD-Q in HS may enable clinicians to screen for neuropathic pain in HS and tailor pain management. In this observational, cross-sectional study, 20 participants with HS underwent QST at a control site on the dorsal hand and a painful HS lesion to evaluate pain phenotype including the presence of neuropathic pain. Participants also completed the PD-Q. Participants were of young age (median 36 years, IQR 30-47) and mostly female (75%) and of Black race (55%). 14 participants (70%) were Hurley stage 2, and 5 (20%) were Hurley stage 3. Participants had substantial inflammatory activity per IHS4 (15, 10-42). 17 HS lesions (85%) were draining tunnels and 3 (15%) were inflammatory nodules. 13 HS lesions (65%) were in the axilla, 6 (30%) were in the groin, and 1 (5%) was on the chest. 10 participants (50%) exhibited neuropathic pain on QST, defined by the presence of dynamic mechanical allodynia at the HS lesion. On the PD-Q, 7 participants (35%) were classified as unlikely having neuropathic pain, 7 (35%) as indeterminate for neuropathic pain, and 6 (30%) as likely having neuropathic pain. QST and the PD-Q demonstrated 75% agreement for pooled likely or indeterminate presence of neuropathic pain versus absence of neuropathic pain with a Cohen's k of 0.5 (p = 0.01) demonstrating moderate agreement. Compared to the gold standard of QST, the PD-Q has modest agreement in screening for neuropathic pain character in HS. Because pain phenotype strongly informs management of chronic pain, the PD-Q may be a useful clinical tool for directing management of HS pain.

P-1 Potential neuroprotective effects of losartan and donepezil on oxaliplatin-induced peripheral neuropathy in rats

Oxaliplatin (OXL) is a platinum-based antineoplastic drug widely used for treating colorectal cancer which induces peripheral neuropathy as dose-limiting toxicity. We assess the neuroprotective effects of losartan (LOS) and donepezil (DPZ) on OXL-induced peripheral neuropathy in rats. Forty Sprague-Dawley rats were divided into four groups; control (vehicle-treated), OXL (2.4 mg/kg/d; intraperitoneal), OXL+LOS (100 mg/kg/d; oral), and OXL+DPZ (1 mg/kg/d; oral). All were given 5 times/week for 2 weeks. Behavioral assessment of pain, sensory, and motor disturbances was done on days 7 and 14 using a paintbrush, acetone, tail-flick latency, and grip strength tests. The levels of interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were measured in L4-L6 samples. Histopathological examination of the sciatic nerve was done to assess nerve degeneration. OXL induced significant mechanical dynamic allodynia, cold allodynia, and thermal hyperalgesia compared to the control group. LOS significantly ameliorated mechanical and cold allodynia, while DPZ improved mechanical allodynia and thermal hyperalgesia. OXL significantly increased IL-1β, and TNF-α compared to the control group. Only LOS significantly attenuated these markers. In the OXL group, the axons were swollen, and nerve fiber degeneration with neuron gaps occurred. Both treatments improved these histopathological changes. LOS and DPZ attenuate the neurotoxic effect of oxaliplatin by attenuating behavioral and histopathological alterations and the protective effect of LOS may involve in the inhibition of spinal pro inflammatory cytokines. Therefore, LOS and DPZ are promising agents to prevent OXA-induced peripheral neuropathy.

Contributions of SARM1 to neuropathic pain vary across nerve injury models

The purpose of this study is to determine if Sarm1 is required for the development of nerve injury induced neuropathic pain. Neuropathic pain after nerve injury often manifests as mechanical allodynia and thermal hyperalgesia. Wallerian degeneration has been reported to play a role in the development of nerve injury induced neuropathic pain. In addition, sterile alpha and TIR motif containing 1 (Sarm1) is a protein required for Wallerian degeneration and has been implicated in several non-axotomy neuropathic pain models. It is thus of our interest to determine the requirement of Sarm1 for the development of nerve injury induced neuropathic pain. Either the spared nerve injury (SNI), L4 Spinal Nerve Ligation (SNL), or chronic constriction injury (CCI) nerve injury model was performed on Sarm1KO mice and their littermate WT controls. Behavioral assays of evoked mechanical (von Frey, dynamic brush) and thermal (Hargreaves) sensitivity were performed at multiple time points before and after surgery to assess pain sensitivity. Alternatively, mice were videorecorded after injury and their spontaneous pain-related behaviors scored. Results Sarm1KO mice did not exhibit deficits in development of punctate or dynamic brush mechanical allodynia after CCI. Interestingly, however, Sarm1KO did exhibit a delay in development of heat hyperalgesia after CCI compared to WT controls. By contrast, Sarm1KO mice did not show deficits in development of either mechanical allodynia or thermal hyperalgesia after SNI and L4 SNL surgeries. However, preliminary results suggest a trend towards reduced spontaneous pain behaviors after SNI in SARM1 KO, compared to WT controls. Our data suggest that Sarm1 is required for the normal development of heat hyperalgesia but not mechanical allodynia after CCI. In summary, the role of Sarm1 in nerve injury induced neuropathic pain is both model and modality dependent. Grant support from Neurosurgery Pain Research Institute at Johns Hopkins Dr. Miriam and Sheldon Adelson Medical Research Foundation. The purpose of this study is to determine if Sarm1 is required for the development of nerve injury induced neuropathic pain. Neuropathic pain after nerve injury often manifests as mechanical allodynia and thermal hyperalgesia. Wallerian degeneration has been reported to play a role in the development of nerve injury induced neuropathic pain. In addition, sterile alpha and TIR motif containing 1 (Sarm1) is a protein required for Wallerian degeneration and has been implicated in several non-axotomy neuropathic pain models. It is thus of our interest to determine the requirement of Sarm1 for the development of nerve injury induced neuropathic pain. Either the spared nerve injury (SNI), L4 Spinal Nerve Ligation (SNL), or chronic constriction injury (CCI) nerve injury model was performed on Sarm1KO mice and their littermate WT controls. Behavioral assays of evoked mechanical (von Frey, dynamic brush) and thermal (Hargreaves) sensitivity were performed at multiple time points before and after surgery to assess pain sensitivity. Alternatively, mice were videorecorded after injury and their spontaneous pain-related behaviors scored. Results Sarm1KO mice did not exhibit deficits in development of punctate or dynamic brush mechanical allodynia after CCI. Interestingly, however, Sarm1KO did exhibit a delay in development of heat hyperalgesia after CCI compared to WT controls. By contrast, Sarm1KO mice did not show deficits in development of either mechanical allodynia or thermal hyperalgesia after SNI and L4 SNL surgeries. However, preliminary results suggest a trend towards reduced spontaneous pain behaviors after SNI in SARM1 KO, compared to WT controls. Our data suggest that Sarm1 is required for the normal development of heat hyperalgesia but not mechanical allodynia after CCI. In summary, the role of Sarm1 in nerve injury induced neuropathic pain is both model and modality dependent. Grant support from Neurosurgery Pain Research Institute at Johns Hopkins Dr. Miriam and Sheldon Adelson Medical Research Foundation.

Cold allodynia is correlated to paroxysmal and evoked mechanical pain in complex regional pain syndrome (CRPS).

Mechanisms of complex regional pain syndrome (CRPS) are still debated. Identifying subgroups of patients have been attempted in the hope of linking clinical findings to possible mechanisms. The aim of the present study was to investigate whether subgroups of CRPS (based on quantitative sensory testing (QST)-results) differed with respect to different characteristics of pain like spontaneous ongoing or paroxysmal pain and mechanical dynamic allodynia. 61 CRPS-patients (type 1 and 2) were examined clinically and with QST, in affected and contralateral extremity, with assessment of thresholds for warmth, cold and heat-and cold pain. 43 patients (20 men, 23 men) were diagnosed with CRPS 1 (70.5%) and 18 patients (8 women and 10 men) with CRPS 2 (29.5%). Three subgroups were defined based on thermal thresholds; A (thermal allodynia 22.9%), B (thermal hyposensitivity 37.3%), C (thermal allodynia and hyposensitivity 39.3%). Paroxysmal pain was more prevalent in patients with thermal allodynia (merging group A+C, 25/38-65.8%) compared to patients without thermal allodynia (group B, 5/23-21.7%) (p-value=0.00085). We suggest that cold allodynia is based on hyper-excitability of very superficial skin nociceptors. The correlation between paroxysmal pain, allodynia to light touch and cold allodynia suggests that activity in those peripheral nociceptors can drive both, paroxysmal pain and spinal sensitization leading to stroke evoked allodynia. Mechanistically, the physical cold stimulus can unmask disease-related hyperexcitability by closure of temperature-sensitive potassium channels or induction of resurgent currents. Small fiber degeneration alone may not be the crucial mechanism in CRPS, nor explain pain.

Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial

BackgroundInduction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain.Methods(1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0–10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS.Results(1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI − 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen’s D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia.ConclusionsResults from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663.

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.