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Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18–63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19–63] were included. The percentage of individuals with SCI responding to stimuli (70–77%; p < 0.001), their response rates (16–21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-taub p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher’s exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Background and purpose: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL‐N), whereas the impact of upper limb neuropathy (UL‐N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL‐N and its functional and psychosocial consequences in type 2 diabetes. Methods: Individuals with type 2 diabetes (n = 141) and an age‐ and sex‐matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status. Results: The prevalence of UL‐N was 30.5% in patients with diabetes and that of LL‐N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL‐N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL‐N had reduced estimates of psychosocial health including health‐related QoL compared to control subjects and patients without UL‐N. UL‐N correlated with the severity of LL‐N, but not with duration of diabetes, glycemia, age, or sex. Conclusions: This study points to a substantial prevalence of UL‐N in type 2 diabetes. The sensory phenotype of patients with UL‐N was similar to LL‐N and was characterized by loss of sensory function. Our study demonstrated an association of UL‐N with impaired manual dexterity and reduced health‐related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA).Methods: Using a phantom-skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra-Med-No. CIV-12-05-006501).Results: Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q-Sense by a floor effect (p < .001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q-Sense was good/excellent for CDT (ICC = 0.894) and WDT (ICC = 0.898), moderate for HPT (ICC = 0.525) and poor for CPT (ICC = 0.305). In diabetic patients, the sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60 years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n = 51) were similar for both devices.Conclusions: Physical characteristics of both thermo-test devices are similarly limited by the poor temperature conduction of the skin. The Q-Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut-off temperature should be set to ≤18°C.Significance: High purchase costs prevent a widespread use of thermo-test devices for diagnosing small fibre neuropathy. The air-cooled "Q-Sense" could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut-off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q-Sense compared to the "Thermal Sensory Analyzer" (TSA). We recommend lowering the cut-off value of the Q-Sense to ≤18°C for its full clinical use. [ABSTRACT FROM AUTHOR]

Background and Aims: Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers.Methods: QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z-values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects.Results: Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z-transformation these differences disappeared except for PPT in CRPS (p = .001).Discussion: Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes.Significance: Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance. [ABSTRACT FROM AUTHOR]

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (Aδ fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aβ-, and Aδ-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN. [ABSTRACT FROM AUTHOR]

Disturbed sleep is known to substantially aggravate both the pain condition and the affective state of pain patients. The neurobiological mechanisms underlying these adverse effects are unknown. Oxytocin (OT), being largely involved in social and emotional behavior, is considered to also play a modulatory role in nociception. We hypothesized a pathophysiological role of OT for the hyperalgesic and anxiogenic effects of sleep loss. An established human model of one night of total sleep deprivation (TSD) was used to test this hypothesis. Twenty young healthy students (n = 10 male and n = 10 female) were investigated in a balanced cross-over design, contrasting TSD with a night of habitual sleep (HS). All females took monophasic oral contraceptives (OC) and were investigated during their ‘pill-free’ phase. Plasma OT concentrations were correlated with (1) pain thresholds, (2) descending pain inhibition, and (3) state-anxiety scores. Compared to the HS condition, the plasma OT concentration was significantly increased in sleep deprived females (p = 0.02) but not males (p = 0.69). TSD resulted in pain hypersensitivity to noxious cold (p = 0.05), noxious heat (p = 0.023), and pricking stimuli (p = 0.013) and significantly increased state-anxiety (p = 0.021). While, independent of sex, lower heat pain thresholds correlated with higher plasma OT (p = 0.036), no such associations were found for cold/mechanical pain. In sleep-deprived females, higher plasma OT showed a mild (but insignificant) association with lower pain inhibition (p = 0.093). We found a positive correlation between anxiety-scores and OT (p = 0.021), which was enhanced when respecting “sex” (p = 0.008) and “sleep” (p = 0.001) in a hierarchical regression analysis. Altogether, our study revealed a complex and partially sex-dependent correlation between plasma OT and TSD-induced changes of experimental pain and anxiety. The minor role of OT for TSD-induced changes of evoked pain, and its major involvement in anxiety, argues against a specific role of OT for linking the adverse effects of TSD on pain sensitivity and anxiety with each other. Future investigations are needed in order to dissect out the effect of OC on the sex-dependent effects of TSD observed in our study. [ABSTRACT FROM AUTHOR]

Objective: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. Methods and Results: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. Conclusion: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine. [ABSTRACT FROM AUTHOR]

Presents a study which investigated the role of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the nitric oxide synthase-dependent vasodilation to acidosis. Materials and methods; Results; Discussion.

Inflammation is a vital process for the injured tissue restoration and one of its hallmarks is inflammatory hyperalgesia. The cyclooxygenase (COX) pathway is strongly related to the inflammatory and painful process. Usually, the COX-1 isoform is described as homeostatic, while COX-2 is characterized as inducible in inflammatory conditions. Although it is well known that neutrophil cells are the first to arrive at the inflamed site and the major source of COX-2 is still unknown, the specific role of neutrophil-derived COX-2 in the pain process is. Thus, in the present study, we demonstrate for the first time that neutrophil-derived COX-2 plays a key role in peripheral inflammatory hyperalgesia. Conditional knockout mice for COX-2 in neutrophils (COX-2 fl/fl: Mrp8cre±) exhibited higher pain sensitivity after carrageenan (CG) injection and long-lasting IL-1β-induced hyperalgesia compared with the control group (COX-2 fl/fl). Also, CG-induced inflammation in COX-2 fl/fl: Mrp8cre± mice showed COX-1 overexpression, and increased neutrophil migration and pro-inflammatory cytokines (e.g., IL-1β and CXCL1). These findings revealed that neutrophil COX-2 has an important role in the regulation of inflammatory hyperalgesia. [ABSTRACT FROM AUTHOR]