Cutaneous Heat Research Articles

Physiological and Psychological Predictors of Short-Term Disability in Workers with a History of Low Back Pain: A Longitudinal Study.

Despite an elusive pathophysiology, common characteristics are often observed in individuals with chronic low back pain (LBP). These include psychological symptoms, altered pain perception, altered pain modulation and altered muscle activation. These factors have been explored as possible determinants of disability, either separately or in cross-sectional studies, but were never assessed in a single longitudinal study. Therefore, the objective was to determine the relative contribution of psychological and neurophysiological factors to future disability in individuals with past LBP. The study included two experimental sessions (baseline and six months later) to assess cutaneous heat pain and pain tolerance thresholds, pain inhibition, as well as trunk muscle activation. Both sessions included the completion of validated questionnaires to determine clinical pain, disability, pain catastrophizing, fear-avoidance beliefs and pain vigilance. One hundred workers with a history of LBP and 19 healthy individuals took part in the first experimental session. The second experimental session was exclusively conducted on workers with a history of LBP (77/100). Correlation analyses between initial measures and disability at six months were conducted, and measures significantly associated with disability were used in multiple regression analyses. A first regression analysis showed that psychological symptoms contributed unique variance to future disability (R2 = 0.093, p = .009). To control for the fluctuating nature of LBP, a hierarchical regression was conducted while controlling for clinical pain at six months (R2 = 0.213, p < .001) where pain inhibition contributed unique variance in the second step of the regression (R2 change = 0.094, p = .005). These results indicate that pain inhibition processes may constitute potential targets for treatment to alleviate future disability in individuals with past or present LBP. Then again, the link between psychological symptoms and pain inhibition needs to be clarified as both of these factors are linked together and influence disability in their own way.

Effect of Experimental Cutaneous Hand Pain on Corticospinal Excitability and Short Afferent Inhibition.

Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20−5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas.

Selective Laser Stimulation of Aδ- or C-Fibers Through Application of a Spatial Filter: A Study in Healthy Volunteers

Background: Pain is perceived through different pathways involving thinly myelinated Aδ-fibers and unmyelinated C-fibers. Aδ-fibers are responsible for a quick, sharp pain, whereas C-fibers relate to a late-onset, burning sensation. Several studies suggest that it is essential to investigate nociceptive fibers separately and in relation to each other. The aim of this study was to selectively stimulate Aδ- and C-fibers using a 980-nm diode laser by varying the laser settings and the stimulated surface area in healthy subjects. Methods: Selective activation of Aδ- and C-fibers is possible using their distinctive physiological characteristics. We used the differences in heat activation threshold and surface density to selectively activate Aδ- and C-fibers. Stimuli from a 980-nm diode laser were applied to 44 healthy volunteers. Two different laser settings were applied for selective stimulation of Aδ-fibers (20 ms at 2.7 W) and C-fibers (50 ms at 0.8 W). A spatial titanium filter, containing 40 holes with varying diameters (0.4, 0.6, 1, and 2 mm), was used to apply the stimuli with varying surface areas. The test subjects received 80 stimuli in total and were asked to press a button when the stimulation was felt. Reaction times between 300 and 650 ms indicate Aδ-fiber activation, whereas reaction times between 650 and 2,000 ms indicate C-fiber activation. Results: First, the usage of response time to discriminate between Aδ- and C-fiber activation was validated. Then, the combined use of the two different stimulation protocols and a spatial filter turned out to be effective to achieve different probabilities of stimulating Aδ- or C-fibers. With the Aδ-protocol and a grid diameter of 2 mm, an Aδ:C response ratio of 1.17:1 was reached, and with the C-protocol and a grid diameter of 0.4 mm, the Aδ:C ratio was 0.05:1. Conclusions: Our results indicate that cutaneous heat stimuli applied with a 980-nm diode laser, using a specific stimulation paradigm and a spatial filter, allow us to selectively activate Aδ- and C-fibers. These findings could serve as a basis for clinical investigation of different involvements of Aδ- and C-fibers in patients suffering from small fiber neuropathies. J Neurol Res. 2016;6(1):1-7 doi: http://dx.doi.org/10.14740/jnr361w

Thermal Sensitivity and Dimethyl Sulfoxide (DMSO).

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound's innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55°C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15-30s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse's footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs.

Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization? A study of healthy volunteers - design and detailed plan of analysis.

BackgroundSeveral factors are believed to influence the development and experience of pain.Human clinical pain models are central tools, in the investigation of basic physiologic pain responses, and can be applied in patients as well as in healthy volunteers. Each clinical pain model investigates different aspects of the human pain response.Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated with the size of the area of secondary hyperalgesia induced by the clinical heat pain model: Brief thermal sensitization.Methods and designWe aim to include 120 healthy participants. The participants will be tested on two separate study days with the following procedures: i) Brief thermal sensitization, ii) heat pain detection threshold and iii) pain during thermal stimulation. Additionally, the participants will be tested with the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale questionnaires.We conducted statistical simulations based on data from our previous study, to estimate an empirical power of 99.9 % with α of 0.05. We define that an R2 < 0.25 and predictive intervals larger than +/−150 cm2 are indications of a weak association.DiscussionThe area of secondary hyperalgesia may serve as a quantitative measure of the central sensitization induced by cutaneous heat stimulation, and thus may be a biomarker of an individual’s pain sensitivity. The number of studies investigating secondary hyperalgesia is growing; however basic knowledge of the physiologic aspects of secondary hyperalgesia in humans is still incomplete. We therefore find it interesting to investigate if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitizationTrial registrationClinicaltrials.gov (Identifier: NCT02527395). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436).Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-016-0193-2) contains supplementary material, which is available to authorized users.

A small yet comprehensive subset of human experimental pain models emerging from correlation analysis with a clinical quantitative sensory testing protocol in healthy subjects.

Picturing the complexity of pain in human experimental settings has increased the predictivity for clinical pain but requires increasingly complex test batteries. This raises problems in studies in which time is objectively limited, for example by the course of action of an analgesic drug. We addressed the selection of a small yet comprehensive set of pain tests for the use in such a situation. Nineteen different pain measures from 'classical' pain models (n = 9) and a clinically established QST-pain test battery (n = 10), were obtained from 72 healthy volunteers (34 men). The nonparametric correlation structure among the various pain measures was analysed using Ward clustering. Four clusters emerged, each consisting of highly correlated pain measures. The pain model groups emerged comprised (I) pain thresholds and tolerances to blunt pressure or electrical pain; (II) pain thresholds to thermal stimuli; (III) pain measures obtained following application of punctate mechanical, intranasal CO2 chemical or cutaneous laser heat stimuli; and (IV) detection thresholds to thermal stimuli. The first three clusters agreed with an immediate mechanistic interpretation as reflecting C-fibre mediated pain, thermal pain and Aδ-fibre mediated pain, respectively, whereas the last cluster contained non-painful measures and was disregarded. When basing a selection of a small comprehensive set of pain models on the assumption that highly correlated pain measures account for redundant results and therefore, one member of each group suffices an economic yet comprehensive pain study, results suggest inclusion of established C-fibre, Aδ-fibre mediated and thermal pain measures.

Pathophysiological alterations induced by sustained 35-GHz radio-frequency energy heating.

Exposure to radio-frequency energy (RFE) of millimeter wavelengths results in a relatively high skin-heating rate, with only a moderate rate of core heating. Yet, prolonged RFE exposure eventuates in severe hypotension and death. In this study, we characterized pathophysiological changes associated with prolonged RFE sufficient to induce hypotension. Anesthetized rats were exposed to 35-GHz RFE with a power density of 75 mW/cm2. Cardiovascular and temperature parameters were continuously recorded. Blood factors and histopathology were compared between sham (n=6) and exposed (n=12) animals. Using infrared thermography, we confirmed a relatively high temperature (>46 °C) at the skin surface of the irradiated site. Histopathological results included hemorrhage and congestion of blood vessels in the dermis and subcutis of irradiated skin without induction of burn. As in environmental heating, significantly greater levels of serum glucose, creatinine, uric acid, and anion gap were observed in rats exposed to longer-duration RFE (approx. 38-min exposures) than in shorter-duration (approx. 19-min exposures) or sham (time control) animals. However, changes in blood electrolytes or liver enzymes (often seen during heatstroke) were not observed after the RFE exposures. Even without major tissue injury or serum/plasma enzyme and electrolyte changes, rapid cutaneous heating via RFE induced profound hypotension that eventuated in death.

Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human.

Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.Trial RegistrationEudraCT 2012-005663-27

Referred pain and cutaneous responses from deep tissue electrical pain stimulation in the groin

Persistent postherniotomy pain is located around the scar and external inguinal ring and is often described as deep rather than cutaneous, with frequent complaints of pain in adjacent areas. Whether this pain is due to local pathology or referred/projected pain is unknown, hindering mechanism-based treatment. Deep tissue electrical pain stimulation by needle electrodes in the right groin (rectus muscle, ilioinguinal/iliohypogastric nerve and perispermatic cord) was combined with assessment of referred/projected pain and the cutaneous heat pain threshold (HPT) at three prespecified areas (both groins and the lower right arm) in 19 healthy subjects. The assessment was repeated 10 days later to assess the reproducibility of individual responses. Deep electrical stimulation elicited pain at the stimulation site in all subjects, and in 15 subjects, pain from areas outside the stimulation area was reported, with 90-100% having the same response on both days, depending on the location. Deep pain stimulation significantly increased the cutaneous HPT (P<0.014). Individual HPT responses before and during deep electrical pain stimulation were significantly correlated (ρ>0.474, P≤0.040) at the two test days for the majority of test areas. Our results corroborate a systematic relationship between deep pain and changes in cutaneous nociception. The individual referred/projected pain patterns and cutaneous responses are variable, but reproducible, supporting individual differences in anatomy and sensory processing. Future studies investigating the responses to deep tissue electrical stimulation in persistent postherniotomy pain patients may advance our understanding of underlying pathophysiological mechanisms and strategies for treatment and prevention. ClinicalTrials.gov (NCT01701427).

Increased brain L-arginine availability facilitates cutaneous heat loss induced by running exercise.

The effects of increased brain availability of L-arginine (L-arg), a precursor for nitric oxide synthesis, on core body temperature (Tcore ) and cutaneous heat loss were evaluated in running rats. One week prior to the experiments, adult male Wistar rats received the following implants: a chronic guide cannula in the lateral cerebral ventricle and a temperature sensor in the abdominal cavity. On the day of the experiments, the rats were assigned to receive a 2-μL intracerebroventricular injection of either NaCl (0.15 mol/L) or L-arg solution (0.825, 1.65 or 3.30 mol/L); Tcore and tail skin temperature were measured while the rats ran at a speed of 18 m/min until they were fatigued. L-arginine induced a dose-dependent reduction in the threshold Tcore required for cutaneous heat loss (38.09 ± 0.20°C for 3.30-mol/L L-arg vs 38.61 ± 0.10°C for saline; P < 0.05), which attenuated the exercise-induced hyperthermia. Although the rats treated with L-arg presented a lower Tcore at the end of exercise (~0.7°C lower after treatment with the highest dose), no changes in the time to fatigue were observed relative to the control trial. These results suggest that brain L-arg controls heat loss during exercise, most likely by modulating the sympathetic vasoconstrictor tonus to skin vessels. Furthermore, despite facilitating cutaneous heat loss mechanisms, increased brain L-arg availability did not enhance physical performance.

Physiological Responses and Lactation to Cutaneous Evaporative Heat Loss in Bos indicus, Bos taurus, and Their Crossbreds.

Cutaneous evaporative heat loss in Bos indicus and Bos taurus has been well documented. Nonetheless, how crossbreds with different fractional genetic proportions respond to such circumstances is of interest. A study to examine the physiological responses to cutaneous evaporative heat loss, also lactation period and milk yield, were conducted in Sahiwal (Bos indicus, n = 10, 444±64.8 kg, 9±2.9 years), Holstein Friesian (Bos taurus, HF100% (n = 10, 488±97.9 kg, 6±2.8 years)) and the following crossbreds: HF50% (n = 10, 355±40.7 kg, 2±0 years) and HF87.5% (n = 10, 489±76.8 kg, 7±1.8 years). They were allocated so as to determine the physiological responses of sweating rate (SR), respiration rate (RR), rectal temperature (RT), and skin temperature (ST) with and without hair from 06:00 h am to 15:00 h pm. And milk yield during 180 days were collected at days from 30 to 180. The ambient temperature-humidity-index (THI) increased from less than 80 in the early morning to more than 90 in the late afternoon. The interaction of THI and breed were highly affected on SR, RR, RT, and ST (p<0.01). The SR was highest in Sahiwal (595 g/m2/h) compared to HF100% (227 g/m2/h), and their crossbreds both HF50% (335 g/m2/h) and HF87.5% (299 g/m2/h). On the other hand, RR was higher in HF87.5% (54 bpm) and both HF100% (48 bpm) and HF50% (42 bpm) than Sahiwal (25 bpm) (p<0.01). The RT showed no significant differences as a result of breed (p>0.05) but did change over time. The ST with and without hair were similar, and was higher in HF100% (37.4°C; 38.0°C) and their crossbred HF50% (35.5°C; 35.5°C) and HF87.5% (37.1°C; 37.9°C) than Sahiwal (34.8°C; 34.8°C) (p<0.01). Moreover, the early lactation were higher at HF100% (25 kg) and 87.5% (25 kg) than HF50% (23 kg) which were higher than Sahiwal (18 kg) while the peak period of lactation was higher at HF100% (35 kg) than crossbreds both HF87.5% and HF50% (32 kg) which was higher than Sahiwal (26 kg) (p<0.05). In conclusion, sweating and respiration were the main vehicle for dissipating excess body heat for Sahiwal, HF and crossbreds, respectively. The THI at 76 to 80 were the critical points where the physiological responses to elevated temperature displayed change.

“Respiratory” turbinates in endotherms and ectotherms

For thirty years respiratory turbinates have been hailed as unequivocal indicators of endothermy in mammals and birds, but their validity as osteologic correlates of metabolic rate is limited to extant mammals. The nasal cavity contributes to heat and water conservation in extant birds, but their trachea also plays an important role. Efficiency of countercurrent heat exchange in the avian trachea increases when cartilaginous conchae are surgically removed. Respiratory turbinates and ectothermy are not mutually exclusive - recent re-examination of the nasal cavity of extant crocodilians reveals presence of a prominent turbinate-like preconcha. Vascularised surface area of the preconcha in the American alligator scales with positive allometry. A larger-than-predicted preconcha provides additional respiratory surface for evaporative cooling in bigger animals, in which cutaneous heat loss is made difficult by the reduced surface area:volume ratio. Thermographic imaging and in vivo measurements of upper respiratory tract temperatures in juvenile alligators provide experimental evidence that the nasal cavity acts as a site of heat dissipation. Heat loss and selective brain cooling, not heat and water conservation, may have been the original selective pressure driving the evolution of respiratory turbinates in archosaurs.

Types of skin afferent fibers and spinal opioid receptors that contribute to touch-induced inhibition of heart rate changes evoked by noxious cutaneous heat stimulation.

BackgroundIn anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch.ResultsThe present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aβ afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; μ-opioid receptor antagonist) injections.ConclusionsMicrocone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of μ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous μ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.

Activation of the habenula complex evokes autonomic physiological responses similar to those associated with emotional stress.

Neurons in the lateral habenula (LHb) discharge when an animal anticipates an aversive outcome or when an expected reward is not forthcoming, contributing to the behavioral response to aversive situations. So far, there is little information as to whether the LHb also contributes to autonomic physiological responses, including increases in body temperature (emotional hyperthermia) that are integrated with defensive behaviors. Vasoconstriction in cutaneous vascular bed and heat production in brown adipose tissue (BAT) both contribute to emotional hyperthermia. Our present study determines whether stimulation of the LHb elicits constriction of the tail artery and BAT thermogenesis in anesthetized Sprague–Dawley rats. Disinhibition of neurons in LHb with focal microinjections of bicuculline (1 nmol in 100 nl, bilaterally) acutely increased BAT temperature (+0.6 ± 0.1°C, n = 9 rats, P < 0.01) and reduced tail artery blood flow (by 88 ± 4%, n = 9 rats, P < 0.01). Falls in mesenteric blood flow, simultaneously recorded, were much less intense. The pattern of BAT thermogenesis and cutaneous vasoconstriction elicited by stimulating the habenula is similar to the pattern observed during stress-induced emotional hyperthermia, suggesting that the habenula may be important in this response.

Low heat pain thresholds in migraineurs between attacks.

Between attacks, migraine is associated with hypersensitivities to sensory stimuli. The objective of this study was to investigate hypersensitivity to pain in migraineurs between attacks. Cutaneous heat pain thresholds were measured in 112 migraineurs, migraine free for ≥ 48 hours, and 75 healthy controls. Pain thresholds at the head and at the arm were compared between migraineurs and controls using two-tailed t-tests. Among migraineurs, correlations between heat pain thresholds and headache frequency, allodynia symptom severity, and time interval until next headache were calculated. Migraineurs had lower pain thresholds than controls at the head (43.9 ℃ ± 3.2 ℃ vs. 45.1 ℃ ± 3.0 ℃, p = 0.015) and arm (43.2 ℃ ± 3.4 ℃ vs. 44.8 ℃ ± 3.3 ℃, p < 0.001). There were not significant correlations between pain thresholds and headache frequency or allodynia symptom severity. For the 41 migraineurs for whom time to next headache was known, there were positive correlations between time to next headache and pain thresholds at the head (r = 0.352, p = 0.024) and arm (r = 0.312, p = 0.047). This study provides evidence that migraineurs have low heat pain thresholds between migraine attacks. Mechanisms underlying these lower pain thresholds could also predispose migraineurs to their next migraine attack, a hypothesis supported by finding positive correlations between pain thresholds and time to next migraine attack.

Measurement of cooling detection thresholds for identification of diabetic sensorimotor polyneuropathy in type 1 diabetes.

ObjectiveCompared to recently-studied novel morphological measures, conventional small nerve fiber functional tests have not been systematically studied for identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine and compare the diagnostic performance of cooling detection thresholds (CDT) in a cross-sectional type 1 diabetes cohort.Research Design and Methods136 subjects with type 1 diabetes and 52 healthy volunteers underwent clinical and electrophysiological examination for DSP classification concomitantly with the Toronto Clinical Neuropathy Score (TCNS) and three small fiber function tests: CDT, heart rate variability (HRV), and laser doppler imaging of axon-mediated neurogenic flare responses to cutaneous heating (LDIFLARE). Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic (ROC) curves in the type 1 diabetes cohort.ResultsType 1 diabetes subjects were 42±17 years of age with mean HbA1c 7.9±1.7%. Fifty-nine (45%) met the case definition for DSP. CDT values were lowest in cases with DSP (18.3±8.4°C) compared to controls without DSP (28.4±3.5°C) and to healthy volunteers (29.6±1.8°C; p-value for both comparisons<0.0001). AUCCDT was 0.863 which was similar to AUCTCNS (0.858, p = 0.24) and AUCHRV (0.788, p = 0.05), but exceeded AUCLDIFLARE (0.750, p = 0.001). The threshold of <25.1°C was equivalent to the lower bound of the healthy volunteer 95% distribution [25.1, 30.8°C] and performed with 83% sensitivity and 82% specificity.ConclusionsAkin to novel small fiber morphological measures, CDT is a functional test that identifies DSP with very good diagnostic performance. These findings support further research that revisits the role of CDT in early DSP detection.

Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans

The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans.

Sex differences in a mouse model of multiple sclerosis: neuropathic pain behavior in females but not males and protection from neurological deficits during proestrus

BackgroundMultiple sclerosis (MS), a demyelinating disease of the central nervous system, is one of the most prevalent neurological disorders in the industrialized world. This disease afflicts more than two million people worldwide, over two thirds of which are women. MS is typically diagnosed between the ages of 20–40 and can produce debilitating neurological impairments including muscle spasticity, muscle paralysis, and chronic pain. Despite the large sex disparity in MS prevalence, clinical and basic research investigations of how sex and estrous cycle impact development, duration, and severity of neurological impairments and pain symptoms are limited. To help address these questions, we evaluated behavioral signs of sensory and motor functions in one of the most widely characterized animal models of MS, the experimental autoimmune encephalomyelitis (EAE) model.MethodsC57BL/6 male and female mice received flank injection of complete Freund’s adjuvant (CFA) or CFA plus myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to induce EAE. Experiment 1 evaluated sex differences of EAE-induced neurological motor deficits and neuropathic pain-like behavior over 3 weeks, while experiment 2 evaluated the effect of estrous phase in female mice on the same behavioral measures for 3 months. EAE-induced neurological motor deficits including gait analysis and forelimb grip strength were assessed. Neuropathic pain-like behaviors evaluated included sensitivity to mechanical, cold, and heat stimulations. Estrous cycle was determined daily via vaginal lavage.ResultsMOG35-55-induced EAE produced neurological impairments (i.e., motor dysfunction) including mild paralysis and decreases in grip strength in both females and males. MOG35-55 produced behavioral signs of neuropathic pain—mechanical and cold hypersensitivity—in females, but not males. MOG35-55 did not change cutaneous heat sensitivity in either sex. Administration of CFA or CFA + MOG35-55 prolonged the time spent in diestrus for 2 weeks, after which normal cycling returned. MOG35-55 produced fewer neurological motor deficits when mice were in proestrus relative to non-proestrus phases.ConclusionsWe conclude that female mice are superior to males for the study of neuropathic pain-like behaviors associated with MOG35-55-induced EAE. Further, proestrus may be protective against EAE-induced neurological deficits, thus necessitating further investigation into the impact that estrous cycle exerts on MS symptoms.

A novel approach to pharmaco‐EEG for investigating analgesics: assessment of spectral indices in single‐sweep evoked brain potentials

To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl. Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps. Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90). In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

An Endogenous Pain Control System is Altered in Subjects with Interstitial Cystitis

Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome. Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity. The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance. An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders.