Strong and aversive cold processing and pain facilitation in fibromyalgia patients relates to augmented thermal grill illusion.

The thermal grill illusion (TGI) is assumed to result from crosstalk between the thermoreceptive and nociceptive pathways. To elucidate this further, we compared 40 female fibromyalgia patients to 20 healthy women in an exploratory cross-sectional study. Sensations (cold, warm/heat, unpleasantness, pain and burning) evoked by 20 °C, 40 °C and alternating 20 °C/40 °C (TGI) and somatosensory profiles according to standardized quantitative sensory testing (QST) were assessed on the palm of the dominant hand. Compared to healthy controls, fibromyalgia patients reported stronger thermal grill-evoked cold, warm, unpleasantness and pain as well as stronger and more aversive 20 °C- and 40 °C-evoked sensations. They showed a loss in warm, mechanical and vibration detection, a gain in thermal pain thresholds and higher temporal summation (TS). Among QST parameters higher TS in fibromyalgia patients was most consistently associated with an augmented TGI. Independently, an increased TGI was linked to cold (20 °C) but less to warm (40 °C) perception. In fibromyalgia patients all thermal grill-evoked sensations were positively related to a higher 20 °C-evoked cold sensation and/or 20 °C-evoked unpleasantness. In conclusion, the TGI appears to be driven mainly by the cold-input. Aversive cold processing and central pain facilitation in fibromyalgia patients seem to independently augment the activation of the pain pathway.

Sex differences in the consumption of over-the-counter analgesics among amateur volleyball players.

BACKGROUND: Compared with the normal adult population, athletes of several sport disciplines, such as endurance sports, ball sports, cycling and swimming, have higher use of over-the-counter analgesics (OTC analgesics). The aim of this study was to describe the epidemiology of OTC analgesic use in volleyball players as a typical competitive sport discipline. One particular focus was placed on the analysis whether the athletes' use of OTC analgesics was influenced by their performance motivation. METHODS: A cross-sectional survey among amateur volleyball players was carried out using a web-based sports questionnaire. The study included athletes of both sexes, 18 years and older, currently playing in a German volleyball league. The athletes' sport-related complaints were evaluated regarding the use of OTC analgesics. The use of OTC analgesics by athletes was compared with their performance motivation, based on the "Achievement Motives Scale - Sport" (AMS-Sport) questionnaire. RESULTS: The analysis of 114 completed questionnaires of amateur athletes revealed that the use of OTC analgesics was sex dependent, with a higher prevalence of use in female players (60%) versus male players (38%). The main reasons for consumption of OTC analgesics were pain in the head, knee and shoulder. The most frequently taken drug was ibuprofen, most often taken at competitions and over a period of 4 years (median). The analysis of the AMS-Sport questionnaire revealed that a logistic regression model for estimating the probability of drug use can be explained by the factors hope of success and years of playing practise in female players but not male players. In females, an increase in the factor hope of success resulted in a lower probability of OTC analgesic use, while an increase in years of playing practise resulted in a higher probability of use. CONCLUSION: The average duration that volleyball players in this study took OTC analgesics was higher than that of the German population, and OTC analgesic use was more prevalent in female than male volleyball players. Thus, to reduce the prevalence of OTC analgesic use, educational programs should be implemented in sports teams; and, to reduce direct and indirect social pressure, sports teams should also receive sex-specific psychological support.

Sex differences in thermal detection and thermal pain threshold and the thermal grill illusion: a psychophysical study in young volunteers.

BACKGROUND: Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli. METHODS: The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 °C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students. RESULTS: The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males. CONCLUSIONS: Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of "cold" and "warm" inputs in thermal perception. The results of the TGI experiment support the assumption that sex differences in cold-related thermoreception are responsible for sex differences in the TGI.

Calcium can mobilize and activate myosin-VI.

The ability to coordinate the timing of motor protein activation lies at the center of a wide range of cellular motile processes including endocytosis, cell division, and cancer cell migration. We show that calcium dramatically alters the conformation and activity of the myosin-VI motor implicated in pivotal steps of these processes. We resolved the change in motor conformation and in structural flexibility using single particle analysis of electron microscopic data and identified interacting domains using fluorescence spectroscopy. We discovered that calcium binding to calmodulin increases the binding affinity by a factor of 2,500 for a bipartite binding site on myosin-VI. The ability of calcium-calmodulin to seek out and bridge between binding site components directs a major rearrangement of the motor from a compact dormant state into a cargo binding primed state that is nonmotile. The lack of motility at high calcium is due to calmodulin switching to a higher affinity binding site, which leaves the original IQ-motif exposed, thereby destabilizing the lever arm. The return to low calcium can either restabilize the lever arm, required for translocating the cargo-bound motors toward the center of the cell, or refold the cargo-free motors into an inactive state ready for the next cellular calcium flux.

Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial.

BACKGROUND: Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine's clinical profile. TRIAL DESIGN: To investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT). METHODS: Threshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm. RESULTS: Flupirtine (3-30 µM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.). CONCLUSIONS: Clinical doses of flupirtine reduce the excitability of peripheral myelinated axons. TRIAL REGISTRATION: ClinicalTrials registration is NCT01450865.

Osteoarthritic mice exhibit enhanced prostaglandin E2 and unchanged calcitonin gene-related peptide release in a novel isolated knee joint model.

OBJECTIVE: Osteoarthritis (OA) is a painful degenerative joint disease. To assess joint nociceptor activation indirectly, we used a novel in vitro knee joint preparation and determined the release of calcitonin gene-related peptide (CGRP) and prostaglandin E2 (PGE2) in osteoarthritic mice. METHODS: We studied STR/1N mice, which spontaneously develop OA, along with CD-1 mice as controls and C57/Bl6 mice with unilateral collagenase-induced OA and C57/Bl6 control mice. The release of CGRP and PGE2 from tibial and femoral joint preparations was determined separately in vitro with enzyme immunoassays; we investigated both basal release and release induced by stimulation with capsaicin (CAP, 1 microM) or bradykinin (BK, 10 microM). RESULTS: Basal PGE2 release from femoral and tibial preparations increased by 79% and 97%, respectively, in STR/1N mice between 6 and 18 weeks of age when they developed OA, while age-matched CD-1 mice exhibited only a weak increase (23%). BK-evoked PGE2 release was significantly higher in 18-week-old STR/1N mice (931 +/- 98 pg/ml and 759 +/- 82 pg/ml from femoral and tibial preparations, respectively) than in age-matched CD-1 controls (236 +/- 38 pg/ml and 246 +/- 34 pg/ml). CAP stimulation induced a significant CGRP release, which, however, did not correlate with the temporal development of OA in STR/1N mice. Tibial but not femoral joint preparations from mice with collagenase-induced OA exhibited a significantly enhanced release upon BK stimulation compared to sham controls, while CAP-induced CGRP release did not reveal such difference. CONCLUSION: Basal and evoked PGE2 release from knee joint preparations rose while osteoarthritic alterations developed, whereas CGRP release remained unaltered. The increased PGE2 release may contribute to enhanced nociceptor sensitivity underlying chronic OA pain.

Stimulation of PAR-2 excites and sensitizes rat cutaneous C-nociceptors to heat.

Proteinase-activated receptor 2 (PAR-2) is expressed on many nociceptive neurons. Application of PAR-2 agonists has been shown to induce behavioral signs of hyperalgesia. We investigated effects of the rat PAR-2 agonist SLIGRL-NH2 in the isolated rat skin-saphenous nerve preparation. SLIGRL-NH2 (100 microM) excited 20% of all C-fiber nociceptors tested. In addition, C-fiber nociceptors were sensitized to heat after SLIGRL-NH2 application resulting in an increase in response magnitude and a decrease of heat threshold. The PAR-2-inactive control peptide LRGILS-NH2 had no effect. The mechanical sensitivity of C-fibers was not affected by SLIGRL-NH2. PAR-2-mediated excitation and sensitization of primary nociceptors may contribute to PAR-2-mediated hyperalgesia.

Substance P and prostaglandin E2 release after shock wave application to the rabbit femur.

The biologic action of extracorporeal shock wave application on the musculoskeletal system is poorly understood. To prove the hypothesis that alterations of tissue concentrations of substance P and prostaglandin E(2) are involved in the biologic action of shock waves, extracorporeal shock waves with energy flux density of 0.9 mJ/mm2 (1500 pulses at 1/second) were applied in vivo to the distal femur of rabbits. The concentrations of substance P and prostaglandin E(2) eluted from the periosteum of the femur were measured. Compared with the untreated contralateral hindlimbs, substance P release from the periosteum from the femur was increased 6 hours and 24 hours after extracorporeal shock wave application, but was decreased 6 weeks after extracorporeal shock wave application. By contrast, extracorporeal shock wave application did not result in altered prostaglandin E(2) release from the periosteum from the femur. Remarkably, there was a close relationship between the time course of substance P release found here, and the well-known clinical time course of initial pain occurrence and subsequent pain relief after extracorporeal shock wave application to tendon diseases. Accordingly, substance P might be involved in the biologic action of extracorporeal shock wave application on tissue of the musculoskeletal system. This is the first study providing insights into the molecular mechanisms of extracorporeal shock wave application to the musculoskeletal system.

Different responses to drugs against overactive bladder in detrusor muscle of pig, guinea pig and mouse.

Direct comparison of experimental data for drugs commonly used in the treatment of overactive bladder is difficult because of possible species differences. In this study, we compare the effects of atropine, propiverine, oxybutynin and tolterodine in strips of pig, guinea pig and mouse detrusor muscle. In the three species, we observed slight differences in potency of carbachol-induced biphasic contractile responses between the species (guinea pig>pig>mouse). Cumulative concentration-response curves for carbachol were shifted to the right by atropine, propiverine, oxybutynin and tolterodine. However, at higher concentrations of the latter three antagonists, the maximum response to carbachol was also reduced. Therefore, propiverine, oxybutynin and tolterodine must have additional pharmacological actions beyond competitive antagonism at muscarinic receptors. Electric field stimulation (30 Hz) of detrusor strips led to contraction amplitudes, which remained constant over time (210 min) in pig, decreased by 17+/-5% in guinea pig, and increased by 28+/-9% in mouse detrusor muscle. Electric field stimulation-evoked contractions were suppressed to 18% of pre-drug control by high concentrations of atropine (10 microM) in pig, but to a much lesser extent in guinea pig and mouse (to 46% and 70%, respectively). In all three species, a myogenic component of contraction was observed in the presence of tetrodotoxin (1 microM). Compared to atropine, the bladder spasmolytic agents propiverine, oxybutynin and tolterodine also reduced electrically evoked contractions in the three species, though higher concentrations were required. The differences in the reported effects of the spasmolytic agents commonly used for treating overactive bladder suggest that drug action is strongly dependent on the species. Thus, a comparison of drug effects is only feasible in the same animal model and the results cannot easily be transferred to humans.