Complex interactions between pain and itch.
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Animals↗
Biomedical subjects
M Schmelz
Publications and source records attributed to M Schmelz.
Continuous brachial plexus blockade in combination with the NMDA receptor antagonist memantine prevents phantom pain in acute traumatic upper limb amputees.
BACKGROUND: Hyperexcitability of N-methyl-d-aspartate acid (NMDA) receptors may play an important role in the development of phantom limb pain (PLP). AIM OF THE STUDY: To investigate whether early treatment with the NMDA antagonist memantine attenuates phantom pain memory formation in traumatic amputees. METHODS: In a randomized, double-blind, controlled trial 19 patients with acute traumatic amputation of the upper extremity were investigated. All patients received postoperative analgesia by continuous brachial plexus anesthesia (ropivacaine 0.375% 5 ml/h) for at least 7 days. In addition, the patients received either memantine (20-30 mg daily, n=10) or placebo (n=9) for 4 weeks. RESULTS: Memantine treatment reduced the number of requested ropivacacine bolus injections during the first week and resulted in a significant decrease of PLP prevalence and intensity at 4 weeks and 6 months follow up, but not at 12 months follow up. CONCLUSIONS: We conclude that memantine can reduce intensity of phantom limb pain and might also prevent the development of PLP. However, despite the very early begin of treatment; no long-term effect on established PLP was evident.
Adult↗
[Interactions between itch and pain].
The discovery of specific pathways for the processing of itch has greatly enhanced our understanding of the physiology of pruritus. However, the complex interactions between itch and pain are only partly understood. This review focuses on the neurophysiological basis of itch under experimental and clinical conditions. Chronic inflammatory diseases can locally sensitize nerve endings and thereby contribute to itch. In addition, there is increasing evidence that also central processing of itch can be sensitized in pruritus patients. Interestingly, this pattern of peripheral and central sensitization in pruritus has striking similarities to the one observed in chronic pain patients. The presumed similarities in underlying sensitizing mechanisms between itch and pain has major therapeutic consequences as successful therapies for chronic pain might be used also in chronic itch.
Humans↗
[Clinical classification of chronic pruritus. Interdisciplinary consensus proposal for a diagnostic algorithm].
Chronic pruritus is a frequent symptom in dermatology caused by a variety of dermatologic, neurologic and other systemic diseases. For adequate, economically-appropriate medical care of patients with chronic pruritus, a clinical classification of pruritus which also serves as a diagnostic algorithm is necessary. Currently suggested classifications are etiologic and not helpful in daily clinical routine. The proposed clinical classification is oriented at the clinical appearance of the patients and differentiates between disorders with or without primary or secondary skin lesions.
Algorithms↗
[Respiratory failure due to delta-9-tetrahydrocannabinol in a tetraplegic patient].
We report on a patient with an incomplete tetraplegia below C2 who suffered from a post-traumatic abdominal spasticity, spasticity of the legs, and bladder contractions of high intensity. Breathing was possible during the day using accessory respiratory musculature. All standard therapeutic regimes against spasticity failed. Treatment was started with delta-9-tetrahydrocannabinol administered orally in a dosage of 2 x 2.5 mg/day. The spasticity of the legs and the bladder improved with the treatment. After 3 days, the patient complained about dyspnea and shortness of breath. Treatment with delta-9-tetrahydrocannabinol was discontinued after 5 days but the patient needed ventilatory support for 1 week. After 1 week, spontaneous breathing was possible again. The reasons for respiratory failure in endangered patients during treatment with delta-9-tetrahydrocannabinol could be effects such as sedation, combined treatment with baclofen, muscle weakness, or central nervous effects in the medulla oblongata.
Adult↗
Postprandial interstitial insulin concentrations in type 2 diabetes relatives.
BACKGROUND: An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue. SUBJECTS AND METHODS: Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively. RESULTS: The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide. CONCLUSIONS: Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.
Adipose Tissue↗
[Mechanisms in the development of pain. Key issue in the periphery].
The interaction between neurons, tissue cells and inflammatory cells is of major importance for the development of pain in the periphery. In this interaction a variety of inhibitory and activating circuits has been identified in recent years. In addition to the receptors for classical inflammatory mediators on the sensory terminals like bradykinin, axonal ion channels have been identified as major modulators of pain and sensitization apart from their traditional role in conduction of action potentials. Sensitization of spinal nociceptive processing is crucial for the expansion of pain beyond the initially injured site and contributes to chronic pain. Learning processes and extinction of aversive memory are of major importance for the development, but also the therapy of chronic pain states.
Animals↗
Inhibition of neutral endopeptidase (NEP) facilitates neurogenic inflammation.
Neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) are involved in neuropeptide degradation and may modulate neurogenic inflammation. We therefore explored the effect of specific blockers of NEP and ACE on the intensity of neurogenic inflammation. We investigated eight subjects on three occasions. Two pairs of microdialysis fibers equipped with intraluminal wires were inserted intracutaneously into the volar forearms and electrical stimuli were delivered via the intraluminal electrodes. The microdialysis fibers were perfused either with normal saline, phosphoramidon (NEP inhibitor), or captopril (ACE inhibitor). CGRP release was assessed in the microdialysis eluate via a specific EIA and by evaluating the extent and intensity of the neurogenic flare via a laser Doppler imager. The area of hyperalgesia and allodynia was assessed during electrical stimulation. Inhibition of NEP with phosphoramidon increased flare intensity (P < 0.002) and size (P < 0.01), while blocking ACE had no effect on neurogenic vasodilation. CGRP release could be measured in microdialysis samples after phosphoramidon perfusion only (P < 0.03), not in samples with captopril or saline perfusion. No effect on the areas of hyperalgesia and allodynia could be detected. Our findings suggest that NEP but not ACE is most important for CGRP degradation in human skin. This may be of particular importance for the understanding of pain disorders like migraine or complex regional pain syndrome.
Adult↗
How best to fight that nasty itch - from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches.
While the enormous clinical and psychosocial importance of pruritus in many areas of medicine and the detrimental effects of chronic 'itch' on the quality of life of an affected individual are widely appreciated, the complexity of this sensation is still often grossly underestimated. The current Controversies feature highlights this complexity by portraying pruritus as a truly interdisciplinary problem at the crossroads of neurophysiology, neuroimmunology, neuropharmacology, protease research, internal medicine, and dermatology, which is combated most successfully if one keeps the multilayered nature of 'itch' in mind and adopts a holistic treatment approach - beyond the customary, frequently frustrane monotherapy with histamine receptor antagonists. In view of the often unsatisfactory, unidimensional, and altogether rather crude standard instruments for pruritus management that we still tend to use in clinical practice today, an interdisciplinary team of pruritus experts here critically examines recent progress in pruritus research that future itch management must take into consideration. Focusing on new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus, and discussing available neuropharmacological tools, specific research avenues are highlighted, whose pursuit promises to lead to novel, and hopefully more effective, forms of pruritus management.
Dermatology↗
Neurophysiological evidence for altered sensory function caused by storage of hydroxyethyl starch in cutaneous nerve fibres.
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Drug Eruptions↗
Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch.
BACKGROUND: Central sensitization for pain is important for patients with chronic pain. The authors investigated a possible role of central sensitization for itch in patients with chronic pruritus. METHODS: Noxious stimuli were applied in lesional and visually nonlesional skin areas of 25 patients with atopic dermatitis, in lesional skin areas of 9 patients with psoriasis vulgaris, and in 20 healthy subjects. The stimuli included mechanical pinpricks, electrical stimuli, contact heat, and injection of low-pH solution. Intensities of itch and pain were assessed separately on a numeric rating scale. RESULTS: All the noxious stimuli primarily evoked pain in control subjects and patients with psoriasis vulgaris. In patients with atopic dermatitis, however, itch was evoked instead of burning pain. In their lesional skin, itch was the predominant sensation. Chemical stimuli evoked intense itch in lesional and visually healthy skin areas (the area under the curve of itch rating compared with the control, mean +/- SEM, 668 +/- 166 and 625 +/- 192 vs 38 +/- 23; p < 0.001; p < 0.01). Chemically induced itch also was observed in healthy subjects after a conditioning histamine stimulus of 15 minutes, but not after a conditioning histamine stimulus of 2 minutes. CONCLUSION: The chronic barrage of pruriceptive input may elicit central sensitization for itch so that nociceptive input no longer inhibits itch but on the contrary is perceived as itch. In contrast to the well-known A-fiber-mediated alloknesis and hyperknesis, this type of central sensitization appears to be elicited by C-nociceptors.
Adult↗
A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).
Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases from six CRPS I families. In conclusion, the results presented herein render this particular ACE gene polymorphism unlikely to be a predisposing factor for CRPS I.
DNA Mutational Analysis↗
Sudomotor function in familial dysautonomia.
BACKGROUND: Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity. METHODS: In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function. RESULTS: Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p<0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function. CONCLUSION: The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.
Acetylcholine↗
Active "itch fibers" in chronic pruritus.
An itch-specific neuronal pathway was recently discovered in healthy humans and animals. Here the authors report that activity in this specific pathway coincides with itch under pathophysiologic conditions in a patient with chronic pruritus. Microneurographic recordings from the symptomatic area revealed spontaneous activity in six single C-fiber afferents that had the characteristic features of "itch fibers." Itch may be caused by activity in a specific subpopulation of C-fiber afferents.
Chronic Disease↗
Differential effects of surgical sympathetic block on sudomotor and vasoconstrictor function.
OBJECTIVE: To assess the effects of a surgical block of the sympathetic chain at the T2 level on vasoconstriction and palmar sweating in patients with palmar hyperhidrosis. METHODS: In a prospective study, sympathetic vasoconstriction was measured by laser-Doppler imaging and by computer-assisted infrared thermography (rewarming kinetics following immersion of both hands in ice water [4 degrees C, 30 seconds]) in 61 patients with hyperhidrosis preoperatively and 2 days and 3 months postoperatively. In addition, palmar sweating preoperatively and 3 months postoperatively was assessed by quantitative sudometry. RESULTS: Before surgery, rewarming kinetics was significantly slower in the patients (n = 61) than in the healthy control subjects (n = 28). Two days after the block, baseline skin temperature increased by about 5 degrees C, and rewarming was massively accelerated in each of the patients. Three months postoperatively, rewarming kinetics was still accelerated in 36 hands, was unchanged from the preoperative condition in 42, and had worsened in 12. These changes were accompanied by parallel alterations of laser-Doppler flux. However, palmar sweating was massively reduced in all but one patient, irrespective of the different rewarming kinetics. CONCLUSIONS: T2 sympathectomy leads to long-lasting inhibition of palmar sweating, which does not correlate to loss of vasoconstriction. Recurrent and enhanced vasoconstrictor function 3 months following endoscopic sympathetic block has major implications for its use to treat enhanced vasoconstriction.
Adolescent↗
Action potential conduction in the terminal arborisation of nociceptive C-fibre afferents.
Recordings of single human peroneal C-fibres and rat saphenous C-fibres confirm two different patterns of conduction at branching points. In general, an action potential (AP) arising from one terminal branch may be propagated not only centrally, but also antidromically into the other branches of the terminal arborisation. If a stimulus activates several converging branches of one unit, at each branching point only the AP arriving first from the simultaneously activated daughter branches will be propagated centrally, resetting the slower branches. However, occasionally a single electrical stimulus may evoke a double response in the parent axon. In this case, these two responses apparently originate from different terminal branches and require unidirectional conduction block to prevent the faster AP from invading and resetting the slower-conducting terminal. This conclusion is supported by the notion that when such a double response occurs, both responses immediately show additional activity-dependent slowing of the conduction velocity due to frequency increase in the parent axon (two spikes per stimulus, one from each of the two excited branches). A comparable discharge pattern in the stem axon can be induced by repetitive paired stimulation of one terminal branch. Then the slowing is induced by the doubled frequency along the whole nerve fibre including the terminal branch. Since in this case not only the stem axon, but also the terminal branches carry two spikes per pulse, activity-dependent slowing is predictably more pronounced. Unidirectional block thus provides insight into the differential amount of activity-dependent slowing (and hence postexcitatory hyperpolarisation) in the stem axon and terminal branches of cutaneous C-fibres. This comparison reveals that more than two-thirds of the slowing can be attributed to the terminal branches, since it is two- to fourfold that observed during double stimulation as compared with the unidirectional block condition. This indicates that the terminal branches are equipped with membrane proteins that are different from those of the parent axon.
Action Potentials↗
Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens.
Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E(2) (PGE(2)) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMi(His-)), and 24 mechanoinsensitive, histamine-positive (CMi(His+)) units were compared. CMi(His+) units were most responsive to histamine and to PGE(2) and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi(His-) units showed significantly weaker responses to histamine, PGE(2), and acetylcholine. Capsaicin and bradykinin responses were not significantly different in the two classes of mechano-insensitive units. We conclude that CMi(His+) units are "selective," but not "specific" for pruritogenic substances and that the pruritic potency of a mediator increases with its ability to activate CMi(His+) units but decreases with activation of CMH and CMi(His-) units.
Acetylcholine↗
Botulinum Toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin.
Botulinum toxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity. There is increasing evidence that BoNT/A might also have analgesic properties, in particular in headache. In the present investigation we tested the often cited hypothesis that BoNT/A-induced analgesia can be attributed to inhibition of neuropeptide release from nociceptive nerve fibers. In 15 healthy volunteers BoNT/A (5, 10, 20 mouse units BOTOX) or saline (contralateral side) was injected intracutaneously on the volar forearm. On day zero, the day of injection, no further tests were performed. We repeatedly elicited pain, mechanical hyperalgesia and neurogenic flare by transcutaneous electrical stimulation simultaneously on the BoNT/A and saline treated side on day 1, 2, 3, 7 and 14 after injection. Before each session, sweating and local anhidrosis was assessed by iodine starch staining.BoNT/A suppressed sweating as early as from the second day after injection (p < 0.001). The size of electrically induced flare was smaller on the BoNT/A treated arm (BoNT/A side: 21.46 cm(2) +/- 3.58, saline side 24.80 +/- 3.46, p < 0.005) and BoNT/A reduced electrically-induced pain by about 10 % (p < 0.001). However, hyperalgesia to pin-prick and allodynia after electrical stimulation were unchanged. In conclusion our results indicate that peripheral neuropeptide release is attenuated by BoNT/A. In contrast, the analgesic effect of BoNT/A was very limited. Therefore we assume that other than neuropeptide mechanisms must be important for BoNT/A induced pain relief in clinical pain syndromes.
Adult↗