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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).
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >Latent sensitization is a long-term model of chronic pain in which hyperalgesia is continuously suppressed by opioid receptors, as demonstrated by the induction of mechanical allodynia by opioid antagonists. Different intracellular signals may mediate the initiation, maintenance and expression of latent sensitization. Our criterion for the involvement of a signal in the maintenance of latent sensitization is that inhibitors should permanently eliminate the allodynia produced by an opioid antagonist. We hypothesized that Src family kinases (SFKs) maintain latent sensitization and tested this hypothesis by inducing latent sensitization in rats with complete Freund's adjuvant (CFA) or spared nerve injury. After measures of mechanical allodynia returned to baseline, vehicle or the SFK inhibitor PP2 were injected intrathecally. The opioid antagonist naltrexone injected intrathecally 15 min later produced allodynia in control rats but not in rats injected with PP2. Vehicle or PP2 were injected daily for two more days and naltrexone was injected five days later. Again, naltrexone induced allodynia in the control rats but not in the rats injected with PP2. Results were similar when latent sensitization was induced with CFA or spared nerve injury. We concluded that an SFK, likely Fyn, maintains latent sensitization induced by inflammation or nerve injury.
Learn More >The pharmacological activation of A receptors has shown potential usefulness in the management of bowel inflammation. However, the role of these receptors in the control of visceral hypersensitivity in the presence of intestinal inflammation has not been investigated. The effects of AR170, a potent and selective A receptor agonist, and dexamethasone (DEX) were tested in rats with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis to assess their tissue inflammatory parameters. The animals received AR170, DEX, or a vehicle intraperitoneally for 6 days, starting 1 day before the induction of colitis. Visceral pain was assessed by recording the abdominal responses to colorectal distension in animals with colitis. Colitis was associated with a decrease in body weight and an increase in spleen weight. The macroscopic damage score and tissue tumor necrosis factor (TNF), interleukin 1β (IL-1β), and myeloperoxidase (MPO) levels were also enhanced. AR170, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight, ameliorated macroscopic colonic damage, and decreased TNF, IL-1β, and MPO tissue levels. The enhanced visceromotor response (VMR) in rats with colitis was decreased via AR170 administration. In rats with colitis, AR170 counteracted colonic inflammatory cell infiltration and decreased pro-inflammatory cytokine levels, thereby relieving visceral hypersensitivity.
Learn More >This systematic review and meta-analysis examined the evidence for altered central pain processing in people with non-traumatic neck pain and the relationship between central pain processing, demographics and pain-related characteristics. Case-control studies reporting measures of altered central pain processing using quantitative sensory testing were reviewed. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) between people with non-traumatic neck pain and controls were calculated. Meta-analysis was performed using random-effects models when appropriate. Associations between SMDs with demographics and pain-related characteristics were explored on a study level using meta-regression. Twenty-six studies were eligible with 25 included for meta-analysis. Meta-analysis demonstrated mechanical hyperalgesia at remote non-painful sites in the full sample [sample size (n)=1305, SMD=-0.68] and in the subgroup with moderate/severe disability [n=165, SMD=-0.86] (moderate-quality evidence). Meta-regression indicated that remote mechanical hyperalgesia was negatively associated with age (R=25.4%, P=0.031). Very-low- to low-quality evidence of remote cold and heat hyperalgesia and dysfunctional conditioned pain modulation were identified. This review suggests that altered central pain processing is present in people with non-traumatic neck pain and may be associated with disability levels and age. Perspective: This review found moderate-quality evidence of mechanical hyperalgesia at remote non-painful sites in patients with non-traumatic neck pain compared to controls, indicating altered central pain processing. However, more studies are needed to confirm findings from dynamic quantitative sensory testing.
Learn More >N-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca influx, contributing to remifentanil-induced hyperalgesia. PERSPECTIVE: Remifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.
Learn More >Pain is a major health problem among US adults. Surprisingly little, however, is known about educational disparities in pain, especially among the nonelderly. In this study, we analyze disparities in pain across levels of educational attainment. Using data from the 2010-2017 National Health Interview Survey among adults aged 30-49 (N=74,051), we estimate logistic regression models of pain prevalence using a dichotomous summary pain index and its five constituent pain sites (low back, joint, neck, headache/migraine, and facial/jaw). We find a significant and steep pain gradient: greater levels of educational attainment are associated with less pain, with two important exceptions. First, adults with a high-school equivalency diploma (GED) and those with 'some college' have significantly higher pain levels than high school graduates despite having an equivalent or higher attainment, respectively. Second, the education-pain gradient is absent for Hispanic adults. After taking into account important covariates including employment, economic resources, health behaviors, physical health conditions, and psychological wellbeing, educational disparities in pain are no longer statistically significant except for the GED and 'some college' categories, which still show significantly higher pain levels than high school graduates. We thus document the overall education-pain gradient in most younger US adult populations, and identify groups where pain is higher than expected (certain educational categories) or lower than expected (e.g., less-educated Hispanics). Understanding the causes of these anomalous findings could clarify factors shaping pain prevalence and disparities therein. PERSPECTIVE Over 50% of US adults age 30-49 report pain. Overall, more educated Americans report substantially less pain than the less educated. However, adults with a GED and 'some college' report more pain than other groups. Understanding the causes could help illuminate the mechanisms through which social factors influence pain.
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