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Chronic itch is one of the disturbing symptoms of inflammatory skin diseases. Kappa opioid receptor agonists are effective in suppressing scratching in mice against different pruritogens. Nalbuphine, a nonscheduled kappa opioid receptor agonist and mu opioid receptor antagonist, has been in clinical use for post-operative pain management since the 1980s and recently has been in clinical trials for chronic itch of prurigo nodularis (https://www.trevitherapeutics.com/nalbuphine). We studied whether nalbuphine is effective against chronic scratching induced by rostral neck application of 1-fluoro-2,4-dinitrobenzene (DNFB), an accepted mouse model of contact dermatitis to study pruritoceptive itch. Mice were treated once a week with either saline or nalbuphine 20 min before the third, fifth, seventh, and ninth sensitizations with DNFB and the number of scratching bouts was counted for 30 min. Skin samples from the neck of mice at week 4 were used to measure protein levels and mRNA expressions of chemokines and cytokines. Different sets of mice were used to study sedation and anhedonic-like behavior of nalbuphine. We found that: nalbuphine (a) antagonized scratching in a dose- and time-dependent manner without affecting locomotion, b) decreased IL-31, and increased anti-inflammatory IL-10, and c) induced more elevations in the levels of CCL2, CCL3, CCL12, CXCL1, CXCL2, CXCL9, CXCL10, IL-1β, IL-16, TIMP-1, M-CSF, TREM-1 and M1-type macrophages compared to saline. Increases in chemokines and cytokines and M1 macrophages by nalbuphine suggest an inflammatory phase of healing in damaged skin due to scratching. Our data indicate that nalbuphine is an effective antipruritic in murine model of pruritoceptive itch.
Learn More >The development and maintenance of pediatric chronic pain and anxiety are complex, underscoring the need to better understand the interactive forces contributing to their co-occurrence. The Shared Vulnerability Model (SVM) was developed to explain the co-occurrence of chronic pain and posttraumatic stress disorder in adults. Though many core tenets have been well supported by pediatric research, the SVM has yet to be extended to pediatric pain populations. We propose a developmentally informed pediatric SVM for advancing our understanding of the co-occurrence of pediatric chronic pain and anxiety disorders. The proposed SVM postulates that youth at increased risk for the development of chronic pain and/or anxiety share predisposing vulnerabilities, including anxiety sensitivity, and that these shared vulnerabilities give rise to negative emotional responses (child and parent) in the context of stressful events. Consequences of fear and anxiety, including avoidance behavior, further contribute to the development of chronic pain, anxiety, and their co-occurrence. The parental, school, and peer contexts in which these problems develop and are maintained in youth are pertinent to integrate into a SVM, as pediatric chronic pain and anxiety disorders share several social-contextual risk and maintenance factors. We also highlight new areas of inquiry.
Learn More >Joint pain is composed of both spontaneous and movement-induced pain. In animal models, static bodyweight distribution is a surrogate for spontaneous joint pain. However, there are no commercially-available instruments that measure static bodyweight distribution in normal, pronograde rodents.
Learn More >Brain functional network properties are globally disrupted in multiple musculoskeletal chronic pain conditions. Back pain with lumbar disc herniation is highly prevalent and a major route for progression to chronic back pain. However, brain functional network properties remain unknown in such patients. Here, we examined resting-state fMRI-based functional connectivity networks in chronic back pain patients with clear evidence for lumbar disc herniation (LDH-CP, n = 146), in comparison to healthy controls (HC, n = 165). The study was conducted in China, thus providing the opportunity to also examine the influence of culture on brain functional reorganization with chronic pain. The data was equally subdivided into Discovery and Validation subgroups (n = 68 LDH-CP and n = 68 HC, for each subgroup), and contrasted to an off-site dataset (n = 272, NITRC 1000).Graph disruption indices derived from three network topological measurements, degree, clustering coefficient, and efficiency, which respectively represent network hubness, segregation, and integration, were significantly decreased compared to HC, across all predefined link densities, in both Discovery and Validation groups. On the other hand, global mean clustering coefficient and betweenness centrality were decreased in the discovery group and showed trend in the validation group. The relationship between pain and graph disruption indices was limited to males with high education. These results deviate somewhat from recent similar analysis for other musculoskeletal chronic pain conditions, yet we cannot determine whether the differences are due to types of pain or also to cultural differences between patients studied in China and the USA.
Learn More >Complex regional pain syndrome (CRPS) is a post-traumatic pain condition with an incompletely understood pathophysiological basis. Here, we have examined the cellular basis of pain in CRPS using behavioral and electrophysiological methods in mice treated with IgG from CRPS patients, in combination with a paw incision. Mice were subjected to a hind paw skin-muscle incision alone, or in combination with administration of IgG purified from either healthy control subjects (HC) or patients with persistent CRPS. Nociceptive function was examined behaviorally in vivo, and electrophysiologically in vitro using skin-nerve preparations to study the major classes of mechanosensitive single units. Administration of IgG from CRPS patients exacerbated and prolonged the post-surgical hypersensitivity to noxious mechanical, cold and heat stimulation, but did not influence tactile sensitivity following a paw incision. Studies of IgG preparations pooled from patient cohorts (n=26-27) show that pathological autoantibodies are present in the wider population of patients with persistent CRPS, and that patients with more severe pain have higher effective autoantibody titres than patients with moderate pain intensity. Electrophysiological investigation of skin-nerve preparations from mice treated with CRPS IgG from a single patient identified both a significantly increased evoked impulse activity in A- and C-nociceptors, and an increased spontaneous impulse rate in the intact saphenous nerve. Our results show that painful hypersensitivity in persistent CRPS is maintained by autoantibodies, which act by sensitizing A- and C-nociceptors.
Learn More >The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target.
Learn More >Itch is a somatosensory sensation that informs the organism about the presence of potentially harmful substances or parasites, and initiates scratching to remove the threat. Itch-inducing (pruritogenic) substances activate primary afferent neurons in the skin through interactions with specific receptors that converts the stimulus into an electrical signal. These signals are conveyed to the dorsal horn of the spinal cord through the release of neurotransmitters such as natriuretic polypeptide b and somatostatin, leading to an integrated response within a complex spinal interneuronal network. A large sub-population of somatostatin-expressing spinal interneurons also carry the Neuropeptide Y (NPY) Y1 receptor, indicating that NPY and somatostatin partly regulate the same neuronal pathway. This review focuses on recent findings regarding the role of the NPY/Y1 and somatostatin/SST receptor in itch, and also presents data integrating the two neurotransmitter systems.
Learn More >Stress and pain are interleaved at multiple levels – interacting and influencing each other. Both are modulated by psychosocial factors including fears, beliefs, and goals, and are served by overlapping neural substrates. One major contributing factor in the development and maintenance of chronic pain is threat learning, with pain as an emotionally-salient threat – or stressor. Here, we argue that threat learning is a central mechanism and contributor, mediating the relationship between stress and chronic pain. We review the state of the art on (mal)adaptive learning in chronic pain, and on effects of stress and particularly cortisol on learning. We then provide a theoretical integration of how stress may affect chronic pain through its effect on threat learning. Prolonged stress, as may be experienced by patients with chronic pain, and its resulting changes in key brain networks modulating stress responses and threat learning, may further exacerbate these impairing effects on threat learning. We provide testable hypotheses and suggestions for how this integration may guide future research and clinical approaches in chronic pain.
Learn More >Itch is often regarded as unpleasant or bothersome and is accompanied by symptoms of distress and impairments in daily life. The biopsychosocial model of chronic itch describes how psychological factors can contribute to the improvement or exacerbation of chronic itch and related scratching behavior. Recent research underlines the important role of cognitive-affective information processing, such as attention, affect, and expectancies. This may not only play a role for acute itch states, but may particularly apply to the process of itch chronification, e.g., due to the vicious cycle in which these factors shape the experience of itch. The present paper focuses on new insights into the relation between itch and the cognitive-affective factors of attention, affect, and expectancies. These factors are thought to play a possible aggravating role in itch in the long term and have received increasing attention in the recent empirical literature on maintaining and exacerbating factors for chronic physical symptoms. Possible psychophysiological and neurobiological pathways regarding these factors are discussed, as well as possible intervention methods. This article is protected by copyright. All rights reserved.
Learn More >Chronic pruritus is defined by itching lasting 6 weeks or more and is known to be both a highly prevalent and burdensome symptom of many pruritogenic diseases. Its status as a symptom has many implications mainly that the symptom should evolve and subside with the disease. However, according to the clinical experience, chronic pruritus often does not parallel the disease course and requires an own management. It is speculated, that neuronal sensitization processes take place which lead to disconnection of the symptom from the underlying disease and establishment of an own course of pruritus. It is thus discussed that pruritus can be both – a symptom of diseases but also an entity by itself. Further studies are needed to learn more and improve our understanding of this condition. This article compares its role in pruritogenic diseases, encourages discussion on the topic and provides an overview of the proper questions to ask. This article is protected by copyright. All rights reserved.
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