Altered cerebral pain processing of noxious stimuli from inflamed joints in rheumatoid arthritis: An event-related fMRI study.

OBJECTIVE: To our knowledge, this is the first study assessing brain activation in response to painful stimulation over disease-relevant (finger joint) vs. neutral area (thumb nail) in patients suffering from rheumatoid arthritis (RA) compared to healthy controls (HC). METHOD: Thirty-one RA patients and 23 HC underwent functional magnetic resonance imaging (fMRI) while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100 mm VAS scale (P50) at disease-affected finger joint and thumbnail (left hand), and corresponding sites in HC. RESULTS: Compared to controls, RA patients had significantly increased pain sensitivity (lower P50) at the inflamed joints but not at the thumbnail. RA patients exhibited significantly less activation in regions related to pain- and somatosensory processing (S1, M1, anterior insula, S2, SMG and MCC) during painful joint stimulation, compared to HC. No group difference in cerebral pain processing was found for the non-affected thumbnail. Within RA patients, significantly less brain activation was found in response to painful stimulation over disease-affected joint compared to non-affected thumbnail in bilateral S1, bilateral S2, and anterior insula. Further, RA patients exhibited a right-sided dlPFC deactivation, psycho-physiologically interacting (PPI) with the left dlPFC in response to painful stimulation at disease-affected joints. CONCLUSION: The results indicate normal pain sensitivity and cerebral pain processing in RA for non-affected sites, while the increased sensitivity at inflamed joints indicate peripheral/spinal sensitization. Brain imaging data suggest that disease-relevant pain processing in RA is marked by aberrations and a failed initiation of cortical top-down regulation.

Plasma Cytokine Levels in Fibromyalgia and Their Response to 15 Weeks of Progressive Resistance Exercise or Relaxation Therapy.

The aims of this study were to compare circulating cytokines between FM and healthy controls and to investigate the effect on cytokine levels by 15 weeks of progressive resistance exercise or relaxation therapy in FM. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. The FM women were then randomized to progressive resistance exercise (n = 49) or relaxation (n = 43). Baseline IL-2, IL-6, TNF-α, IP-10, and eotaxin were higher in FM than in healthy controls (P < 0.041), whereas IL-1ß was lower (P < 0.001). There were weak correlations between cytokine levels and clinical variables. After both interventions, IL-1ra had increased (P = 0.004), while IL-1ß had increased in the relaxation group (P = 0.002). Changes of IFN-γ, IL-2, IL-4, IL-6, IL-8, and IL-17A were weakly correlated with changes of PPT, but there were no significant correlations between changes of cytokine and changes in other clinical variables. The elevated plasma levels of several cytokines supports the hypothesis that chronic systemic inflammation may underlie the pathophysiology of FM even if the relation to clinical variables was weak. However, 15 weeks of resistance exercise, as performed in this study, did not show any anti-inflammatory effect on neither FM symptoms nor clinical and functional variables. This trial is registered with ClinicalTrials.gov NCT01226784, registered October 21, 2010. The first patient was recruited October 28, 2010.

EULAR revised recommendations for the management of fibromyalgia.

OBJECTIVE: The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. METHODS: A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. RESULTS: 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). CONCLUSIONS: These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

Why sickness hurts: A central mechanism for pain induced by peripheral inflammation.

Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

Modality and sex differences in pain sensitivity during human endotoxemia.

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis--treatment effects of neuromuscular exercise and total joint replacement.

OBJECTIVE: To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters. DESIGN: The dataset consisted of knee (n = 66) and hip (n = 47) OA patients assigned for total joint replacement at Lund University Hospital undergoing pre-operative neuromuscular exercise and 43 matched controls. Sensitivity to pressure pain was assessed by pressure algometry at 10 sites. Subjects were then instructed to perform a standardized static knee extension. Pressure pain thresholds (PPTs) were assessed at the contracting quadriceps muscle (Q) and at the resting deltoid muscle (D) before and during contraction. The relative increase in PPTs during contraction was taken as a measure of localized (Q) or generalized (D) EIA. Patients were assessed at baseline, following on average 12 weeks of neuromuscular exercise and 3 months following surgery. RESULTS: We found a normal function of EIA in OA patients at baseline. Previous studies have reported beneficial effects of physical exercise on pain modulation in healthy subjects. However, no treatment effects on EIA were seen in OA patients despite the increase in muscle strength following neuromuscular exercise and reduced pain following surgery. Compared to controls, OA patients had increased pain sensitivity and no beneficial effects on pain sensitivity were seen following treatment. CONCLUSIONS: To our knowledge, this is the first study of EIA in OA patients. Despite increased pain sensitivity, OA patients had a normal function of EIA.

Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [11C]PBR28 positron emission tomography.

Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [11C]PBR28. The outcome measure was total distribution volume (VT) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome VT or when normalizing VT to the lateral occipital cortex (p > 0.05). RA patients had numerically lower VT values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [11C]PBR28 VT in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [11C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.

EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

OBJECTIVE: To develop evidence-based recommendations for the management of fibromyalgia syndrome. METHODS: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. RESULTS: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. CONCLUSIONS: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

Differences in neuroimmune signalling between male and female patients suffering from knee osteoarthritis.

The primary aim was to identify cytokines involved in blood borne, neuroimmune joint-to-CNS signalling in knee osteoarthritis (OA) patients. Monocyte chemoattractant protein 1 (MCP1) and Interleukin-8 (IL-8) were elevated in the cerebrospinal fluid (CSF) in patients indicating neuroinflammation. Significant positive correlations were found for MCP1 across CSF, serum and synovial fluid (SF), in female, but not male patients. The results revealed sex differences in neuroimmune signalling and implicated MCP1 in blood borne joint-to-CNS signalling in female patients. Symptom severity correlated with IL-6 and IL-8 levels in SF, but was inversely associated with IL-6 and IL-8 levels in CSF, indicating that neuroinflammation in OA may be an adaptive, possibly neuroprotective mechanism promoting symptom reduction.

The role of long-term physical exercise on performance and brain activation during the Stroop colour word task in fibromyalgia patients.

The Stroop colour word test (SCWT) has been widely used to assess changes in cognitive performance such as processing speed, selective attention and the degree of automaticity. Moreover, the SCWT has proven to be a valuable tool to assess neuronal plasticity that is coupled to improvement in performance in clinical populations. In a previous study, we showed impaired cognitive processing during SCWT along with reduced task-related activations in patients with fibromyalgia. In this study, we used SCWT and functional magnetic resonance imagingFMRI to investigate the effects of a 15-week physical exercise intervention on cognitive performance, task-related cortical activation and distraction-induced analgesia (DIA) in patients with fibromyalgia and healthy controls. The exercise intervention yielded reduced fibromyalgia symptoms, improved cognitive processing and increased task-related activation of amygdala, but no effect on DIA. Our results suggest beneficial effects of physical exercise on cognitive functioning in FM.

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

Systemic differences in serum metabolome: a cross sectional comparison of women with localised and widespread pain and controls.

Chronic musculoskeletal pain exists either as localised to a single region or as widespread to multiple sites in several quadrants of the body. Prospective studies indicate that widespread pain could act as a far end of a continuum of musculoskeletal pain that started with chronic localised pain. The mechanism by which the transition from localised pain to widespread occurs is not clear, although many studies suggest it to be an altered metabolism. In this study, systemic metabolic differences between women with chronic localised neck-shoulder pain (NP), women with chronic widespread pain (CWP) and women who were healthy (CON) were assessed. Blood samples were analysed taking a metabolomics approach using gas chromatography mass spectrometry (GC-MS) and orthogonal partial least square discriminant analysis (OPLS-DA). The metabolomics analysis showed a clear systematic difference in the metabolic profiles between the subjects with NP and the CON but only a weak systematic difference between the subjects with CWP and the CON. This most likely reflects a difference in the portion of the metabolome influenced by the two pain conditions. In the NP group, the overall metabolic profile suggests that processes related to energy utilisation and lipid metabolism could be central aspects of mechanisms maintaining disorder.

Normalization of aberrant resting state functional connectivity in fibromyalgia patients following a three month physical exercise therapy.

Physical exercise is one of the most efficient interventions to mitigate chronic pain symptoms in fibromyalgia (FM). However, little is known about the neurophysiological mechanisms mediating these effects. In this study we investigated resting-state connectivity using functional magnetic resonance imaging (fMRI) before and after a 15 week standardized exercise program supervised by physical therapists. Our aim was to gain an understanding of how physical exercise influences previously shown aberrant patterns of intrinsic brain activity in FM. Fourteen FM patients and eleven healthy controls successfully completed the physical exercise treatment. We investigated post- versus pre-treatment changes of brain connectivity, as well as changes in clinical symptoms in the patient group. FM patients reported improvements in symptom severity. Although several brain regions showed a treatment-related change in connectivity, only the connectivity between the right anterior insula and the left primary sensorimotor area was significantly more affected by the physical exercise among the fibromyalgia patients compared to healthy controls. Our results suggest that previously observed aberrant intrinsic brain connectivity patterns in FM are partly normalized by the physical exercise therapy. However, none of the observed normalizations in intrinsic brain connectivity were significantly correlated with symptom changes. Further studies conducted in larger cohorts are warranted to investigate the precise relationship between improvements in fibromyalgia symptoms and changes in intrinsic brain activity.

Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects.

In order to assess the function of endogenous mechanisms modulating somatosensory input in fibromyalgia (FM), the effect of vibratory stimulation (VS) and heterotopic noxious conditioning stimulation (HNCS) on perception of various somatosensory modalities was assessed. Ten female FM patients and 10 healthy, age-matched, females participated. VS (100 Hz) was applied to the left forearm for 45 min and quantitative sensory testing (QST) was performed within the vibrated area and in the right thigh before, during and 45 min following vibration. Pressure pain thresholds (PPTs) were assessed by pressure algometry. Perception thresholds to non-painful cold (CT) and warmth (WT), heat pain thresholds (HPTs), cold pain thresholds (CPTs) and stimulus-response curves of pain intensity as a function of graded nociceptive heat stimulation were assessed using a Peltier element based thermal stimulator. The effects of HNCS were tested using the upper extremity submaximal effort tourniquet test. Subjects rated tourniquet induced pain intensity on a visual analogue scale (VAS). QST was performed in the right thigh before, during and 60 min following the tourniquet. FM patients did not differ from controls in the response to VS. There was a local increase of PPTs during vibration (P < 0.001) and of WTs following vibration (P < 0.001). HPTs increased in the forearm and in the thigh (P < 0.009) during vibration. CTs and sensitivity to suprathreshold heat pain were not influenced by VS. The intensity of pain induced by the tourniquet did not differ between groups. PPTs increased during the tourniquet in controls (P < 0.001) but not in FM patients (difference between groups P < 0.001). Decreased sensitivity to non-painful cold (P < 0.001) and non-painful warmth (P < 0.001) was seen during and following (P < 0.001; P < 0.05, respectively) the tourniquet in both groups alike. HPTs and perception of suprathreshold heat pain remained unaffected in both groups. In conclusion, FM patients did not differ from healthy controls in their response to vibration, but no modulation of pressure pain was induced by HNCS, as opposed to controls, suggesting a dysfunction in systems subserving 'diffuse noxious inhibitory controls' (DNIC).

Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms.

This study, addressing etiologic and pathogenic aspects of fibromyalgia (FM), aimed at examining whether sensory abnormalities in FM patients are generalized or confined to areas with spontaneous pain. Ten female FM patients and 10 healthy, age-matched females participated. The patients were asked to rate the intensity of ongoing pain using a visual analogue scale (VAS) at the site of maximal pain, the homologous contralateral site and two homologous sites with no or minimal pain. Quantitative sensory testing was performed for assessment of perception thresholds in these four sites. Von Frey filaments were used to test low-threshold mechanoreceptive function. Pressure pain sensitivity was assessed with a pressure algometer and thermal sensitivity with a Thermotest. In addition the stimulus-response curve of pain intensity as a function of graded nociceptive heat stimulation was studied at the site of maximal pain and at the homologous contralateral site. FM patients had increased sensitivity to non-painful warmth (P < 0.01) over painful sites and a tendency to increased sensitivity to non-painful cold (P < 0.06) at all sites compared to controls, but there was no difference between groups regarding tactile perception thresholds. Compared to controls, patients demonstrated increased sensitivity to pressure pain (P < 0.001), cold pain (P < 0.001) and heat pain (P < 0.02) over all tested sites. The stimulus-response curve was parallely shifted to the left of the curve obtained from controls (P < 0.003). Intragroup comparisons showed that patients had increased sensitivity to pressure pain (P < 0.01) and light touch (P < 0.05) in the site of maximal pain compared to the homologous contralateral site. These findings could be explained in terms of sensitization of primary afferent pathways or as a dysfunction of endogenous systems modulating afferent activity. However, the generalized increase in sensitivity found in FM patients was unrelated to spontaneous pain and thus most likely due to a central nervous system (CNS) dysfunction. The additional hyperphenomena related to spontaneous pain are probably dependent on disinhibition/facilitation of nociceptive afferent input from normal (or ischemic) muscles.

Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment.

To investigate the effect of chronic nociceptive pain on somatosensory perception, quantitative sensibility testing was performed in the most painful area and the homologous contralateral side in 14 patients with painful osteoarthritis of the hip. Twelve patients were reassessed in a painfree state 6-14 months following surgery. Von Frey filaments were used to test low-threshold mechanoreceptive function. Pressure pain sensitivity was assessed with a pressure algometer and thermal sensitivity with a Thermotest. Sex- and age-matched controls were examined in the corresponding areas at similar time intervals. There was no statistically significant difference between groups in the sensitivity to light touch and innocuous cold in either session. Compared to controls, patients had increased sensitivity to pressure pain in the most painful area (p < 0.002), bilaterally increased sensitivity to innocuous warmth (p < 0.03), cold pain (p< 0.05) and a tendency toward bilaterally increased sensitivity to heat pain (p = 0.054) before surgery. In the painful area, patients' sensitivity to pressure pain decreased (p < 0.04) and, remaining within normal limits, sensitivity to light touch increased (p < 0.006) compared to values prior to surgery. No statistically significant differences between the groups were seen following surgery, indicating that the sensibility changes had been maintained by chronic nociceptive pain.

The influence of pain intensity on somatosensory perception in patients suffering from subacute/chronic lateral epicondylalgia.

A confounding factor in the analysis of chronic pain patients is the finding of signs of somatosensory disturbances not only in neuropathic pain patients but also in a subgroup of patients with musculoskeletal pain. The purpose was to investigate if patients suffering from subacute/chronic lateral epicondylalgia demonstrated altered sensibility, and if this was affected by pain intensity. At the start of the experiment, quantitative sensory testing (QST) (thermal, pressure pain, touch) was performed in the local pain area and in the area of pain referral. QST was repeated following pain provocation (weight lifting). A local anaesthetic was then injected into the lateral epicondyle and QST was repeated in the area of pain referral. The contralateral arm was assessed, treated and injected in the same way. At the baseline assessment there was no difference in sensibility between sides, with the exception of a significantly lowered threshold to noxious heat (p<0.04) in the area of pain referral, present during the whole experiment. In the affected arm only, weight lifting resulted in significantly increased pain intensity in the local (p<0.01) and referred (p<0.01) pain areas, respectively. Repeated muscle contractions resulted in altered somatosensory functions in both the affected arm and the unaffected arm, consequently not dependent on ongoing pain in the assessed area. Tactile perception thresholds increased significantly following pain provocation in the area of pain referral (p<0.04) only and normalized following injection of local anaesthetic (p<0.02), indicating that the sensitivity to light touch was altered by the nociceptive input from the affected arm.

Injection of hypertonic saline into musculus infraspinatus resulted in referred pain and sensory disturbances in the ipsilateral upper arm.

A confounding factor in the analysis of chronic pain patients is the finding of somatosensory disturbances not only in neuropathic pain patients, but also in a subgroup of patients with musculoskeletal pain. The purpose of the study was to examine if referred pain, induced by intramuscular injections of hypertonic saline (5% NaCl) into the left musculus infraspinatus, resulted in somatosensory alterations. Thermal sensitivity, pressure pain sensitivity, as well as low threshold mechanoreceptive function, were assessed in the referred pain area and the homologous contralateral site before, during and following the injections. In 10 out of 12 subjects the procedure induced only referred pain localized in the dorsolateral part of the ipsilateral proximal upper arm. In this referred pain area there was a significantly decreased sensitivity to light touch, as tested with von Frey filaments, during the pain period and the post-injection period compared to the contralateral side (p<0.004 and p<0.009, respectively). A trend for thermal hypoaesthesia, which was only demonstrable in the sum of warm and cold thresholds, was found in the referred pain area, but not contralaterally, during the pain period compared to the pre-injection period. Significantly increased sensitivity to threshold and suprathreshold heat pain was found bilaterally during post-injection assessments (p<0.02 and p<0.006, respectively). There were no statistically significant changes in sensitivity to innocuous thermal stimuli when assessing the two percepts separately, or to pressure pain or brush-evoked touch. In conclusion, intramuscular injections of hypertonic saline resulted in referred pain and tactile hypoaesthesia in the referred pain area.

Epithelial surface changes and induction of gallstones in the male Syrian hamster gallbladder as a result of a two-month sex steroid treatment.

Transmission (TEM) and scanning (SEM) electron microscopic observations were correlated to characterize morphologic changes induced in the gallbladder of male Syrian hamsters following a two-month estradiol (E) and estradiol + medroxyprogesterone (E + MP) treatment. Compared to control (C), E-treated surface epithelial cells show pleomorphism, cytoplasmic vacuolizations, apical granules, excrescences and decapitations, and small gallstone-like deposits. Following both E + MP treatment, a large accumulation of apical granules containing acidic mucoid products, abundant intraluminal deposits and numerous fields of observation suggest that cell debris and mucous condensation could participate in the formation of the large intraluminal gallstone-like deposits detected as a result of this treatment. In control gallbladders these events were never observed. MP added to E also increases liver and gallbladder weight as well as blood lipid levels. These findings complement and confirm other previous data obtained following short steroid treatment in male, ovariectomized and intact female hamsters. In addition, these results support our hypothesis that gallstone nucleation and growth originate from multiple factors, hormonal disturbance, modulation of liver lipid metabolism, production of cell debris and mucus, can be responsible for the initial gallstone nucleation.

Sex steroid induction of gallstones in the male Syrian hamster.

Light (LM), transmission (TEM) and scanning (SEM) electron microscopic techniques were used to characterize morphologic changes induced in the gallbladder of Syrian hamsters following a one-month estradiol (E) and estradiol + medroxyprogesterone (E+MP) treatment. The TEM results were correlated with the SEM findings. Compared to control (C), E-treated surface epithelial cells contain abundant RER, enlarged Golgi, multivesicular (foamy-heterophagosomes) bodies or lipofuscin inclusions. A 10-day E treatment showed large vesicles develop and, after longer E treatment, they could coalesce and create some of the large multivesicular bodies. Interestingly, E+MP epithelia are characterized by distinct bulging apices where a large number of apical granules accumulate, and contain an anionic mucous core. After a 4-week E+MP treatment, even though all the hamsters were fed a diet with trace cholesterol, significant increase in hamster liver weight, serum level of cholesterol and HDL were measured and, correspondingly, gallstones were found exclusively in E+MP-treated hamsters. Our results showed that not only does the Syrian hamster provide an appropriate model to study experimental lithogenesis without manipulating the diet. In addition, MP appears to induce morphologic changes associated with the formation of gallstones.