Browse by Audience
There is now a consensus in the literature that future improvements in outcomes obtained from cognitive behavioral therapy (CBT) for chronic pain will require research to identify patient and treatment variables that help explain outcomes. The first aim of this study was to assess whether pre-treatment scores on measures of psychological (in)flexibility, acceptance, committed action, cognitive (de)fusion, and values-based action predict outcomes in a multidisciplinary, multicomponent, group-based CBT program for adults with chronic pain. The second aim was to assess whether change scores on these same measures mediate outcomes in the treatment program. Participants were 232 people attending treatment for chronic pain. Of the psychological flexibility measures, only pre-treatment scores on the psychological inflexibility scale predicted outcomes; higher scores on this measure were associated with worse outcomes. However, change scores on each of the psychological flexibility measures separately mediated outcomes. The efficacy of CBT for chronic pain may be improved with a greater focus on methods that increase psychological flexibility.
The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.
Cyclin-dependent-like kinase 5 () gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)-derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent signaling, which are disrupted in both mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.
Pannexin 1 (Panx1) channels are transmembrane proteins that release ATP and play an important role in intercellular communication. They are widely expressed in somatic and nervous system tissues, and their activity has been associated with many pathologies such as stroke, epilepsy, inflammation, and chronic pain. While there are a variety of small molecules known to inhibit Panx1, currently little is known about the mechanism of channel inhibition, and there is a dearth of sufficiently potent and selective drugs targeting Panx1. Herein we provide a review of the current literature on Panx1 structural biology and known pharmacological agents that will help provide a basis for rational development of Panx1 chemical modulators.
Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31 mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-β1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1 CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-β-IL-31 axis with implications for treatment of wound itching.
The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia.
Two-pore domain potassium channels (K2P) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability. These channels form homodimers, however, a few examples of heterodimerization have also been reported. The K2P channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single channel conductance compared to the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that wild type TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.
Secondary analysis of an observational cohort study.
To assess efficacy and tolerability of 1-year erenumab treatment in patients with episodic migraine.
The current study explored whether the chances of having migraine are influenced by a youth's friendship with a migraineur.