Peripheral transduction mechanisms for heat pain
Free nociceptive nerve endings are the peripheral terminals of axons of small dorsal root ganglion neurons. We study the somata of those neurones as models for their own peripheral and central terminals, using patch-clamp experiments, live cell imaging, immunocytochemistry and molecular biology. The temporal patterns of adaptation and sensitization indicate that at least two heat-sensors are present in the nociceptive neuron membrane, most likely TRPV1 and TRPV2. Heat responses are modulated by mitogen-activated protein kinases and extracellular signal-related protein kinase (ERK) as well as by the cannabinoid receptor CB1. Shaping of action potential discharges appears to involve the potassium channel Kv 1.4. Beyond the gain in knowledge for basic research, new targets for peripherally acting pharmaceuticals are identified and characterized.
Plasticity of the nociceptive system and pain memory
Strong activation of nociceptive afferents - e.g. after intradermal capsaicin injection - leads to a long-lasting increase of spinal synaptic transmission (central sensitization), which is typically followed by an increase of perceived pain to mechanical stimuli mediated by A-fiber mechano-nociceptors in an area adjacent to the site of an injury (secondary hyperalgesia). Physiologically this type of central nervous plasticity is reversible within hours, but may become chronic under some circumstances (e.g. lesions of the nervous system; neuropathic pain). We were able to show by psychophysical and electrophysiological techniques that blockade of NMDA-receptors reduced the normal pain perception (analgesia) but couldn't prevent the induction of the increase of pain perception after capsaicin injection (absent anti-hyperalgesic effect). This is in line with further results of our group showing, that an NMDA-insensitive type of heterosynaptic long-term potentiation (LTP) of synaptic transmission in the spinal cord may underlie secondary hyperalgesia in humans. Moreover, an NMDA-sensitive type of homosynaptic LTP as well as a long-lasting depression of homosynaptic synaptic transmission (LTD) does also exist in humans. The latter may contribute to the analgesic effect of transcutanous electrical nerve stimulation (TENS).
Cortical representation of pain
In this research project we investigate which brain areas are involved in perception and processing of noxious and non-noxious stimuli and how these areas interact with each other. Our main focus is on the secondary somatosensory cortex and the insula. We use infrared laser stimuli (nociceptive specific) as well as non-painful tactile stimuli directed to the skin of healthy humans and patients and measure EEG and MEG responses from the scalp, which are then fed into dipole source analyses (BESA) or measure brain activity related increases in cerebral bloodflow (fMRI). Using positron emission tomography (PET) we further quantify and compare opiate receptor density in different brain regions that are involved in nociception. We also use immunohistochemistry and in-situ hybridisation to characterize the distribution of the opioid receptor µOR, cannabinoid receptor CB1 and dopamine receptor D2 in the operculo-insular cortex.
Dipole source analysis in presurgical epilepsy diagnostics
In collaboration with the Neurosurgery Department of the Johns Hopkins University, patients undergoing epilepsy surgery are evaluated using subdural recordings. These recordings are obtained from implanted electrode grids (typically 8x8 contacts) directly from the brain surface with the advantage of a favorable signal-to-noise ratio, since there is no dampening of the brain responses by the skull as is the case in normal scalp recordings. Data obtained from these patients comprise auditory evoked potentials (AEP), somatosensory-evoked potentials (SEP), nociceptive specific laser-evoked potentials (LEP) and vibratotactile-evoked potentials. Recent findings showed that the generators of LEP were located near the sylvian fissure, slightly anterior of the secondary somatosensory cortex. For electrical stimuli (median nerve SEP), we could identify activity during the sequential activation in different subregions of the primary somatosensory cortex (SI). Future analyses will include comparison of localization of LEP vs. vibrotactile-evoked potentials.
Nociceptive processing in mental disorders
In collaboration with the Department of Clinical Psychology in Mainz and the Central Institute of Mental Health in Mannheim, we study nociceptive signal processing in patients with mental disorders. Patients with borderline personality disorder (BPD) or Major Depression (MD) both exhibit normal performance in nociceptive discrimination tasks and normal cortical responses up to the operculo-insular cortex. Patients with BPD frequently injure themselves, but without suicidal intention. This behaviour is accompanied by a reduction or absence of pain perception during their self-injury. Brain imaging studies suggest that this analgesic state can be ascribed to an enhanced prefrontal cortical control. Patients with major depression frequently suffer from chronic pain, but they seem to be less sensitive to acute (and experimental) pain compared to healthy controls. Studies are under way to characterize the altered nociceptive signal processing in MD with respect to perceived controllability and positive/negative emotional modulation.
Quantitative sensory testing (QST) in Neuropathic pain syndromes
Quantitative sensory testing (QST) of thermal and mechanical detection and pain thresholds allows to quantify sensory signs which point to specific neurobiological mechanisms of chronic pain. We have developed and implemented a standardized QST battery for the German Research Network on Neuropathic Pain (DFNS). A reference data base including 180 healthy subjects was established using a multicenter approach. Currently, validity, reliability and quality management are evaluated in the DFNS project. In cooperation with further DFNS-centers (Kiel, Munich) sensory changes after experimentally induced neuropathic pain - like syndromes (intradermal capsaicin application, A-fiber block) are characterized using a standardized, z-transformed QST-profile. Following this, QST-profiles in these surrogate models are compared to QST-profiles in patients so that inferences concerning the underlying neuropathic pain mechanism can be drawn.
The role of the endogenous cannabinoid system in human pain perception
The aim of this project (DFG research group FOR 926) is the investigation of the role of endocannabinoids in human pain perception. Pain phenotype is to be identified in healthy subjects. To this end we analyze on the one hand somatosensory sensitivity in general (mechanoreception, thermoreception, pain) using a quantitative sensory testing (QST), on the other hand we test habituation of pain sensation (time course, half-life, duration) in unconditioned (normal) and conditioned (hyperalgesic) skin. The state of hyperalgesia will be reached by short painful electrical high frequency stimulation. Subsequently decay of that experimental induced long term potentiation (LTP) of pain perception will be analyzed. Occurrence and duration of possible changes refer to individual pain memory and are based on synaptic memory (implicit pain memory). Furthermore we investigate the effect of genetic polymorphisms to individual pain sensitivity and to the variability of habituation and to pain plasticity. Genotyping focuses on polymorphisms of the endogenous cannabinoid system such as genes of cannabinoid receptors CB1 and CB2 (CNR1 and CNR2) and the enzyme FAAH (fatty acid amino hydrolase) which hydrolizes endogenous lipid agonists of cannabinoid receptors. Another part of the project investigates the influence of pharmacologic modulation (randomized controlled trial) on the pain habituation and pain plasticity using cannabinoid CB 1 receptor agonists and antagonists.