The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

The runner's high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the opioidergic mechanisms of the runner's high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography "ligand activation" study with the nonselective opioidergic ligand 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 +/- 4.7 km). Binding kinetics of [(18)F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the "opioid theory" of the runner's high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood.

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called 'medial pain system'. Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.