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The transient receptor potential cation channel subfamily V member 3 (TRPV3) channel plays a critical role in skin physiology, and mutations in TRPV3 result in the development of a congenital skin disorder, Olmsted syndrome. Here we describe multiple cryo-electron microscopy structures of human TRPV3 reconstituted into lipid nanodiscs, representing distinct functional states during the gating cycle. The ligand-free, closed conformation reveals well-ordered lipids interacting with the channel and two physical constrictions along the ion-conduction pore involving both the extracellular selectivity filter and intracellular helix bundle crossing. Both the selectivity filter and bundle crossing expand upon activation, accompanied by substantial structural rearrangements at the cytoplasmic intersubunit interface. Transition to the inactivated state involves a secondary structure change of the pore-lining helix, which contains a π-helical segment in the closed and open conformations, but becomes entirely α-helical upon inactivation. Together with electrophysiological characterization, structures of TRPV3 in a lipid membrane environment provide unique insights into channel activation and inactivation mechanisms.
Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by α-to-π helical transitions of the nearby S6 helix. However, it remains unclear how physiological lipids are involved in the TRPV3 activation. Here we determined the apo state structure of mouse (Mus musculus) TRPV3 in a lipid nanodisc at 3.3 Å resolution. The structure revealed that lipids bound to the pore domain stabilize the selectivity filter in the narrow state, suggesting that the selectivity filter of TRPV3 affects cation permeation. When the lower gate is closed in nanodisc-reconstituted TRPV3, the S6 helix adopts the π-helical conformation without agonist- or heat-sensitization, potentially stabilized by putative intra-subunit hydrogen bonds and lipid binding. Our findings provide insights into the lipid-associated gating mechanism of TRPV3.
To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack.
Chronic pain is consistently associated with the presence of mental health disorders. Although previous research has shown relations between low levels of self-efficacy with chronic pain severity as well as comorbid mental health symptoms, the link between self-efficacy and mental health symptoms in chronic pain is not well understood. This study examined whether pain centrality, the extent to which pain is viewed as central to self-identity, may underlie these associations. Individuals with a diagnosis of chronic pain (N = 89) recruited through MTurkcompleted self-report measures including demographics, self-efficacy, pain centrality, pain severity, depression, and anxiety. Pain severity was associated with higher levels of pain centrality, depression, anxiety, and lower levels of self-efficacy. Path analysis demonstrated pain centrality significantly mediated the relationship between self-efficacy and pain severity, depression, and anxiety. Future studies would benefit from testing whether modifying pain centrality beliefs shift perceptions of control as well as pain and psychological outcomes.
Exercise is a core treatment for persistent non-specific low back pain (NSLBP), but results from randomised controlled trials (RCTs) of exercise typically show only small to moderate standardised mean differences (SMDs) compared to non-exercise controls. The choice of primary outcome, and relationship to the specific targets of exercise may influence this. This systematic review aimed to explore whether primary outcomes match the exercise treatment targets used in NSLBP RCTs and the potential impact of matching on SMDs. Included RCTs were conducted with patients with persistent NSLBP, compared exercise to no exercise, with sample sizes >60 per arm. Screening, data extraction and risk of bias assessment were independently undertaken by paired reviewers. Of 19272 initial titles, 27 RCTs were included with 31 treatment targets and 6 primary outcome domains identified. Only 25% of included RCTs had primary outcomes that matched the treatment targets. SMDs of exercise versus comparison arms were observed to be larger in the matched (SMD 0.54 (95% CI 0.23 to 0.85), p=0.0006) compared to the unmatched category (SMD 0.22 (95% CI 0.01, 0.44) p=0.04) but this difference was not statistically significant (p=0.10). These exploratory findings may have implications for future teams developing RCTs of exercise for NSLBP and warrant further investigation in larger datasets. Perspective This review was an exploratory study that investigated the primary outcome and treatment targets used in RCTs of exercise for NSLBP. The SMDs of the matched group were descriptively larger than those of the unmatched group, but further analysis with larger sample sizes is required to have confidence in these results.
Binaural Beats (BB) consist of two artificial acoustic stimuli with different frequency, presented simultaneously but independently to each ear. The human brain perceives and synchronizes to this frequency difference (entrainment).
Diphenhydramine (DPH) has been broadly used to treat allergy. When used as a topical medicine, DPH temporarily relieves itching and pain. Although transient receptor potential type A1 (TRPA1) channel is known to play roles in both acute and chronic itch and pain, whether DPH affects the activities of TRPA1 remains unclear. Using whole-cell patch clamp recordings, we demonstrated that DPH modulates the voltage-dependence of TRPA1. When co-applied with a TRPA1 agonist, DPH significantly enhanced the inward currents while suppressing the outward currents of TRPA1, converting the channel from outwardly rectifying to inwardly rectifying. This effect of DPH occurred no matter TRPA1 was activated by an electrophilic or non-electrophilic agonist and for both mouse and human TRPA1. The modulation of TRPA1 by DPH was maintained in the L906C mutant, which by itself also causes inward rectification of TRPA1, indicating that additional acting sites are present for the modulation of TRPA1 currents by DPH. Our recordings also revealed that DPH partially blocked capsaicin evoked TRPV1 currents. These data suggest that DPH may exert its therapeutic effects on itch and pain, through modulation of TRPA1 in a voltage-dependent fashion.
The goal of the current study was to enhance the measurement of the pediatric chronic pain experience through a methodologically rigorous approach. This paper outlines the development and initial validation of a pain intensity measure for pediatric patients with chronic pain using PROMIS® methodology. Measure development incorporated feedback from children with painful conditions. Based on input from pediatric participants and content experts, four candidate items assessing pain intensity were included for large scale testing. Children completed self-report items pertaining to their pain experience that were developed as part of a larger pool of new candidate PROMIS® pediatric pain domain items as well as measures of pain interference, depressive symptoms, fatigue, pain behavior, pain intensity, and pain catastrophizing. The final sample for the large scale testing included N = 442 pediatric patients between the ages 8 to 18 years (Mean age = 13.54, SD = 2.78; 71.27% female) experiencing chronic pain. Psychometric analysis resulted in a final measure that included three items with evidence of reliability (Cronbach alpha = 0.82) and convergent validity. The Likert format of the response options may be preferable to the traditional numeric rating scale for use in pediatric populations who experience chronic pain based on patients' feedback, which was directly utilized in designing the scale. Further, the inclusion of fewer and clinically meaningful response options should reduce ambiguity for young respondents. Perspective: We have developed and evaluated a clinically sensitive and psychometrically precise 3-item pain intensity measure with Likert-type responses for self-report use among children and adolescents ages 8-18 with chronic pain. Development of the item content and response options included input from children and adolescents with chronic pain. The development of pain intensity items with pediatric appropriate language, and labeled, fewer response options to yield maximal clinically meaningful information improves the precision of pain intensity measurement in children.
Glycine receptors (GlyRs) mediate inhibitory neurotransmission within the spinal cord and play a crucial role in nociceptive signalling. This makes them primary targets for the development of novel chronic pain therapies. Endogenous lipids have previously been shown to modulate glycine receptors and produce analgesia in pain models, however little is known about what chemical features mediate these effects. In this study, we characterised lipid modulation of GlyRs by screening a library of N-acyl amino acids across all receptor subtypes and determined chemical features crucial for their activity. Acyl-glycine's with a C18 carbon tail were found to produce the greatest potentiation, and require a cis double bond within the central region of the carbon tail (ω6 – ω9) to be active. At 1 µM, C18 ω6,9 glycine potentiated glycine induced currents in α and αβ receptors by over 50%, and α, α, αβ and αβ receptors by over 100%. C18 ω9 glycine (N-oleoyl glycine) significantly enhance glycine induced peak currents and cause a dose-dependent shift in the glycine concentration response. In the presence of 3 µM C18 ω9 glycine, the EC of glycine at the α receptor was reduced from 17 µM to 10 µM. This study has identified several acyl-amino acids which are positive allosteric modulators of GlyRs and make promising lead compounds for the development of novel chronic pain therapies.
Glycine receptor α1 subunit is located at inhibitory synapses in the superficial dorsal horn of adult spinal cord and is engaged in the glycinergic inhibition of nociceptive neuronal excitability and transmission. The α1 phosphorylation at Ser380 by extracellular signal-regulated kinase (ERK) has been shown to decrease glycinergic synaptic currents and contribute to spinal disinhibition. Here we found that peripheral inflammation induced by Complete Freund's Adjuvant increased Ser380 phosphorylation in spinal cord dorsal horn of mice, which was repressed by specific activation of adenosine A1 receptor (A1R). Protein phosphatase-1 (PP1), a ubiquitously-distributed serine/threonine phosphatase, was required for A1R to reduce Ser380 phosphorylation. Our data showed that Gβγ dimer, when released after activation of Gi protein-coupled A1R, interacted with PP1 and directed this phosphatase to α1, allowing for the full dephosphorylation of Ser380 residue. Sequestration of Gβγ dimer by viral expression of the C-terminal tail of β-adrenergic receptor kinase (βARKct) dissociated PP1 from α1 complex, leading to robust Ser380 phosphorylation. Meanwhile, Gβγ inhibition compromised the ability of A1R to alleviate inflammatory pain. The inhibitory effect of A1R on Ser380 phosphorylation was also attributed to the inactivation of ERK in CFA mice. Our data thus identified glycine receptor α1 subunit as an important target for adenosinergic suppression of inflammatory pain.