389 HIGH-FREQUENCY STIMULATION-INDUCED LONG-TERM POTENTIATION (LTP) AND LOW-FREQUENCY STIMULATION-INDUCED DEPOTENTIATION (DE-LTP) OF PAIN PERCEPTION IN HUMANS

Comparison of Direct and Indirect Antioxidant Effects of Linagliptin (BI 1356, ONDERO) with other Gliptins – Evidence for Anti-inflammatory Properties of Linagliptin

Comparison of DPP‐4 inhibition versus GLP‐1 analogue supplementation on survival and vascular complications in experimental sepsis (145.2)

Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of hyperglycemia and recent studies revealed anti-inflammatory effects of these gliptins in experimenta...

Regulation of cyclooxygenase-2 expression by cyclic AMP.

Abstract Prostaglandins (PG) regulate many biological processes, among others inflammatory reactions. Cyclooxygenases-1 and -2 (COX-1 and COX-2) catalyse PG synthesis. Since this step is rate limiting, the regulation of COX expression is of critical importance to PG biology. Contrary to COX-1, which is constitutively expressed, COX-2 expression is subject to regulation. For example, COX-2 levels are increased in inflammatory reactions. Many signalling pathways can regulate COX-2 expression, not least those involving receptors for COX products themselves. Analysis of the intracellular signal transducers involved reveals a crucial role for cAMP, albeit as a modulator rather than direct induce…

416 POTENTIATION AND DEPOTENTIATION OF PAIN PERCEPTION IN A HUMAN SURROGATE MODEL OF NOCICEPTIVE LTP

Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system

We recently reported perceptual correlates of long-term potentiation (LTP) of synaptic strength within the nociceptive system demonstrating the functional relevance of LTP for human pain sensation. LTP is generally classified as NMDA-receptor dependent or independent. Here we show that low doses of the NMDA-receptor antagonist ketamine (0.25 mg/kg) prevented the long-term increase in perceived pain to electrical test stimuli, which was induced by high-frequency electrical stimulation (HFS) of nociceptive afferents. Whereas in a control experiment HFS led to a stable increase in perceived pain by 51% for the entire observation period of 1 h HFS given 4 min after i.v. ketamine was ineffective…

Perceptual Correlate of Nociceptive Long-Term Potentiation (LTP) in Humans Shares the Time Course of Early-LTP

As in neocortex and hippocampus, neurons in the dorsal horn of the spinal cord develop long-term potentiation of synaptic efficacy (LTP) on high-frequency stimulation (HFS) of their afferent input, although how long LTP lasts in this nociceptive relay nucleus has not yet been addressed. Here we studied neurogenic hyperalgesia, a perceptual correlate of nociceptive LTP, in 13 healthy subjects, after HFS (5 × 1 s at 100 Hz) of superficial cutaneous afferents. HFS led to a mean upward shift of the stimulus–response function for pinprick-evoked pain (punctate mechanical hyperalgesia) in all subjects by a factor of 2.5 ( P < 0.001) that lasted undiminished for the initial 1-h observation per…

Test–retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): A multi-centre study

Quantitative sensory testing (QST) is an instrument to assess positive and negative sensory signs, helping to identify mechanisms underlying pathologic pain conditions. In this study, we evaluated the test-retest reliability (TR-R) and the interobserver reliability (IO-R) of QST in patients with sensory disturbances of different etiologies. In 4 centres, 60 patients (37 male and 23 female, 56.4±1.9years) with lesions or diseases of the somatosensory system were included. QST comprised 13 parameters including detection and pain thresholds for thermal and mechanical stimuli. QST was performed in the clinically most affected test area and a less or unaffected control area in a morning and an a…

Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice

Background and purpose Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated with organ dysfunction and high mortality. The present studies aimed to investigate whether inhibition of dipeptidyl peptidase-4 (DPP-4) and supplementation with glucagon-like peptide-1 (GLP-1) receptor agonists improved endotoxaemia-associated microvascular thrombosis via immunomodulatory effects. Experimental approach Endotoxaemia was induced in C57BL/6J mice by a single injection of LPS (17.5 mg kg-1 for survival and 10 mg kg-1 for all other studies). For survival studies, treatment was started 6 h after LPS injection. For all other studies, drugs were injected 48 h bef…

Comparison of Linagliptin, Sitagliptin and Liraglutide Effects on Survival and Vascular Complications in Experimental Sepsis

Erratum to “Human surrogate models of neuropathic pain” [Pain 115 (2005) 227–233]☆

Antihyperalgesic and analgesic properties of the N-methyl-d-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia

Abstract NMDA-receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti-hyperalgesic (prevention of central sensitization) properties of the NMDA-receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40 mg p.o.), flupirtine (100 m…

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1mm). Thresholds and stimulus-response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2mm). Allodynia was tested by light stroking with a brush, Q-tip, and…

Comparison of direct and indirect antioxidant effects of linagliptin with other gliptins — Evidence for antioxidant and antiinflammatory properties of linagliptin

Psychophysical evidence for long-term potentiation of C-fiber and Adelta-fiber pathways in humans by analysis of pain descriptors.

Long-term potentiation of human pain perception (nociceptive LTP) to single electrical test stimuli was induced by high-frequency stimulation (HFS) of cutaneous nociceptive afferents. Numerical pain ratings and a list of sensory pain descriptors disclosed the same magnitude of nociceptive LTP (23% increase for >60 min, P < 0.001), whereas affective pain descriptors were not significantly enhanced. Factor analysis of the sensory pain descriptors showed that facilitation was restricted to two factors characterized by hot and burning (+41%) and piercing and stinging (+21%, both P < 0.01), whereas a factor represented by throbbing and beating was not significantly increased (+9%, P = …

Human surrogate models of neuropathic pain.

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994). Current efforts to refine this definition focus on the terms ‘dysfunction’ and ‘nervous system’ with the intention to clarify that there has to be an identifiable lesion or disease process affecting the somatosensory system. Experimental models of neuropathic pain according to either one of these definitions are expected to imitate mechanisms of nerve damage within the peripheral or central parts of the somatosensory system and the ensuing processes of degeneration and regeneration. Whereas this approach to model the etiology and pathophysiology of the…

25 HUMAN SURROGATE MODELS OF PAIN MEMORY: IMPLICATIONS FOR MECHANISMS OF CENTRAL SENSITIZATION AND RELATED TREATMENT OPTIONS IN NEUROPATHIC PAIN PATIENTS

200 TEST/RETEST- AND INTEROBSERVER-RELIABILITIY IN QUANTITATIVE SENSORY TESTING ACCORDING TO THE PROTOCOL OF THE GERMAN NETWORK ON NEUROPATHIC PAIN (DFNS)

451 SPATIAL AND TEMPORAL STIMULUS PARAMETERS OF CONDITIONING STIMULATION AFFECT THE MAGNITUDE AND DIRECTION OF HUMAN PAIN PLASTICITY

24 Workshop Summary: HUMAN SURROGATE MODELS OF NEUROPATHIC PAIN: AN OBLIGATORY INTERMEDIARY OF TRANSLATIONAL RESEARCH

Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition.

Aims Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties. Methods and results Linagliptin (83 mg/kg chow for 7days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxida…

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 × 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 μm diameter) in skin adjacent to the HFS–LFS con…

Forget about your chronic pain

Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways.

The impact of long-term potentiation (LTP) in nociceptive pathways on somatosensory perception was examined by means of quantitative sensory testing (QST) in the ventral forearm of 12 healthy human subjects. Electrical high-frequency stimulation of the forearm skin (HFS; 5 x 1 s at 100 Hz and 10 x detection threshold) led to an abrupt increase of pain to single electrical test stimuli, which were applied through the same electrode (perceptual LTP +72%, p0.01). Perceptual LTP outlasted the 1-h observation period. The effects of HFS on somatosensory perception of natural test stimuli in the conditioned skin area were restricted to mechanical submodalities. Subjects exhibited a significant dec…

Chapter 33 Experimental human models of neuropathic pain

Publisher Summary This chapter reviews human surrogate models of neuropathic pain that focus on the mechanisms of symptom generation. A vast array of human surrogate models exists for ongoing symptoms, for positive sensory symptoms, and for sensory loss. The chapter discusses that by design, human surrogate models of neuropathic pain involve a reversible modulation of the properties of the nociceptive system such as its acute plasticity (phase 2). They usually do not create a long-lasting and potentially irreversible modification (phase 3). The denervation and ectopic activity of phase 3 can be modeled to a certain extent by transient nerve compression–ischemia and by topical capsaicin. By …

Gliptins Suppress Inflammatory Macrophage Activation to Mitigate Inflammation, Fibrosis, Oxidative Stress, and Vascular Dysfunction in Models of Nonalcoholic Steatohepatitis and Liver Fibrosis

Abstract Aims: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis, and increased cardiovascular mortality. Dipeptidyl peptidase-4 inhibitors (gliptins) are indirect glucagon-like peptide 1 agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. Results: In the methionine/choline-deficient (MCD) diet and Mdr2−/− models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steat…

The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation

Long-term potentiation (LTP) of nociceptive synaptic transmission induced by high-frequency electrical stimulation (HFS) predominantly modulates natural somatosensory perceptions mediated by Adelta- and Abeta-fibers in humans at the site of conditioning stimulation. The relative contribution of homo- and heterosynaptic mechanisms underlying those perceptual changes remained unclear. We therefore compared changes of the somatosensory profile between a conditioned skin site (homotopic zone) and an area adjacent to conditioning HFS (heterotopic zone). HFS of the ventral forearm in 24 healthy subjects (mean pain 41/100) led to an abrupt increase of pain to single electrical test stimuli (pain a…