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Investigates the effect of high intensity pain stimulation on the blood flow of orofacial region and hand in humans. Stimulation of upper central incisor with pain; Use of doppler imaging and infrared thermography in measuring blood flow responses; Vasodilatation in the lower lips.

Pain research is based broadly on physiological disciplines and its development follows the methodological progress of the era, from classical psychophysiology to electrophysiological investigations at peripheral and central nociceptive systems, single cells and ion channels to modern imaging of nociceptive processing. Physiological pain research in Germany has long been part of an interdisciplinary research network extending beyond all political boundaries, and this situation has continued since molecular techniques started to dominate all biomedical research. Current scientific questions, such as intracellular nociceptive signal mechanisms, interactions with other physiological systems including the immune system, or the genetic basis of epidemic and chronic pain diseases can only be solved interdisciplinary and with international collaboration.

Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.

This functional magnetic resonance imaging (fMRI) study explored the central nervous processing of itch induced by histamine and capsaicin, delivered via inactivated cowhage spicules, and the influence of low-dose naltrexone. Scratch bouts were delivered at regular intervals after spicule insertion in order temporarily to suppress the itch. At the end of each trial the subjects rated their itch and scratch-related sensations. Stepwise multiple regression analyses were employed for identifying cerebral networks contributing to the intensities of "itching", "burning", "stinging", "pricking" and "itch relief by scratching". In the capsaicin experiments a network for "burning" was identified, which included the posterior insula, caudate and putamen. In the histamine experiments networks for "itching" and "itch relief" were found, which included operculum, hippocampus and amygdala. Naltrexone generally reduced fMRI activation and the correlations between fMRI signal and ratings. Furthermore, scratching was significantly less pleasant under naltrexone.

Cowhage, capsaicin and histamine, all applied via spicules, were used to induce itch and pain-related sensations in 15 male and 15 female subjects. Sensory qualities were assessed by questionnaire; intensities and time courses of the "itching" and "burning" sensation were measured alternately, but continuously on a VAS. In addition, axon reflexes were assessed. Only histamine and capsaicin produced a clear axon reflex flare (histamine > capsaicin, male = female). The 3 types of spicules caused mixed burning and itching sensations with different time courses. In the beginning burning prevailed, in the following minutes histamine induced mostly itching, capsaicin predominantly burning, cowhage both sensory components equally. Female subjects experienced more pain-related sensations (questionnaire), and their ratings leaned more toward burning than those of males. These findings indicate that the mixed itching and burning sensations are differentially processed by both genders. No indications were found for gender specific differential processing in the primary afferents as reflected by nearly identical flare responses.

Introduction: Objective diagnosis of small fiber impairment is difficult., Methods: We used the quantitative sudomotor axon reflex test (QSART) and axon-reflex-flare-test in the foot and thigh of 46 patients with peripheral neuropathy to assess C-fiber function in addition to conventional neurography and thermal threshold testing., Results: In all patients, small fiber impairment was suspected because of abnormal warmth detection thresholds (76% of all tested) and/or pain in the feet. A total of 83% had reduced axon-reflex flare areas and 17% lower QSART scores. Patients with pure small fiber neuropathy had higher rates of reduced flare areas (87.5%) and sweating rates (25.5%). There was no difference between patients with and without pain regarding thermotesting and axon-reflex testing., Conclusions: Both axon-reflex tests are helpful to identify objectively patients with small fiber impairment. Afferent and efferent C-fiber classes can be impaired differently. These tests detect small fiber impairment, but they cannot differentiate between painful and nonpainful neuropathy., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Delayed onset muscle soreness (DOMS) is a subacute pain state arising 24-48 hours after a bout of unaccustomed eccentric muscle contractions. Functional magnetic resonance imaging (fMRI) was used to examine the patterns of cortical activation arising during DOMS-related pain in the quadriceps muscle of healthy volunteers evoked by either voluntary contraction or physical stimulation. The painful movement or physical stimulation of the DOMS-affected thigh disclosed widespread activation in the primary somatosensory and motor (S1, M1) cortices, stretching far beyond the corresponding areas somatotopically related to contraction or physical stimulation of the thigh; activation also included a large area within the cingulate cortex encompassing posteroanterior regions and the cingulate motor area. Pain-related activations were also found in premotor (M2) areas, bilateral in the insular cortex and the thalamic nuclei. In contrast, movement of a DOMS-affected limb led also to activation in the ipsilateral anterior cerebellum, while DOMS-related pain evoked by physical stimulation devoid of limb movement did not.

Microneurography of human skin nerves has recently contributed detailed information on the peripheral input leading to itch sensations. In this context it has been demonstrated that itch induced by different agents activates different neuronal populations in the PNS. Histamine acts on a specific subgroup of mechano-insensitive C-fibers which are also sensitive to other endogenous mediators, e.g. prostaglandine E2 and acetylcholine, and to capsaicin. Since these agents can also provoke pain, a "selectivity hypothesis" may explain the differentiation between the itch and pain pathways. Though histamine seemed to be the prototypical itch mediator it plays a minor role in part of the clinical itch states. Experimentally, the spicules of mucuna pruriens (cowhage) induce strong non-histaminergic itch. It turned out that they excite an entirely different population of C-fibers, namely mechano-responsive polymodal nociceptor units (CMH) and Adelta units. The neuronal mechanisms of clinically important pruritic states, e.g. in uremia are still unexplored.

Cerebral processing of itch-scratching cycles was studied with functional magnetic resonance imaging (fMRI) in healthy volunteers. The back of the hand was repetitively scratched in the absence and presence of itch induced by histamine applied close to the scratched site. Blood-oxygenation-level-dependent (BOLD) effects were assessed in predefined cortical and subcortical brain regions of interest. Scratch-related activation clusters were found in cortical and subcortical areas which had been associated before with pain processing, namely S1, S2, parietal association cortex, motor and premotor cortex, anterior and posterior insula, anterior and medial cingulum, lateral and medial frontal areas, ipsilateral cerebellum and contralateral putamen. Cortical activations were generally stronger in the contralateral hemisphere. General linear model (GLM) analysis and GLM contrast analysis revealed stronger activations during itch-related trials in the motor and premotor cortex, in lateral frontal fields of both sides, and in a left medial frontal cluster. Subcortically, stronger activation during itch-related scratching trials was found in the contralateral putamen and in the ipsilateral cerebellum. Time course analysis showed significantly higher BOLD levels during the last 3-6 s before the start of scratching when the itch intensity was strongest. This effect was found in frontal areas, in the putamen, and in the somatosensory projection areas. During the scratching, no significant differences were found between itch and control conditions with the exception of the putamen, which showed stronger activations during itch-related scratch bouts. We interpret these itch-related activations anticipating the scratching as possible cerebral correlates of the itch processing and the craving for scratch.

Microneurography is a method for recording single unit action potentials with microelectrodes from the nerves of awake cooperating humans. Although this method is now in use since almost 40 years, its potency has been strengthened by the recent technical developments. A great progress was the discovery that different functional groups of nociceptors are characterized by a distinctly different post-excitatory slowing of their conduction velocities. Microneurography is now powerful enough to analyze the nerve activity pattern of enigmatic sensations such as pruritus. Furthermore, it is the only method providing direct insight in the changes which human nerves undergo with aging. Recently, reliable recordings from patients suffering from painful neuropathies came into reach. It has been shown that different types of neuropathies are characterized by different patterns of abnormal nociceptor functions. Although some of them are characterized by abnormal spontaneous activity in C-nociceptors, others show mainly signs of denervation. Microneurography is, therefore, a tool for translational studies on human nociceptor functions by linking direct animal studies on experimental neuropathies with human diseases.

Physiological changes in the nervous system occur with ageing. Both a decline of function and a decrease in the number of C-fibres in the skin have been reported for healthy aged subjects. With the use of microneurographic recordings from single C-fibres in humans we have compared the sensory and axonal properties of these neurones in young and aged healthy subjects. A total of 146 C-fibres were recorded from the common peroneal nerve in young subjects (mean age 24.7 years) and 230 C-fibres were recorded in aged subjects (mean age 56.2 years). In aged subjects, changes were found in the composition of the C-fibre population and in sensory and axonal properties. The relative incidence of afferent to efferent C-fibres was relatively constant independent of the age of subjects. The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 8 : 2 in the young controls while in aged subjects it was 7 : 3. In aged subjects 13% of the fibres showed atypical discharge characteristics, while this was not observed in young subjects. Spontaneous activity, sensitization and loss of sensory function were found regularly. Changes in functions of the conductile membrane were also observed in fibres from aged subjects. The degree of activity-dependent conduction velocity slowing in response to high frequency stimulation (2 Hz) was more pronounced, while the normalization of conduction velocity subsequent to high frequency stimulation was protracted. We found that both sensitization and desensitization or degeneration of afferent C-fibres occur with age, but are still rare compared to patients with neuropathy. The changes in the axonal properties of C-fibres in aged subjects are compatible with hypoexcitability of the fibres. These findings are important for the understanding and differential diagnoses regarding pathological processes and normal ageing.

Recent findings suggest that itch produced by intradermal insertion of cowhage spicules in human is histamine independent. Neuronal mechanisms underlying nonhistaminergic itch are poorly understood. To investigate which nerve fibers mediate cowhage induced itch in man, action potentials were recorded from cutaneous C-fibers of the peroneal nerve in healthy volunteers using microneurography. Mechano-responsive and -insensitive C-nociceptors were tested for their responsiveness to cowhage spicules, histamine, and capsaicin. Cowhage spicules induced itching and activated all tested mechano-responsive C-units (24/24), but no mechano-insensitive C-fibers (0/17). Histamine also induced itch, but in contrast to cowhage, it caused lasting activation only in mechano-insensitive units (8/12). In mechano-responsive C-units, histamine caused no or only short and weak responses unrelated to the time course of itching. Capsaicin injections activated four of six mechano-responsive fibers and three of four mechano-insensitive C-fibers. Cowhage and histamine activate distinctly different nonoverlapping populations of C-fibers while inducing similar sensations of itch. We hypothesize that cowhage activates a pathway for itch that originates peripherally from superficial mechano-responsive (polymodal) C-fibers and perhaps other afferent units. It is distinct from the pathway for histamine-mediated pruritus and does not involve the histamine-sensitive mechano-insensitive fibers.

This fMRI study investigates the influence of a rating procedure on BOLD signals in common pain-activated cortical brain regions. Painful and non-painful mechanical impact stimuli were applied to the left hand of healthy volunteers. Subjects performed ratings of the perceived intensity during every second stimulation period by operating a visual analogue scale with the right hand. During every other stimulus period the subjects rested passively. Pain and touch stimuli were found to activate the same cortical areas previously defined as the "cortical pain matrix". General Linear Models were used to calculate contrasts between cortical activations during the "rating" and "non-rating" paradigm. In most brain regions activation following pain and touch was stronger during "rating" compared to "non-rating" conditions. Only the responses in the S1 projection field of the stimulated hand following pain were not influenced by the rating procedure. Furthermore, activations in the right and left posterior insular cortex and in the left superior frontal gyrus showed an opposite pattern, namely a stronger BOLD signal during "non-rating". We concluded: (1) Cortical areas regularly activated by painful stimuli may also be activated by touch stimulation. (2) Enhancement of the BOLD contrast by a rating procedure is probably an effect of closer stimulus evaluation and attention focussing. (3) In contrast to most other cortical regions, the posterior insular cortex, which is crucial for the integration of interoceptive afferent input, shows stronger responses in the absence of ratings, which points to a unique role of this region in the processing of somato-visceral information.

The inflammation process underlying rheumatic diseases is a complex cascade of events that involves several mediators, leading to a chronic condition of pain and correlated symptoms that affect the quality of life. As opposed to physiological pain, inflammatory pain arises from tissue damage via the sensitization of pain receptors (nociceptors). Sensitization leads to a lowering of the threshold for activation of nociceptors and an increase in the pain response to a given stimulus, and can occur at both a peripheral and central level. Following peripheral trauma or injury, inflammatory mediators such as phospholipase A(2) are upregulated, inducing the release of arachidonic acid, which is then converted to prostanoids such as prostaglandin E(2) (PGE(2)) via the action of the enzyme cyclo-oxygenase (COX)-2. PGE(2), the most abundant prostanoid found in injured tissue, is believed to be the principal mediator of hypersensitivity and is implicated in the processes of primary and secondary hyperalgesia. At a peripheral level, PGE(2) interacts with other inflammatory mediators to sensitize the peripheral terminals of the primary afferent nociceptors (primary hyperalgesia). In addition to its effect on peripheral pain, at a central level PGE(2) enhances excitatory glutaminergic transmission and downregulates inhibitory glycinergic transmission through the blockade of a glycine receptor subtype (GlyR α-3). These central mechanisms play an important role in the increase of pain sensitivity following inflammation and are responsible for the development of secondary hyperalgesia to regions beyond the injured tissue. Understanding the physiological mechanisms of inflammatory pain as well as preventing peripheral and central prostanoids production are important steps forward when considering the symptomatic treatment of patients with rheumatic conditions.