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While psychological factors are relevant in many patients with chronic pruritus, not all patients can be offered psychologic, psychosomatic or psychiatric consultation. The aim of this exploratory study was to identify criteria suggestive of psychological factors relevant for the etiology of chronic pruritus and of somatoform pruritus. Routine data from the database of the Center for Chronic Pruritus of the University Hospital Münster were used, including the Neuroderm Questionnaire, Dermatology Life Quality Index and Hospital Anxiety and Depression Scale. chronic pruritus patients (n = 3,391) without a psychiatric diagnosis in their medical history were compared to the 331 chronic pruritus patients with diagnoses of "psychological factors associated with etiology and course of chronic pruritus" (ICD-10:F54) or "somatoform pruritus" (F45.8) confirmed by an expert. The latter reported more pruritus triggers, especially "strain" and "emotional tension" and used more emotional adjectives to describe their pruritus. They reported more often scratching leading to excoriations, higher levels of pruritus, impairment of quality of life, anxiety and depression. These aspects suggest the presence of psychological factors in the etiology of chronic pruritus and somatoform pruritus. Prospective validation, however, needs to be carried out.
Learn More >Approximately one-third of adults with chronic pain also report clinically relevant levels of depression. Internet-delivered psychological therapies such as Cognitive Behavioural Therapy (iCBT) and Acceptance and Commitment Therapy (iACT) have been developed to overcome barriers of access to services and ensure the timely delivery of care. The objective of this trial is to collect data on feasibility, acceptability and range of probable effect sizes for iCBT and iACT interventions tailored towards the treatment of depression and chronic pain using a randomised controlled patient-preference design.
Learn More >Insomnia commonly co-occurs with chronic migraines (CM). Non-pharmacological treatments for insomnia in CM patients remain understudied. This is a proof-of-concept study, which aims to evaluate the feasibility, acceptability, and preliminary efficacy of a digital cognitive behavioral therapy for insomnia (dCBT-I) for individuals with CM and insomnia (CM-I) in the United States.
Learn More >To summarize the available evidence on disability, quality of life (QoL), and economic burden on societies of cluster headache (CH), and to present which tools have been used to measure these domains with indications for future research.
Learn More >EphrinB-EphB receptor tyrosine kinases have been demonstrated to play important roles in pain processing after peripheral nerve injury. We have previously reported that ephrinB-EphB receptor signaling can regulate excitability and plasticity of neurons in spinal dorsal horn, and thus contribute to spinal central sensitization in neuropathic pain. How EphB receptor activation influences excitability of primary neurons in dorsal root ganglion (DRG), however, remains unknown. Here we report that EphB receptor activation facilitates calcium influx through NMDA receptor dependent and independent manners. In cultured DRG cells from adult rats, EphB1 and EphB2 receptors were expressed in neurons, but not the glial cells. Bath application of EphB receptor agonist ephrinB2-Fc induced NMDA-independent Ca influx, which was from the extracellular space rather than endoplasmic reticulum. EphB receptor activation also greatly enhanced NMDA-dependent Ca influx and NR2B phosphorylation, which was prevented by pre-treatment of Src kinase inhibitor PP2. In nerve-injured DRG neurons, elevated expression and activation of EphB1 and EphB2 receptors contributed to the increased intracellular Ca concentration and NMDA-induced Ca influx. Repetitive intrathecal administration of EphB2-Fc inhibited the increased phosphorylation of NR2B and Ca-dependent subsequent signals Src, ERK, and CaMKII as well as behaviorally expressed pain after nerve injury. These findings demonstrate that activation of EphB receptors can modulate DRG neuron excitability by facilitating Ca influx directly or through Src kinase activation-mediated NMDA receptor phosphorylation and that EphB receptor activation is critical to DRG neuron hyperexcitability, which has been considered critical to the subsequent spinal central sensitization and neuropathic pain.
Learn More >Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically inflammatory swelling lasts about three weeks. Pain-related behaviors were monitored for 84 days after AIA induction. Unbiased cluster analysis of intra-group-differences at day 84 of AIA revealed that about one third of the rats (cluster 1) showed persistent mechanical hyperalgesia at the injected knee joint, whereas the other rats (cluster 2) had recovered from pain. Retrograde analysis of pain-related behaviors revealed that cluster 1 rats exhibited more severe mechanical hyperalgesia at the injected knee from day 3 of AIA, and mechanical hyperalgesia at the contralateral knee. Cluster 1 and 2 rats did not show different inflammatory swelling, secondary mechanical and thermal hyperalgesia at the ipsilateral hindpaw, guarding score and asymmetry of weight bearing during AIA. Thus in particular early severe mechanical hyperalgesia in the inflamed joint and segmental contralateral mechanical hyperalgesia seem to be a risk factor for the development of persistent mechanical hyperalgesia pointing to the importance of spinal mechanisms. However, none of the rats showed an expression of ATF3 in DRG neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in DRG neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.
Learn More >Endometriosis is an estrogen-dependent inflammatory disease that affects approximately 10% of women. Debilitating pelvic or abdominal pain is one of its major clinical features. Current animal models of endometriosis-associated pain require surgery either to implant tissue or to remove the ovaries. Moreover, existing models do not induce spontaneous pain, which is the primary symptom of patients with chronic pain, including endometriosis. A lack of models that accurately recapitulate the disease phenotype must contribute to the high failure rate of clinical trials for analgesic drugs directed at chronic pain, including those for endometriosis. We set out to establish a murine model of endometriosis-associated pain. Endometriosis was induced non-surgically by injecting a dissociated uterine horn into a recipient mouse. The induced lesions exhibited histological features that resemble human lesions along with an increase in pro-inflammatory cytokines and recruitment of immune cells. We also observed the presence of CGRP-, TRPA1-, and TRPV1-expressing nerve fibers in the lesions. This model induced mechanical allodynia, spontaneous abdominal pain, and changes in thermal selection behavior that indicate discomfort. These behavioral changes were reduced by drugs used clinically for endometriosis, specifically letrozole (aromatase inhibitor) and danazol (androgen). Endometriosis also induced neuronal changes as evidenced by activation of the NF-κB signaling pathway in TRPA1- and TRPV1-expressing DRG neurons. In conclusion, we have established a model of endometriosis-associated pain that responds to clinically active drugs and can, therefore, be used to identify novel therapies.
Learn More >Prior studies have demonstrated that parental cognitive, behavioral and emotional factors are related to child functioning in children and adolescents with chronic pain. This is particularly important to understand how to potentially enhance the efficacy of psychological interventions for children by incorporating interventions targeting parents. We conducted a systematic review and meta-analysis to identify the specific parent factors that have been examined in the literature and to quantify the associations observed between parent factors and child pain and disability. A search of the electronic databases EMBASE, PsychINFO, Medline and PubMed was conducted, using search terms related to chronic pain, pediatric population and parents. 54 studies met criteria and were included in the review. Parent pain catastrophizing and protective behavior were the most commonly assessed parental constructs in the literature. Meta-analyses were conducted for associations between: parent pain catastrophizing, parent protective behaviors, parent anxiety and depression and parent stress associated with parenting a child with chronic pain with child pain, disability, school functioning and emotional functioning. Correlation coefficients were pooled using the random-effects model. A medium relationship was observed between higher protective behavior and poorer school functioning (r = -0.39); and small relationships were found between higher parent pain catastrophizing and increased child disability (r = 0.29); higher protective behaviors and increased child disability (r = 0.25); and increased parent depression and anxiety with increased child disability (r = 0.23 and r = 0.24 respectively). Future research is needed to investigate broader parent variables and overcome methodological weaknesses in this field.
Learn More >Mutations in Nav1.9 encoded by SCN11A have been associated with episodic pain, small-fiber neuropathy and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. The SCN11A mutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in three patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through non-inactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a mice. The Scn11a mice showed increased sensitivity to mechanical, heat and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNav1.9 channel current and excitability of Scn11a mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a mice. These results indicated that Scn11a mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.
Learn More >Low back pain (LBP) is a highly prevalent and disabling condition whose initiating factors are poorly understood. It is known that psychological and physical stress is associated with LBP but the causal relationship, mechanisms and mediators have not been elucidated, and a preclinical model enabling the investigation of causality and thereby critically contributing to clinical translation does not exist.In the present study, we first established and characterized a myofascial LBP model in mice based on NGF injection into the low back muscles. Secondly, we investigated the effect of two different stress paradigms on this mouse LBP model by applying the chronic unpredictable stress (CUS) and vertical chronic restraint stress (vCRS) paradigms, to mimic psychological and psychophysical stress, respectively. In these studies, we combined longitudinal behavioral tests with gene and protein expression analysis in the muscle, dorsal root ganglia and spinal cord. NGF-induced LBP was characterized by long-lasting local and plantar mechanical hypersensitivity, cold hyperalgesia, decreased grip strength and wheel running activity, and time-dependent changes of neuropeptide and glial markers in the spinal cord. Interestingly, the exposure to CUS slightly worsened pain behavior, whereas vCRS primed and highly aggravated pain in this LBP model, by causing per se the intramuscular upregulation of endogenous NGF and increased spinal astrocyte expression.Our mouse model, particularly the combination of NGF injection and vCRS suggest that similar mechanisms are important in non-specific LBP and might help to investigate certain aspects of stress-induced exacerbation of pain.
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