Are changes in nociceptive withdrawal reflex magnitude a viable central sensitization proxy? Implications of a replication attempt.

OBJECTIVE: The nociceptive withdrawal reflex (NWR) has been proposed to read-out central sensitization (CS). Replicating a published study, it was assessed if the NWR magnitude reflects sensitization by painful heat. Additionally, NWR response rates were compared for two stimulation, the sural nerve at the lateral malleolus (SU) and the medial plantar nerve on the foot sole (MP), and three recording sites, biceps femoris (BF), rectus femoris (RF), and tibialis anterior (TA) muscles. METHODS: 16 subjects underwent one experiment with six blocks of eight transcutaneous electrical stimulations to elicit the NWR while surface electromyography was collected. Tonic heat was concurrently applied in the same dermatome. Temperatures rose from 32 °C in the first to 46 °C in the last block following the previously published protocol. RESULTS: Tonic heat did not influence NWR magnitude. The highest NWR response rate was obtained for MP-TA combination (79%). Regarding elicitation in all three muscles, SU stimulation outperformed MP (59% vs 57%). CONCLUSIONS: The replication failed. NWR magnitude as a CS proxy in healthy subjects needs continued investigation. With respect to response rates, MP-TA proved efficient, whereas SU stimulation seemed preferable for multiple muscle recordings. SIGNIFICANCE: Unclear methodological descriptions in the original study affected CS and NWR replication. The NWR magnitude changes induced by CS may closely depend on the different stimulation methods used.

Characterization of a novel capsaicin/heat ongoing pain model.

BACKGROUND: Human experimental pain models provide an important translational link between pre-clinical models and clinical pain. Using topical capsaicin and continuous heat application, the novel capsaicin/heat ongoing pain (CHOP) model induces long-lasting experimental pain of which the perceived intensity can be individually adjusted. METHODS: In the CHOP model, capsaicin or control cream is applied to a 10 × 10 cm skin area and a heating pad is applied over the area after cream removal. Two experiments in healthy participants were performed for model characterization. In Experiment 1, a constant temperature was applied for 60 min; in Experiment 2, temperature was adjusted to maintain a constant perceived intensity for 60 min. RESULTS: Experiment 1: across participants, constant temperature induced initial habituation followed by an increase in sensation back to baseline. Cluster analysis revealed that half the participants sensitized to the constant temperature, while the other half did not. The degree of sensitization was related to the baseline pain unpleasantness, relative to pain intensity. Experiment 2: constant perceived intensity was achieved in the painful and a non-painful control condition. The two conditions did not differ regarding possibly confounding variables, including blood pressure, heart rate, inflammation or physiological stress as measured by surrogate markers. Secondary allodynia and hyperalgesia were reported more following painful compared to control stimulation. Sensitizers as determined in Experiment 1 were also more pain sensitive in Experiment 2. CONCLUSION: The CHOP model reproduces some aspects of clinical pain, such as longer duration, sensitization, secondary allodynia and hyperalgesia. SIGNIFICANCE: Here we demonstrate a novel pain model that can be applied for up to an hour without tissue damage. The CHOP model allows for investigation of primary and secondary hyperalgesia as well as top-down influences on sensitization, thereby providing an experimental model that can be used to assess clinically-oriented questions.

Pain increases motivational drive to obtain reward, but does not affect associated hedonic responses: a behavioural study in healthy volunteers.

BACKGROUND: Pain and reward have been suggested to interact, and some evidence is provided by a rodent study showing that acutely injured animals are more motivated to reach a food reward while they do not increase food consumption, pointing at unaltered reward liking. Since no data exist in humans, we conducted a psychophysical experiment to test the effects of experimentally induced tonic pain on (1) the motivation to receive reward and (2) hedonic responses when being rewarded. METHODS: Forty healthy participants underwent two experimental sessions: in one, painful heat stimulation was continuously applied while participants played a monetary reward task; in the other, participants experienced non-painful warm stimulation while playing the task. In the task, participants needed to react quickly enough to a target cue to win the money associated with the particular trial ($0.04, $1 or $4). Reaction time to the target cue served as measure of motivation. Ratings after each trial on how much the participant liked the trial's outcome served as a measure of hedonic responses. RESULTS: Pain increased the motivation to obtain reward when the incentive was high, indexed by decreased reaction times (repeated-measures analysis of variance, interaction pain × incentive; p = 0.009). In contrast to motivational drive, hedonic ratings of the rewarding stimuli were not influenced by pain. CONCLUSION: Similar to existing rodent data, our results suggest a pain-induced mismatch of increased motivational drive with a lack of increased hedonic responses. This mismatch is discussed as perhaps reflecting a failed coping attempt, which is potentially relevant for chronic pain patients.

The role of excess subcutaneous fat in pain and sensory sensitivity in obesity.

BACKGROUND: Previous studies suggest pain sensitivity may be decreased in obesity, but it is unknown whether this is a global or a site-specific phenomenon related to the amount of excess fat. DESIGN: a cross-sectional study comparing obese and non-obese participants on body sites with much and little excess subcutaneous fat in obesity. Hot and cold sensory detection thresholds, pain thresholds, pain tolerance and subjective ratings for a cold (0 °C) and hot (48 °C) stimulus were assessed using a 16 × 16 mm thermode (Medoc, Israel) on the forehead and abdomen. Pressure pain thresholds were measured on the hand. Cold water immersion tolerance duration and subjective ratings were assessed on the hand. Two indices of central pain processing, i.e., temporal summation and heterotopic noxious stimulation, were assessed. RESULTS: A total of 20 obese participants [10M/10F, BMI mean (SD) =41.5 kg/m(2) (9.4 kg/m(2) )] and 20 age- and gender-matched non-obese controls [10M/10F, BMI mean (SD) =23.5 kg/m(2) (2.9 kg/m(2) )] were studied. Compared with non-obese, obese participants had higher thresholds and lower subjective ratings, indexing decreased sensitivity, for painful and non-painful thermal stimuli on the abdomen, an area with much excess subcutaneous fat. Decreases in abdominal sensitivity correlated with measures of adiposity (i.e., waist-to-hip ratio and subcutaneous fat thickness). On areas with little excess subcutaneous fat (forehead and hand), obese and non-obese groups did not differ in measures of thermal or pressure sensitivity, nor for indices of central pain processing. CONCLUSION: Obese participants are less sensitive than non-obese individuals, but only on areas with excess subcutaneous fat.

Effects of intravenous propranolol on heat pain sensitivity in healthy men.

BACKGROUND: Clinical studies have shown opioid-sparing effects of ß-adrenergic antagonists perioperatively and ß-blockers are being investigated for chronic musculoskeletal pain. However, the direct analgesic effects of ß-blockers have rarely been examined in healthy humans. METHODS: In a randomized, counter-balanced, double-blind, within-subject crossover design, we tested the effect of the lipophilic ß-blocker propranolol (0.035 mg/kg body weight i.v.) on heat pain sensitivity in 39 healthy males, compared with placebo. To test for peripheral versus central effects, the peripherally acting ß-blocker sotalol was also examined. Experimental stimuli were brief superficial noxious heat stimuli applied to the volar forearm. Non-painful cold stimuli were included to test for specificity. Sedation, mood and anxiety were assessed to investigate potential mechanisms underlying any analgesic effect. ß-blocker effects on blood pressure were incorporated into the analysis because of a known inverse relationship between pain sensitivity and systolic blood pressure. RESULTS: Propranolol significantly decreased perceived intensity of heat pain stimuli but only in participants with small propranolol-induced blood pressure decreases. Even in this group, the effect was small (4%). Propranolol did not influence perceived intensity of non-noxious stimuli and had no effect on sedation, anxiety or mood. Sotalol did not influence heat pain sensitivity. CONCLUSIONS: Propranolol decreased pain sensitivity but its analgesic effects were small and counteracted by blood pressure decreases. The analgesic effects were not mediated by peripheral ß-receptor blockade, sedation, mood or anxiety. The small effect indicates that the utility of ß-blockers for clinical pain must be related to factors that do not play a significant role for experimental pain.

Perceptions of the painful body: the relationship between body perception disturbance, pain and tactile discrimination in complex regional pain syndrome.

BACKGROUND: Disturbances in body perception are increasingly acknowledged as a feature of complex regional pain syndrome (CRPS). Conventional treatments have limited success particularly among those with long-standing disease. Understanding the relationship between body perception disturbance, pain and tactile acuity might provide insight into alternative avenues for treatment. The aim of this study was to test the hypotheses that (1) body perception disturbance is positively related to pain and (2) decreased tactile acuity is related to increased body perception disturbance. METHODS: A controlled observational design was used to measure these features among those with CRPS of one arm. The extent of body perception disturbance was assessed using the Bath CRPS body perception disturbance scale and pain was measured using the neuropathic pain symptom inventory. Two-point discrimination threshold testing was performed as a measure of tactile acuity. RESULTS: Findings confirmed both hypotheses. Body perception disturbance was found to positively correlate with pain such that those in greater pain had more extensive body perception disturbance (r = 0.57, p < 0.01). Furthermore, a positive correlation was revealed between body perception disturbance and two-point discrimination thresholds (r = 0.5, p < 0.025) so those with greater body perception disturbance had worse tactile acuity. Interestingly, those with longer disease duration had significantly greater body perception disturbance (r = 0.66, p < 0.001). CONCLUSION: Aberrant central processing is suggested as the neural correlate of body perception disturbance and tactile impairment. The exact relationship between body perception disturbance, pain and tactile acuity and how they may be modulated for pain relief requires further exploration.

Increased gray matter density in young women with chronic vulvar pain.

Provoked vestibulodynia (PVD) is a common form of chronic vulvar pain with unknown aetiology. Central pain regulatory mechanisms have been suggested to be disrupted in PVD, and consequently, PVD may be associated with anatomical changes in pain modulatory brain areas. Here, we compared total gray matter volumes and regional gray matter densities between 14 medication-free young women with relatively short-standing PVD (1 to 9 yrs) and 14 control subjects using whole brain voxel-based morphometry (VBM). VBM revealed that PVD subjects had significantly higher gray matter densities in pain modulatory and stress-related areas, i.e. the parahippocampal gyrus/hippocampus and basal ganglia (globus pallidus, caudate nucleus, and substantia nigra). In several of these regions, gray matter was related to clinical symptoms, namely lowered pain thresholds and increased pain catastrophizing scores. No region showed decreased gray matter density in the PVD group. These results point at the morphological alterations in supra-spinal pain modulatory circuitry, which might contribute to the clinical symptoms of patients with PVD. Previous VBM studies in older subjects with a longstanding chronic pain condition have demonstrated gray matter decreases in similar areas. We therefore speculate that gray matter density might increase in young pain patients with short disease duration and decrease in older subjects with longstanding disease, similarly to some psychiatric conditions, in which bi-directional changes of gray matter have been observed.

Noninvasive estimation of tumour viability in a xenograft model of human neuroblastoma with proton magnetic resonance spectroscopy (1H MRS).

The aim of the study was to evaluate proton magnetic resonance spectroscopy ((1)H MRS) for noninvasive biological characterisation of neuroblastoma xenografts in vivo. For designing the experiments, human neuroblastoma xenografts growing subcutaneously in nude rats were analysed in vivo with (1)H MRS and magnetic resonance imaging at 4.7 T. The effects of spontaneous tumour growth and antiangiogenesis treatment, respectively, on spectral characteristics were evaluated. The spectroscopic findings were compared to tumour morphology, proliferation and viable tumour tissue fraction. The results showed that signals from choline (Cho)-containing compounds and mobile lipids (MLs) dominated the spectra. The individual ML/Cho ratios for both treated and untreated tumours were positively correlated with tumour volume (P<0.05). There was an inverse correlation between the ML/Cho ratio and the viable tumour fraction (r=-0.86, P<0.001). Higher ML/Cho ratios concomitant with pronounced histological changes were seen in spectra from tumours treated with the antiangiogenic drug TNP-470, compared to untreated control tumours (P<0.05). In conclusion, the ML/Cho ratio obtained in vivo by (1)H MRS enabled accurate assessment of the viable tumour fraction in a human neuroblastoma xenograft model. (1)H MRS also revealed early metabolic effects of antiangiogenesis treatment. (1)H MRS could prove useful as a tool to monitor experimental therapy in preclinical models of neuroblastoma, and possibly also in children.