Autoimmune thyroiditis with transient thyrotoxicosis: comparison between painful thyroiditis and painless thyroiditis

Clinical and laboratory findings and long-term outcomes in 8 patients (7 women) with autoimmune thyroiditis (AT), aged 34-59 years, who had a painful tender goiter and a transient thyrotoxicosis with a low thyroid radioactive iodine uptake (RAIU), were compared with those in 15 patients (13 women) with painless thyroiditis (PT), aged 23-69 years. Six painful AT and 6 PT patients had a history of prior awareness of goiter. All patients with painful AT had a moderate or marked elevation of erythrocyte sedimentation rate and a positive result for C-reactive protein, while only 3 PT patients (group B) did. There were no significant differences between the mean age, duration of symptoms, white blood cell count, serum triiodothyronine (T3) and thyroxine (T4) concentrations, serum T3/T4 ratio and duration of thyrotoxicosis after the initial examination and prevalences of positive results for antithyroglobulin and -microsomal antibodies in the two diseases. Two of 8 painful AT patients showed a histologically chronic fibrous variant and 6 others showed chronic lymphocytic thyroiditis. All PT patients examined also showed lymphocytic thyroiditis. Two and 5 painful AT patients developed transient and persistent hypothyroidism, respectively, while 8 [7 in group A (normal ESR), 1 in group B] and 3 PT patients (1 in group A, 2 in group B) did, respectively. The mean serum thyroid-stimulating hormone level in the hypothyroid phase in painful AT patients was higher than that in PT patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

L-phenylisopropyladenosine (L-PIA) diminishes halothane anesthetic requirements and decreases noradrenergic neurotransmission in rats

The effect of L-phenylisopropyladenosine (L-PIA), the A1 adenosine agonist, on the depth of anesthesia was investigated in halothane-anesthetized rats. L-PIA treatment reduced the minimum anesthetic concentration (MAC) of halothane that prevented 50% of animals from moving in response to a painful stimulus by 49%. MAC experiments performed with L-PIA given in conjunction with A1 adenosine receptor antagonists which either permeate the blood-brain barrier (8-phenyltheophylline [8-PT] or do not (8-sulphophenyltheophylline [8-So-PT]) indicate that central mechanisms are involved. Noradrenergic neurotransmission was diminished following L-PIA administration in halothane-anesthetized rats in all brain regions. These data suggest that acute L-PIA treatment decreases central noradrenergic neurotransmission and may represent the mechanism for the decrease in halothane dose to achieve an anesthetic endpoint anesthetic response to halothane.     

Believing is seeing: expectations alter visual awareness

Expectations have been shown to be powerful modulators of pain [1] and emotion [2] in placebo studies. In such experiments, expectations are induced by instructions combined with manipulation of the sensory experience that is unknown to the subjects. After an expectation learning phase where a painful stimulation is surreptitiously lowered following placebo application, the placebo effectively reduces subjective pain intensity in a subsequent test phase [3]. The strength of this placebo effect is closely related to the induced expectation [4]. Here, we asked whether this powerful cognitive bias reflects a general property of sensory information processing and tested whether the contents of visual awareness could be altered by a placebo-like expectation manipulation. We found a dramatic effect of experimentally induced expectations on the perception of an ambiguous visual motion stimulus. This shows that expectations have a strong and general influence on our experience of the sensory input independently of its specific type and content.     

Lower Brainstem Pathways Regulating Sympathetically Mediated Changes in Cutaneous Blood Flow

1. When the individual is alerted by painful or salient stimuli, there is a vigorous sympathetically mediated constriction of the cutaneous vascular bed. We investigated central pathways mediating this response using chronically implanted Doppler ultrasonic probes to measure cutaneous blood flow in the rabbit ear pinna and in the rat tail.2. Blockade of neuronal function in the amygdala prevents cutaneous vasoconstriction elicited by salient stimuli, but does not prevent the response to painful stimuli. Blockade of neuronal function in raphe magnus/pallidus and the parapyramidal region in anesthetized rabbits prevents cutaneous vasoconstriction elicited by painful stimuli. A similar region of the medullary raphe regulates tail artery vasoconstriction in rats. Inhibition of neuronal function in this region reverses cutaneous vasoconstriction induced by cooling the animal.3. Bulbospinal presympathetic neurons in the rostral medullary raphe region appear to regulate cutaneous blood flow responses occurring as part of the response to painful or dangerous environmental events and as part of the regulation of body temperature.     

The habenula prevents helpless behavior in larval zebrafish

Animals quickly learn to avoid predictable danger. However, if pre-exposed to a strong stressor, they do not display avoidance even if this causes continued contact with painful stimuli [1, 2]. In rodents, lesioning the habenula, an epithalamic structure that regulates the monoaminergic system, has been reported to reduce avoidance deficits caused by inescapable shock [3]. This is consistent with findings that inability to overcome a stressor is accompanied by an increase in serotonin levels [4]. However, other studies conclude that habenula lesions cause avoidance deficits [5, 6]. These contradictory results may be caused by lesions affecting unintended regions [6]. To clarify the role of the habenula, we used larval zebrafish, whose transparency and amenability to genetic manipulation enables more precise disruption of cells. We show that larval zebrafish learn to avoid a light that has been paired with a mild shock but fail to do so when pre-exposed to inescapable shock. Photobleaching of habenula afferents expressing the photosensitizer KillerRed causes a similar failure in avoidance. Expression of tetanus toxin in dorsal habenula neurons is sufficient to prevent avoidance. We suggest that this region may signal the ability to control a stressor, and that its disruption could contribute to anxiety disorders.     

Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia

Background

Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN.

Methods

Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8).

Results

IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar.

Conclusion

While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered.     

Interleukin-1β signaling in osteoarthritis – chondrocytes in focus

Osteoarthritis (OA) can be regarded as a chronic, painful and degenerative disease that affects all tissues of a joint and one of the major endpoints being loss of articular cartilage. In most cases, OA is associated with a variable degree of synovial inflammation. A variety of different cell types including chondrocytes, synovial fibroblasts, adipocytes, osteoblasts and osteoclasts as well as stem and immune cells are involved in catabolic and inflammatory processes but also in attempts to counteract the cartilage loss. At the molecular level, these changes are regulated by a complex network of proteolytic enzymes, chemokines and cytokines (for review: [1]). Here, interleukin-1 signaling (IL-1) plays a central role and its effects on the different cell types involved in OA are discussed in this review with a special focus on the chondrocyte.     

Experimental muscle pain reduces initial motor unit discharge rates during sustained submaximal contractions.

The aim of this human study was to investigate the effect of experimentally induced muscle pain on the modifications of motor unit discharge rate during sustained, constant-force contractions. Intramuscular and multichannel surface electromyographic (EMG) signals were collected from the right and left tibialis anterior muscle of 11 volunteers. The subjects performed two 4-min-long isometric contractions at 25% of the maximal dorsiflexion torque, separated by a 20-min rest. Before the beginning of the second contraction, hypertonic (painful; right leg) or isotonic (nonpainful; left leg) saline was injected into the tibialis anterior. Pain intensity scores did not change significantly in the first 150 s of the painful contraction. Exerted torque and its coefficient of variation were the same for the painful and nonpainful contractions. Motor unit discharge rate was higher in the beginning of the nonpainful contraction than the painful contraction on the right side [means +/- SE, 11.3 +/- 0.2 vs. 10.6 +/- 0.2 pulses/s (pps); P < 0.01] whereas it was the same for the two contractions on the left side (11.6 +/- 0.2 vs. 11.5 +/- 0.2 pps). The decrease in discharge rate in 4 min was smaller for the painful (0.4 +/- 0.1 pps) than for the control contractions (1.3 +/- 0.1 pps). Initial value and decrease in motor unit conduction velocity were not different in the four contractions (right leg, 4.0 +/- 0.1 m/s with decrease of 0.6 +/- 0.1 m/s in 4 min; left leg, 4.1 +/- 0.1 m/s with 0.7 +/- 0.1 m/s decrease). In conclusion, stimulation of nociceptive afferents by injection of hypertonic saline did not alter motor unit conduction velocity but reduced the initial motor unit discharge rates and the difference between initial and final discharge rates during sustained contraction.     

Expertise modulates the perception of pain in others

Perceiving the pain of others activates a large part of the pain matrix in the observer [1]. Because this shared neural representation can lead to empathy or personal distress [2, 3], regulatory mechanisms must operate in people who inflict painful procedures in their practice with patient populations in order to prevent their distress from impairing their ability to be of assistance. In this functional magnetic resonance imaging MRI study, physicians who practice acupuncture were compared to naive participants while observing animated visual stimuli depicting needles being inserted into different body parts, including the mouth region, hands, and feet. Results indicate that the anterior insula somatosensory cortex, periaqueducal gray, and anterior cingulate cortex were significantly activated in the control group, but not in the expert group, who instead showed activation of the medial and superior prefrontal cortices and the temporoparietal junction, involved in emotion regulation and theory of mind.     

Effect of chronic lithium on mechanical sensitivity and trabecular bone loss induced by type-1 diabetes mellitus in mice

BioMetals - Type-1 diabetes mellitus (T1DM) is a chronic condition characterized by long-term hyperglycemia that results in several complications such as painful peripheral neuropathy, bone...     

Endothelin-1 potentiates capsaicin-induced TRPV1 currents via the endothelin A receptor

Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to painful stimuli. The cellular mechanisms of the ET-1-mediated effects are only poorly understood. TRPV1, the heat-, proton-, and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released by painful stimuli and during inflammation, is a potential target for the action of ET-1. In immunocytochemistry of rat lumbar dorsal root ganglion using TRPV1- and ET(A) receptor-specific antibodies, both proteins were found to be co-expressed in small sensory neurons. To provide evidence that ET-1 can modulate TRPV1 activity via the ET(A) receptor, we used HEK 293 cells transiently co-expressing a fusion protein of TRPV1 and the yellow fluorescent protein (TRPV1-YFP) and the ET(A) receptor. In whole-cell patch clamp recordings of HEK293 cells co-expressing TRPV1-YFP and the ET(A) receptor, capsaicin (10 nM) elicited small currents, which were markedly potentiated when capsaicin (10 nM) and ET-1 (100 nM) were applied simultaneously. The data indicate that ET-1 potentiates TRPV1 activity via the ET(A) receptor and that this process is likely to play a crucial role in the pain-producing and pain-potentiating effects of ET-1. Thus, ET(A) receptor antagonists may be of importance in painful states with increased circulating ET-1 levels, as found in cancer and in chronic inflammation.     

The Spared Nerve Injury (SNI) Model of Induced Mechanical Allodynia in Mice

Peripheral neuropathic pain is a severe chronic pain condition which may result from trauma to sensory nerves in the peripheral nervous system. The spared nerve injury (SNI) model induces symptoms of neuropathic pain such as mechanical allodynia i.e. pain due to tactile stimuli that do not normally provoke a painful response [1]. The SNI mouse model involves ligation of two of the three branches of the sciatic nerve (the tibial nerve and the common peroneal nerve), while the sural nerve is left intact [2]. The lesion results in marked hypersensitivity in the lateral area of the paw, which is innervated by the spared sural nerve. The non-operated side of the mouse can be used as a control. The advantages of the SNI model are the robustness of the response and that it doesn’t require expert microsurgical skills.The threshold for mechanical pain response is determined by testing with von Frey filaments of increasing bending force, which are repetitively pressed against the lateral area of the paw [3], [4]. A positive pain reaction is defined as sudden paw withdrawal, flinching and/or paw licking induced by the filament. A positive response in three out of five repetitive stimuli is defined as the pain threshold. As demonstrated in the video protocol, C57BL/6 mice experience profound allodynia as early as the day following surgery and maintain this for several weeks.     

CX3CR1-Mediated Akt1 Activation Contributes to the Paclitaxel-Induced Painful Peripheral Neuropathy in Rats

Painful peripheral neuropathy is a serious dose-limiting side effect of paclitaxel therapy, which unfortunately often happens during the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms of the painful peripheral neuropathy remain largely unknown. Here, we found that paclitaxel treatment (3 × 8 mg/kg, cumulative dose 24 mg/kg) upregulated the expression of CX3CR1 and phosphorylated Akt1 in DRG and spinal dorsal horn. Blocking of Akt1 pathway activation with different inhibitor (MK-2206 or LY294002) significantly attenuated mechanical allodynia and thermal hyperalgesia induced by paclitaxel. Furthermore, inhibition of CX3CR1 by using neutralizing antibody not only prevented Akt1 activation in DRG and spinal dorsal horn but also alleviated pain-related behavior induced by paclitaxel treatment. This study suggested that CX3CR1/Akt1 signaling pathway may be a potential target for prevention and reversion of the painful peripheral neuropathy induced by paclitaxel.     

Differential effects of painful and non-painful stimulation on tactile processing in fibromyalgia syndrome and subjects with masochistic behaviour

Background

In healthy subjects repeated tactile stimulation in a conditioning test stimulation paradigm yields attenuation of primary (S1) and secondary (S2) somatosensory cortical activation, whereas a preceding painful stimulus results in facilitation.

Methodology/Principal Findings

Since previous data suggest that cognitive processes might affect somatosensory processing in S1, the present study aims at investigating to what extent cortical reactivity is altered by the subjective estimation of pain. To this end, the effect of painful and tactile stimulation on processing of subsequently applied tactile stimuli was investigated in patients with fibromyalgia syndrome (FMS) and in subjects with masochistic behaviour (MB) by means of a 122-channel whole-head magnetoencephalography (MEG) system. Ten patients fulfilling the criteria for the diagnosis of FMS, 10 subjects with MB and 20 control subjects matched with respect to age, gender and handedness participated in the present study. Tactile or brief painful cutaneous laser stimuli were applied as conditioning stimulus (CS) followed by a tactile test stimulus (TS) 500 ms later. While in FMS patients significant attenuation following conditioning tactile stimulation was evident, no facilitation following painful stimulation was found. By contrast, in subjects with MB no attenuation but significant facilitation occurred. Attenuation as well as facilitation applied to cortical responses occurring at about 70 ms but not to early S1 or S2 responses. Additionally, in FMS patients the amount of attenuation was inversely correlated with catastrophizing tendency.

Conclusion

The present results imply altered cortical reactivity of the primary somatosensory cortex in FMS patients and MB possibly reflecting differences of individual pain experience.     

Sensory symptom profiles and co-morbidities in painful radiculopathy

Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD.     

A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10^-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10^-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10^-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.     

Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors

Fourteen new 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives were synthesized. Six compounds displayed potent inhibitory activities against COX-1/2 and 5-LOX with IC(50) in the range of 0.10-9.87 μM. Particularly, 10f exhibited well balanced inhibitory action on these enzymes (IC(50)=0.10-0.56 μM). More importantly, 10f and several other compounds had comparable or stronger anti-inflammatory and analgesic activities, but better gastric tolerability in vivo, as compared with darbufelone mesilate and tenidap sodium. Therefore, our findings may aid in the design of new and safe anti-inflammatory reagents for the intervention of painful inflammatory diseases, such as rheumatoid arthritis at clinic.     

Experimental Muscle Pain Impairs the Synergistic Modular Control of Neck Muscles

A motor task can be performed via different patterns of muscle activation that show regularities that can be factorized in combinations of a reduced number of muscle groupings (also referred to as motor modules, or muscle synergies). In this study we evaluate whether an acute noxious stimulus induces a change in the way motor modules are combined to generate movement by neck muscles. The neck region was selected as it is a region with potentially high muscular redundancy. We used the motor modules framework to assess the redistribution of muscular activity of 12 muscles (6 per side) in the neck region of 8 healthy individuals engaged in a head and neck aiming task, in non-painful conditions (baseline, isotonic saline injection, post pain) and after the injection of hypertonic saline into the right splenius capitis muscle. The kinematics of the task was similar in the painful and control conditions. A general decrease of activity was noted for the injected muscle during the painful condition together with an increase or decrease of the activity of the other muscles. Subjects did not adopt shared control strategies (motor modules inter subject similarity at baseline 0.73±0.14); the motor modules recorded during the painful condition could not be used to reconstruct the activation patterns of the control conditions, and the painful stimulus triggered a subject-specific redistribution of muscular activation (i.e., in some subjects the activity of a given muscle increased, whereas in other subjects it decreased with pain). Alterations of afferent input (i.e., painful stimulus) influenced motor control at a multi muscular level, but not kinematic output. These findings provide new insights into the motor adaptation to pain.     

Does exogenous melatonin influence the free radicals metabolism and pain sensation in rat?

Melatonin has been shown to play a role in antioxidative defence. We therefore studied its effect on oxidative damage to the rat cerebral cortex evoked by painful stimulation and immobilization-induced stress. Moreover, the effect of melatonin on chronic pain perception was examined. Rats were injected with either a high dose of melatonin (100 mg/kg i.p.) or a vehicle for five days and were subjected to painful stimulation or immobilization stress 30 min after the treatment. To determine the degree of oxidative stress, the levels of free radicals, thiobarbituric acid reactive substances (TBARS) as indicators of lipid peroxidation and glutathione peroxidase (GSHPx) were estimated in somatosensory cortex. Pain perception was measured by the tail-flick and plantar test. Melatonin reduced the level of TBARS previously increased by painful stimulation. Melatonin also exhibited a slight analgesic effect in those animals exposed to painful stimulation but its role in free radical scavenging did not contribute to this effect.