Thomas Klein

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

&NA; 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 (1.1 mm ∅). Thresholds and stimulus–response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2 mm ∅). Allodynia was tested by light stroking with a brush, Q‐tip, and cotton wisp. Perceptual wind‐up was tested by trains of punctate stimuli at 0.2 or 1 Hz. Intradermal injection of capsaicin (n=7) and A‐fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52±0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by −1.94±0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02±0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus–response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus–response function with a decrease in slope). Perceptual wind‐up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism‐based classification of neuropathic pain.

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 underlying disease process is the focus of various animal models of neuropathic pain, for obvious ethical reasons these processes cannot be induced in healthy human subjects. Human surrogate models of neuropathic pain focus on the sensory signs and symptoms. On one hand, this is a limitation. On the other hand, the investigation of sensory symptoms exploits the unique human capacity for verbal communication, which allows the direct assessment of quality and intensity as well as location and duration of ongoing signs (pain, paraesthesia) and evoked signs (evoked pain, sensory loss) without relying on reflexes. In addition, laboratory studies in human surrogate models with electrophysiological and imaging techniques are immediately transferable to patient populations

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

Abstract 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 × 1 s at 100 Hz and 10 × detection threshold) led to an abrupt increase of pain to single electrical test stimuli, which were applied through the same electrode (perceptual LTP +72%, p < 0.01). 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 decrease of pain threshold and an increase of pain ratings to suprathreshold pinprick stimuli (p < 0.01). In 5 out of 12 subjects (42%) light tactile stimuli led to painful sensations (dynamic mechanical allodynia). Furthermore, a small but significant decrease of threshold to blunt pressure stimuli (p < 0.05) was found. In contrast, all thermal modalities comprising cold and warm detection thresholds, cold and heat pain thresholds as well as pain summation (perceptual wind up) remained unaltered. These data show that HFS of peptidergic cutaneous C‐fiber afferents predominantly modulates Aδ‐ and Aβ‐fiber mediated somatosensory functions, suggesting that LTP in nociceptive pathways enhances human pain sensitivity via interaction of two afferent pathways (extrinsic sensitization).Abbreviations: ALL: dynamic mechanical allodynia; CDT: cold detection threshold; CPT: cold pain threshold; EDT: electrical detection threshold; HFS: high frequency stimulation; HPT: heat pain threshold; ISI: inter‐stimulus interval; LTP: long‐term potentiation; MDT: mechanical detection threshold; MPS: mechanical pain sensitivity; MPT: mechanical pain threshold; NRS: numerical rating scale; PHS: paradoxical heat sensation; PPT: pressure pain threshold; QST: quantitative sensory testing; TSL: thermal sensory limen; WDT: warm detection threshold; WUR: windup ratio.

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 1h HFS given 4 min after i.v. ketamine was ineffective. In contrast, HFS induced a two-fold increase of pinprick-evoked pain surrounding the HFS site (secondary neurogenic hyperalgesia) in both experiments. Pain evoked by light tactile stimuli (allodynia) was also unaffected by ketamine. These data support the concept that homotopic hyperalgesia to electrical stimulation of the conditioned pathway is a perceptual correlate of NMDA-receptor sensitive homosynaptic LTP in the nociceptive system, e.g. in the spinal cord. Although secondary neurogenic hyperalgesia and allodynia are induced by the same HFS protocol, they involve additional NMDA-receptor insensitive mechanisms of heterosynaptic facilitation.

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

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.

200 Test/retest- and interobserver-reliabilitiy in quantitative sensory testing according to the protocol of the german network on neuropathic pain (DFNS)

MRI was abnormal, in 1/3 pt the pain is derived from odontoiatric procedures. In 12 pts NFS evaluation was normal. Conclusion. the NFS evaluation disclosed a neurological involvement related to FP in a small portion of the pts; NFS data correlated with imaging results and in 2/3 patients only large-fiber assessing methods showed abnormalities. These results indicate the usefulness of performing a complete panel of NFS examinations in order to improve the diagnosis of PIFP.

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 being models for phase 2 mechanisms, however, most human surrogate models mimic sensory symptoms that may occur in both neuropathic and nociceptive pain. The chapter reviews that each sensory finding is compatible with several neurobiological and neuropharmacological mechanisms, because of convergence in the generation of clinical manifestations. Thorough characterization of human surrogate models may in the future lead to a refinement of the proposed grouping scheme. Already at the present stage, human surrogate models of neuropathic pain are useful for the investigation of pharmacological mechanisms of action and therapeutic efficacy, because they are based on identical assessment techniques as in the actual patient studies.

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

pharmacology. Gunnar Wasner will detail models for a hitherto unresolved problem of neuropathic pain, namely cold pain focussing on the discrimination of nociceptive and neuropathic cold pain and on cold hyperalgesia. Boris Chizh shall pinpoint the utility of human surrogate models from the viewpoint of translational pharmaceutical pain research namely as a rational strategy to hand over knowledge from animal research (i.e. from animal surrogate models) into clinical studies on neuropathic pain.

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

channel, which is preferentially expressed in small DRG and sympathetic ganglion neurons, produce inherited erythromelalgia (erythermalgia), a disorder in which patients experience severe burning pain in their extremities in response to mild warmth. These mutations hyperpolarize the channel’s activation voltage-dependence, thus decreasing the threshold for channel opening; slow deactivation, thereby keeping the channel open longer once activated; and increase the ‘‘ramp response’’ to small, slow depolarizations, thereby amplifying small stimuli such as generator potentials to a greater degree than normal. Some of these mutations also depolarize resting potential via increased overlap between activation and steady-state inactivation. When introduced into small DRG neurons, these Nav1.7 mutations produce hyperexcitability, lowering the threshold for generation of single action potentials and increasing the firing rate in response to graded stimuli. One mutation, L858H, has been expressed and studied within both DRG and sympathetic ganglion neurons. This mutation depolarizes both cell types by approximately 5mV, but produces hyperexcitability in DRG neurons, and hypoexcitability in sympathetic ganglion neurons. This is due to the selective expression of Nav1.8 sodium channels within DRG neurons, and the participation of Nav1.8 in action potential electrogenesis following depolarization which inactivates other sodium channel isoforms.

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

Pain rating scales include Pain Castastrophizing Scale, Coping Strategies Questionnaire and McGill Pain Questionnaire. Anxiety and depression are measured with Symptom Checklist-92, Hamilton Depression and Anxiety Rating Scales, Major Depression Inventory, Anxiety Inventory GAD-10 and SF-36 Health Survey. The patients are compared to 25 ageand gender-matched healthy controls. Results. Data collection is ongoing. Preliminary results will be ready for presentation at the conference.