Antigen-induced arthritis in rats is associated with increased growth-associated protein 43-positive intraepidermal nerve fibres remote from the joint.

INTRODUCTION: Pain in arthritis may be experienced in regions outside the affected joint, and hyperalgesia may even be widespread. The spread of pain is usually attributed to mechanisms in the central nervous system. We investigated whether rats with antigen-induced arthritis (AIA) exhibit peripheral changes in skin innervation remote from the inflamed joint. METHODS: After immunization, unilateral AIA in the knee joint was induced in rats. Intraepidermal nerve fibre density was determined by immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and for nerve fibres expressing calcitonin gene-related peptide (CGRP), substance P (SP), transient receptor potential vanilloid 1 (TRPV1; the heat and capsaicin receptor), ß-tubulin, and growth-associated protein 43 (GAP-43; a marker of regenerating nerve fibres) in paw pad skin and back skin. Cluster of differentiation 11b (CD11b)-positive macrophages and CD3-positive T cells were quantified in skin, and macrophages were quantified in the lumbar dorsal root ganglia. In addition, pain-related behaviour was assessed. RESULTS: Intraepidermal nerve fibre density (PGP 9.5) and the numbers of fibres expressing CGRP, SP, TRPV1, or ß-tubulin did not show a significant change in the acute (3 days) or chronic phase (21 days) of AIA compared with control rats that were only immunized. However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA. The skin of arthritic rats in these regions did not contain a greater density of CD11b and CD3 immune cells than the skin of control rats. Enhanced expression of GAP-43 in nerve fibres of the skin was not related to hyperalgesia in the joint, but it accompanied persistent secondary cutaneous hyperalgesia in the skin remote from the inflamed joint. CONCLUSIONS: Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous. The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint.

Repeated autologous intraarticular blood injections as an animal model for joint pain in haemophilic arthropathy.

INTRODUCTION: Haemophilic arthropathy following recurrent joint bleedings is one of the major disease-related complications in people with haemophilia (PWH), leading to mostly chronic joint pain. Since many antinociceptive principles interfere with the clotting system, PWH are restricted in treatment options, thereby defining a medical need for novel therapeutic principles. However, we lack the availability of an animal model for joint pain in haemophilic arthropathy for testing these. METHODS: In this study, we aimed to validate the rat model of repeated autologous intraarticular blood injections specifically for pain-related behavior. During an observation period of 50 days, groups of animals were injected weekly into one knee joint with either whole blood or cellular/plasma components. RESULTS: Injections induced primary hyperalgesia starting after the third injection, accompanied by mild functional gait changes and joint swelling. Secondary hyperalgesia and quantitative gait disturbances were not observed. This phenotype was most prominent in whole blood injected animals, with effect sizes of cells and plasma being additive. In order to differentiate haemophilia-related arthropathy from traumatic joint bleeding, another group was injected with whole blood only once, which did not cause any alterations. CONCLUSIONS: Repeated autologous intraarticular injections of blood showed a time course, inflammatory response and reduction in pain thresholds similar to the signs and symptoms observed in PWH. Therefore, this model may be utilised in the future for testing novel antinociceptive principles in haemophilia-associated joint pain.

Assessment of rat antigen-induced arthritis and its suppression during glucocorticoid therapy by use of hemicyanine dye probes with different molecular weight in near-infrared fluorescence optical imaging.

PURPOSE: Arthritic joints are ideal disease entities to be assessed via optical imaging. Here, we investigated the selective accumulation behavior of two differently sized hemicyanine optical probes in arthritic joints and its modification during glucocorticoid therapy in the course of inflammation. MATERIALS AND METHODS: The well-standardized preclinical antigen-induced arthritis (AIA) model in rats was used. The animals were divided into 3 groups: arthritic, arthritic and dexamethasone-treated, and immunized only. After intravenous coinjection of DY-752 (size, 800 Da) and DY-682-(rat) IgG (size, 150 kDa) probes, spectrally unmixed near-infrared fluorescence images were acquired and analyzed semiquantitatively. Probe organ distribution, joint swelling, blood cell counts, joint vessel density, and histological scoring of arthritis were determined. RESULTS: The local joint accumulation kinetics of the DY-752 probe differed from the DY-682-IgG one. In the course of AIA, probe signaling in arthritic joints was similar between each other. Joint swelling and histological scoring were in accordance with signaling. Dexamethasone treatment of rats with AIA significantly reduced both the near-infrared fluorescence signals and severity of arthritis but did not change the joint vascular density or the uptake of the probes by phagocytes. A differential biodistribution of both probes was encountered, but such an accumulation was prevented by dexamethasone treatment. CONCLUSIONS: Near-infrared fluorescence signaling in the course of AIA closely reflects the pathophysiological events of the arthritic joint and the effects of therapy independently of the molecular size of the probe. The results show the suitability of our hemicyanine probes for imaging of arthritis.

Thresholds and perception of cold pain, heat pain, and the thermal grill illusion in patients with major depressive disorder.

OBJECTIVE: The thermal grill illusion (TGI) in which interlacing cold and warm bars create the illusion of a painful sensation has been suggested as an experimental model for central pain states and pain processing. The aim of this study was to use this technique to gain further insights into the altered pain perception in major depressive disorder (MDD). METHODS: In 18 unmedicated patients with MDD, cold and heat pain thresholds (CPT/HPT) as well as the perception of the TGI were examined and compared with 18 matched controls. RESULTS: CPT and HPT were significantly increased in patients (7.9°C and 47.5°C) compared with controls (15.9°C and 45.2°C, respectively; p < .05). In the range of TGI stimuli that were perceived painful by controls, the patients did not indicate painful sensations, thereby indicating a shift of the stimulus-response curve of TGI pain perception toward higher stimulus intensities, that is, greater temperature differentials between cold and warm bars (11.5°C for controls, 16.7°C for patients). The patients rated the pain intensity perceived at the respective pain thresholds (CPT and HPT) in tendency higher than did the controls, whereas they perceived the TGI less painful despite increased stimulus intensities. Unpleasantness ratings were similar between groups. CONCLUSIONS: CPT, HPT and temperature differentials for the perception of the TGI, were increased in patients with MDD as compared with controls. Pain intensity, however, was rated differently for CPT and HPT, where patients indicated higher ratings in tendency, and for the TGI stimulation, where pain was perceived less intense.

Evaluation of long-term antinociceptive properties of stabilized hyaluronic acid preparation (NASHA) in an animal model of repetitive joint pain.

INTRODUCTION: Clinical trials provided controversial results on whether the injection of hyaluronan preparations into osteoarthritic joints reduces pain. Problems of clinical studies may be the substantial placebo effects of intra-articular injections, different severity and rate of progression of the disease and others. We hypothesize that the use of preclinical pain models may help to clarify whether a certain hyaluronan exerts antinociceptive effects upon intra-articular injection. In the present study we tested in the bradykinin/prostaglandin E(2) (PGE(2)) model primarily the putative antinociceptive effect of stabilized hyaluronic acid from a non animal source (NASHA), a stabilized hyaluronic acid based gel for intra-articular treatment of OA. We established a dose-response relationship for NASHA and we compared NASHA to other hyaluronans with different formulations that are in clinical use. METHODS: To induce transient joint pain episodes bradykinin and PGE(2) were repetitively administered intra-articularly and unilaterally into rat knee joints during short anaesthesia. After establishment of the predrug nociceptive responses, a single intra-articular injection of saline or NASHA at different concentrations was administered and pain responses to further bradykinin/PGE(2) injections were monitored up to 56 days after NASHA. Furthermore, the obtained effective dose was compared to clinically defined concentrations of Hylan GF20 and sodium hyaluronate. The primary outcome measures were primary mechanical hyperalgesia at the knee joint and pain-induced weight bearing. RESULTS: On day 1 after injection, all tested hyaluronan preparations showed an antinociceptive effect >50% compared to saline. Single injections of higher doses of NASHA (50, 75 and 100 µl) were antinociceptive up to 56 days. When injection volumes in rat knee joints were adapted to clinical injection volumes in humans, the antinociceptive effects of the cross-linked NASHA and Hylan GF20 had a longer duration than that of the non cross-linked sodium hyaluronate (with a slightly better effect of NASHA than Hylan GF20). CONCLUSIONS: In the bradykinin/PGE(2) model of joint pain a single injection of all hyaluronan preparations provided significant antinociceptive effects compared to saline. It appeared that the duration of the antinociceptive effect of the cross-linked hyaluronan preparations NASHA and Hylan GF20 was more prolonged. In addition, the gel beads structure allowing only a slow release of hyaluronic acid (NASHA) may even enhance this prolonged antinociceptive effect.

Joint pain in people with hemophilia depends on joint status.

Recurrent joint bleedings in people with hemophilia (PWH) often progress into the full clinical picture of hemophilic arthropathy, accompanied by chronic pain. Although chronic pain is commonly present in PWH, investigations assessing pain thresholds have not been performed yet. Thus, the aim of this study was to obtain objective and subjective measures of joint pain in PWH and to relate these to the severity of joint pathology. Thirty-six patients (aged 43±11 years) with hemophilia A and B (31 severe A, 1 B; 3 moderate A, 1 B) and 40 healthy control subjects (aged 42±14 years) participated in this study. Mechanical pain thresholds were obtained as objective parameters using an algometer, while subjective pain intensity and quality were assessed using numeric analogue scales. Quality of life was estimated using the Short-Form Health Survey (SF-36) questionnaire. Overall, we found reduced mechanical pain thresholds as obtained from the knee (PWH--left 38.1 [28.7/57.7], right 29.5 [20.9/49.3]; control--left 67.4 [56.8/112.6], right 60.9 [42.6/97.2]), and elbow (PWH--left 23.4 [15.3/33.4], right 23.5 [20.1/35.1]; control--left 56.7 [32.6/86.6], right 53.0 [30.7/87.7] in N; median [25th/75th percentile]) joints in PWH. Interestingly, this increased pain sensitivity was related to the severity of clinical joint pathology. In addition, PWH reported their pain in a more descriptive and not affective manner and scored similar to controls in the mental domain of the SF-36, thereby indicating good coping strategies despite the chronic nature of their complaints. In conclusion, pain sensitivity at the site of the affected joints is increased and closely related to joint pathology in people with hemophilia.

Gender-dependent impact of major depression on autonomic cardiovascular modulation.

Depression has been shown to increase the risk for cardiovascular disease (CVD) more strongly in women than in men. Although the underlying mechanisms are unknown, a putative role of increased sympathetic modulation has been suggested for the association of CVD and depression. The aim of this study was to investigate possible gender-associated differences of autonomic function in healthy volunteers and patients suffering from major depressive disorder (MDD). Linear as well as non-linear measures of heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were obtained in each 18 male and 18 female unmedicated patients and respective control subjects. Gender differences were detectable in healthy subjects showing predominant sympathetic modulation in males. This was most obvious in BPV analysis. These gender differences were abolished in patients suffering from MDD, mainly due to altered autonomic modulation in female patients. Our results indicate that BPV is more sensitive to reveal depression-associated changes of autonomic function as compared to HRV. Moreover, female patients contribute most to the overall difference between patients and controls. The shift in the balance of autonomic function in women might account for the increased prevalence of CVD in these patients.

Nonlinear relationship between electrodermal activity and heart rate variability in patients with acute schizophrenia.

We investigated to what degree tonic skin conductance levels (SCL) and cardiac autonomic dysfunction are interrelated in schizophrenia. Heart rate variability (HRV) and SCL were simultaneously assessed in 18 unmedicated patients and 18 controls matched for age, sex, weight, and smoking habits. For comparison to prior studies, phasic sympathetic skin responses (SPR) were also recorded. Compared to controls, patients had prolonged SPR latency and reduced SPR amplitude with a right-greater-than-left asymmetry, which was inversely correlated with positive symptoms. An autonomic imbalance was reflected in linear and nonlinear measures of HRV and increased SCL. Patients showed a stronger nonlinear association between SCL and heart rate than controls. HRV and SCL findings were strongly affected by group differences in breathing rate. Stronger HRV-SCL coupling in patients may suggest augmented sympathetic modulation in schizophrenia.

Peripheral endothelial dysfunction in patients suffering from acute schizophrenia: a potential marker for cardiovascular morbidity?

Patients suffering from schizophrenia have an increased standardized ratio for cardiovascular mortality compared to the general population. Endothelial function was identified as a prominent parameter for cardiac risk stratification in patients with heart disease. Here, we aimed to analyze the reactivity of the microcirculation applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of endothelial function. We investigated 21 unmedicated patients suffering from paranoid schizophrenia as well as 21 matched controls. The capillary blood flow was assessed on the right forearm after compression of the brachial artery. Parameters of PORH such as time to peak (TP) or PORH index were calculated. In addition, spectral analysis of skin vasomotion was performed and five frequency bands (endothelial, sympathetic, vascular myogenic, respiratory and heart beat activity) were studied. Psychotic symptoms were quantified using the Positive and Negative Syndrome Scale (PANSS) and correlated to the parameters obtained. We report a blunted hyperemic response in patients after occlusion of the brachial artery indicated by significantly increased TP and decreased PORH indices. In contrast, vasomotion as investigated by spectral analysis of skin flow was rather sparsely altered showing differences at rest for the sympathetic and cardiac components only. Our results are suggestive of peripheral endothelial dysfunction in unmedicated patients suffering from schizophrenia. Future, prospective studies should address the relation of endothelial dysfunction to cardiac morbidity in patients with schizophrenia.

Sad mood increases pain sensitivity upon thermal grill illusion stimulation: implications for central pain processing.

In different fields of neuroscience research, illusions have successfully been used to unravel underlying mechanisms of stimulus processing. One such illusion existing for the field of pain research is the so-called thermal grill illusion. Here, painful sensations are elicited by interlacing warm and cold bars, with stimulus intensities (temperatures) of these bars being below the respective heat pain or cold pain thresholds. To date, the underlying mechanisms of this phenomenon are not completely understood. There is some agreement, however, that the sensation evoked by this stimulation is generated by central nervous interactions. Therefore, we followed two approaches in this study: firstly, we aimed at developing and validating a water-driven device which might be used in fMRI scanners in future studies - subject to minor adaptations. Secondly, we aimed to interfere with this illusion by induction of a sad mood state, a procedure which is suggested to influence central nervous structures that are also involved in pain processing. The newly developed device induced thermal grill sensations similar to those reported in the literature. Induction of sad, but not neutral mood states, resulted in higher pain and unpleasantness ratings of the painful illusion. These findings might be of importance for the understanding of pain processing in healthy volunteers, but putatively even more so in patients with major depressive disorder. Moreover, our results might indicate that central nervous structures involved in the affective domain or cognitive domain of pain processing might be involved in the perception of the illusion.

Pseudohypoalgesia on the skin: a novel view on the paradox of pain perception in depression.

Previous studies reported increased heat pain thresholds and decreased ischemic pain thresholds in patients experiencing depression. The increased sensitivity to ischemic muscle pain was assumed to represent a model for the investigation of physical symptoms in the disease. Here, we explored how the serotonin and noradrenaline reuptake inhibitor duloxetine influences experimental pain thresholds and tolerances in depressed patients during treatment. Twenty-two patients experiencing unipolar depression were included. Pain assessments were conducted unmedicated at baseline, after 1 week, and after 6 weeks of duloxetine treatment. We observed the expected clinical response of patients indicated by a significant reduction in the Montgomery Depression Rating Scale after 6 weeks. At baseline, we found increased heat pain thresholds in patients in comparison to controls while patients simultaneously rated augmented pain perception on the visual analog scale. In contrast, patients were significantly more perceptive to ischemic muscle pain at baseline. During treatment, the examined pain thresholds showed differential changes: Increased heat pain thresholds of patients normalized during treatment, whereas no significant change was observed for ischemic pain thresholds. Thus, our results might change the view on the paradox of pain perception in major depression because increased heat pain thresholds are associated with augmented pain perception in the disease.

Does parasympathetic modulation prior to ECT treatment influence therapeutic outcome?

Electroconvulsive therapy (ECT) is an established treatment option for major depressive disorder when other treatments have failed. However, the underlying mechanisms responsible for these therapeutical effects are insufficiently understood to date. Furthermore, treatment outcome is difficult to predict. Recent research suggested an important role of autonomic modulation for successful treatment. We aimed to examine putative associations between autonomic modulation and response to ECT treatment and hypothesized a role for vagal modulation prior to therapy. Twenty-four patients with MDD who received ECT were assessed by means of heart rate and blood pressure variability analysis as well as baroreflex sensitivity measurements before, during and after a course of ECT. Autonomic parameters from the complete study population revealed that ECT did not significantly alter basic autonomic modulation after six sessions. Analyses showed a significant association of the reduction of HAMD scores during therapy when compared with baseline autonomic function as reflected in SDNN(RR) (p<0.004), Forbword(RR) (p<0.025) and compression entropy Hc(RR) (p<0.0003). A significant correlation was observed when overall HAMD reduction and changes of LFnu(RR) (p<0.026) or HFnu(RR) (p<0.026) during the course of therapy were analyzed. Our findings suggest that high levels of parasympathetic modulation at baseline might be associated with a beneficial effect upon ECT treatment. Adding to this, levels of parasympathetic activity seemed to increase in patients who respond to ECT treatment. Given these findings can be confirmed in future studies, autonomic modulation might be used as a predictor for therapeutic efficacy of ECT.

Is successful electroconvulsive therapy related to stimulation of the vagal system?

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to exhibit strong beneficial effects in the treatment of major depressive disorder (MDD). While the exact underlying mechanisms are under debate, a role for the sympathetic response upon ECT has been suggested. When assessing patients with MDD for autonomic function, however, a loss of vagal function is prominent. OBJECTIVE: Here, we aimed to assess the immediate effects of ECT on vagal activity and to test the hypothesis that surrogates of the latter correlate with therapeutic outcome. METHODS: Twenty patients with MDD who underwent ECT treatment were assessed regarding their vagal function using electrophysiological measures and determination of pancreatic polypeptide (PP), which is known to be released upon vagal stimulation. Parameters were correlated to the improvement of disease severity upon ECT treatment. RESULTS: Patients showed a significant increase of PP shortly after ECT which correlated with clinical improvement. Furthermore, the described association with the sympathetic phase after ECT could be verified. CONCLUSION: ECT increases vagal activity which might be associated with the beneficial effect seen following this treatment. PP elevation after administration of ECT might be a useful parameter to estimate the degree of such vagal stimulation after treatment.

Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation.

OBJECTIVE: In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation. METHODS: Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. RESULTS: Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. CONCLUSION: Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation.

Sympathetic skin response following painful electrical stimulation is increased in major depression.

Patients with major depressive disorder have repeatedly been described to exhibit increased thresholds upon experimentally applied pain stimuli to the skin as compared to respective controls. Since the sensory-discriminative component of stimulus perception, e.g. for warmth, cold and vibration, appears to be unaltered in depression, higher central nervous centres have been assumed to cause this phenomenon. To date, hardly any attention has been paid to the efferent components of the noxious reflex loop. Here, we aimed to assess the autonomic reaction upon a painful stimulus and to examine whether this is likewise reduced in major depression. For this purpose, sympathetic skin response was obtained from 22 patients with major depression and 20 matched controls. To induce sympathetic skin responses, we applied either noxious electrical stimuli (12 and 18 mA) or innocuous acoustic stimuli (85 dB SPL). Pain intensity was rated using a numeric analogue scale. In contrast to our a priori hypothesis patients showed shorter latencies and higher amplitudes of skin potentials upon noxious stimulation, i.e. a stronger sympathetic response. Intriguingly, the noxious stimuli were still perceived less painful in the patient group. Pain perception weakly correlated with disease severity. From these data, we conclude that despite the diminished pain perception, the autonomic reflex loop following noxious stimulation is not affected in patients with major depressive disorder, and that the increase in sympathetic outflow is not directly related to the perceived pain as in controls, but might rather be attributed to the autonomic dysfunction known for the disease.

Reduced cardio-respiratory coupling indicates suppression of vagal activity in healthy relatives of patients with schizophrenia.

Previous studies have observed reduced vagal modulation in patients with acute schizophrenia and their first-degree relatives, thus suggesting a genetic predisposition. To investigate vagal modulation, we analyzed the coupling between heart rate and breathing as a putative measure of central autonomic function in 19 patients, 19 of their relatives and 19 matched control subjects. The interaction of heart rate and breathing was investigated in all groups applying the non-linear parameter cross-ApEn, indicating the asynchrony between both time series. In addition, measures of the time and frequency domain of heart rate variability (HRV) were obtained. The main finding of our study is a significantly increased cross-ApEn value, indicating reduced central vagal modulation both in relatives and patients suffering from schizophrenia. Non-linear measures of HRV proved to more sensitively differentiate relatives from control subjects. Furthermore, we observed a correlation between psychopathology and breathing, indicating that positive symptoms are associated with a higher degree of regularity in the breathing pattern. Our results suggest that autonomic dysfunction previously described for patients suffering from schizophrenia is also present in first-degree relatives. This might relate to changes of brainstem activity in patients and relatives, and a common genetic background in patients and their family members can be assumed.

Increased cold-pain thresholds in major depression.

UNLABELLED: Most previous studies indicated that patients suffering from major depressive disorder (MDD) showed a decreased sensitivity for external or skin surface pain, eg, for heat or electrical stimuli, as compared to healthy controls. Here, we investigated cold-pain thresholds in 20 unmedicated patients suffering from MDD and 20 matched controls. We applied the ascending method of limits which has previously been used for heat-pain assessment in patients with depression. Similar to previous results for heat-pain thresholds we found a decreased sensitivity for cold pain in patients with MDD as indicated by increased cold-pain thresholds. This difference was significant on the right arm, whereas only a trend was obtained on the left arm, thus suggesting a certain degree of lateralization, similar to that seen in heat-pain perception in patients suffering from MDD or adjustment disorder. The study confirms our previous results of a lower sensitivity for externally induced pain in patients with MDD. Moreover, it adds weight to the assumption of a lateralized perception of thermal pain in depression. PERSPECTIVE: This investigation provides further evidence for reduced pain perception of externally applied stimuli in major depression. Thus, central-nervous correlates for this altered pain perception in major depression are worth examining in future studies in order to gain more insight into mechanisms of pain perception on the one hand, and pathology of depression on the other.

Increased sensitivity to heat pain after sad mood induction in female patients with major depression.

Patients suffering from major depressive disorder (MDD) have been shown to exhibit increased thresholds towards experimentally induced thermal pain applied to the skin. In contrast, the induction of sad mood can increase pain perception in healthy controls. Here, we aimed to test the hypothesis that heat pain thresholds are further increased after sad mood induction in depressed patients. Thermal pain thresholds were obtained from 25 female depressed patients and 25 controls before and after sad mood induction applying a modified Velten Mood Induction procedure (MIP). Valence and arousal ratings were obtained using the self-assessment manikin. The Montgomery Depression Rating Scale and the Beck Depression Inventory (BDI) were obtained at baseline from all participants. Pain thresholds at baseline did not significantly differ between groups. Pain thresholds and valence of mood significantly decreased both in patients and controls, while arousal showed an inverse time course between groups. Therefore, our hypothesis could not be confirmed. From these data, we propose that the depressed mood as seen in MDD patients influences pain experience differently as compared to the shorter-lasting mood change after MIP. A differential interaction of both affective states with brain areas of the pain matrix might be assumed. Eventually, the induction of sad mood might mirror the increased number of pain complaints in depressed patients and thus adds to the current concept of adjuvant antidepressant treatment both in depressed patients with pain complaints and in chronic pain patients.

Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis.

Inflammation causes sensitization of peripheral and central nociceptive neurons. Pharmacological modulation of the latter has successfully been used for clinical pain relief. In particular, inhibitors of the NMDA glutamate receptor such as ketamine and agonists at the mu-opioid receptor such as morphine are broadly used. Besides driving the propagation of pain signals, spinal mechanisms are also discussed to modulate inflammation in the periphery. Here, we tested the hypothesis that intrathecally applied ketamine or morphine not only reduce pain-related behavior, but also attenuate induction and maintenance of the inflammatory response in a model of chronic antigen-induced arthritis (AIA). Ketamine, morphine or vehicle was applied to the spinal cords of anesthesized animals with AIA. Swelling and histopathological changes were assessed after 6h (acute phase). Intrathecal catheters were implanted in another set of animals with AIA and substances were applied continuously. During the observation period of 21 days, inflammation and pain-related behavior were assessed. Ketamine and morphine significantly reduced arthritis severity as indicated by reduced joint swelling, but even more intriguingly by reduced infiltration with inflammatory cells and joint destruction in the acute and the chronic phase of arthritis. Morphine showed strong antinociceptive effects in the acute phase only, while the newly established effective dose for ketamine in a continuous application design reduced hyperalgesia in the acute and the chronic stage. In conclusion, both compounds exhibit anti-inflammatory effects during induction and maintenance of arthritis when applied intrathecally. These data thus propose a role of spinal NMDA- and opioid-receptors in the neuronal control of immune-mediated inflammation.

Cardio-respiratory coupling indicates suppression of vagal activity in acute schizophrenia.

Altered amygdala activity in patients with schizophrenia can influence respiratory patterns and consequently cardiovascular parameters. Hence, we examined respiration and heart rate time series complexity as well as coupling of both signals. Electrocardiograms and respiratory signals were obtained from 25 unmedicated patients with schizophrenia and controls. Approximate entropy (ApEn) was calculated for heart and respiratory rates as well as cross-ApEn reflecting coupling of both signals. Coupling was decreased indicating diminished vagal modulation at the brain stem level. Regularity of breathing correlated with disease severity. These data might reflect a lack of inhibitory control over brainstem centers in schizophrenia.