PAIN®最新文献

Abstract: Voltage-gated potassium channel subfamily q member 4 (Kcnq4) is predominantly expressed by hair cells and auditory neurons and regulates the neuronal excitability in the auditory pathway. Although it is further detected in myelinated large-diameter dorsal root ganglia (DRG) neurons in the periphery, the expression and function of Kcnq4 channel in nociceptors remains unknown. Here we showed that Kcnq4 is substantially expressed by unmyelinated small-diameter DRG neurons in both human and mouse. In spite of a dispensable role in acute pain and chronic skin inflammation, Kcnq4 is specifically involved in the regulation of scratching behavior through controlling action potential firing properties, evidenced by the increased neuronal excitability in small-diameter DRG neurons isolated from Kcnq4 deficient mice. Moreover, genetic ablation of Kcnq4 in Trpv1-positive neurons exacerbates both acute and chronic itch behavior in mice. Taken together, our results uncover a functional role of Trpv1-lineage neuron-expressing Kcnq4 channel in the modulation of itch-specific neuronal excitation in the periphery.

Abstract: Advancements in clinical science have shown the necessity for a paradigm shift away from a biomedical toward a biopsychosocial approach. Yet, the translation from clinical science into clinical practice is challenging. The aim of this study was to assess the short-term and mid-term changes in pain knowledge and attitudes and guideline-adherent recommendations of healthcare professionals (HCP) by means of an interdisciplinary training program (ITP) about chronic pain. Belgian HCPs, with a priority for medical doctors, physiotherapists, occupational therapists, nurses, psychologists, and pharmacists in primary care, participated in the ITP, which contained 2 e-learning modules and two 7-hour workshops provided in small interdisciplinary groups in 5 cities. The objective of ITP was to improve HCP's competencies for integrating biopsychosocial chronic pain management with a cognitive behavioral approach into clinical practice. Primary outcomes were changes in knowledge and attitudes about pain and guideline-adherent recommendations for continuation of physical activity, sports, and work; avoiding bed rest; and not supporting opioid usage measured through 2 clinical vignettes. They were measured before, immediately after, and 6 months after the ITP. Changes were analyzed using (generalized) linear mixed models. A total of 405 HCPs participated. The knowledge and attitudes about pain scores improved at post-training (Δ = 9.04, 95% confidence interval 7.72-10.36) and at 6-month follow-up (Δ = 7.16, 95% confidence interval 5.73-8.59). After the training program, HCPs provided significantly more recommendations in accordance with clinical guidelines. Thus, an ITP can improve the biopsychosocial perspective of chronic pain management among HCPs in the short-term and mid-term.

Abstract: In phase II clinical trials, NaV1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and NaV1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of NaV1.8 channels, which attenuated neuropathic pain behavior in mice. NaV1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and NaV1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show NaV1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the NaV1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced NaV1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the NaV1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to NaV1.8 pore blockers.

Abstract: There is growing acceptance for combining complementary and integrative health (CIH) therapies with standard rehabilitative care (SRC) for chronic pain management, yet little evidence on the best sequence of therapies. We investigated whether starting with CIH therapies or SRC is more effective in reducing pain impact. Participants were 280 service members with predominantly (88%) musculoskeletal chronic pain referred to an interdisciplinary pain management center who were randomized to a twice weekly program of either CIH therapies (n = 140) or SRC (n = 140) for the 3-week first stage of treatment. The composition of a second 3-week treatment stage depended upon response to the first stage. The primary outcome measure was the impact score (range 8-50) from the NIH Task Force on Research Standards for Chronic Low-Back Pain. Outcomes were measured after 3 and 6 weeks of treatment and at 3- and 6-month follow-ups. Most participants were men (76.8%) and mean age was 34.7 years (SD 8.0). At end of stage 1, pain impact decreased significantly more in the CIH group (29.8 points [SD 7.2] at baseline to 26.3 points [SD 7.9], change of -3.3 points [95% confidence interval, -4.2 to -2.5]) than in the SRC group (30.8 [SD 7.6] to 29.4 [SD 7.8], change of -0.9 points [95% confidence interval, -1.8 to -0.1]; P < 0.001). No significant between-group differences were observed after 6 weeks of treatment nor at 3- or 6-month follow-ups. Complementary and integrative health therapies may provide earlier improvement in pain impact than SRC, but this difference is not sustained.

Abstract: A pain inequity exists for Native Americans (NAs), but the mechanisms are poorly understood. The Oklahoma Study of Native American Pain Risk (OK-SNAP) addressed this issue and recruited healthy, pain-free NAs and non-Hispanic Whites (NHWs) to attend 2 laboratory visits and assessed mechanisms consistent with the biopsychosocial model of pain: demographics, physical variables, psychosocial factors, and nociceptive/pain phenotypes. Then participants were surveyed every 6 months to assess for chronic pain onset. Results at the 2-year follow-up found that NAs were ∼3x more likely than NHWs to develop chronic pain. Moreover, psychosocial factors (discrimination, stress, pain-related anxiety), cardiometabolic load (higher body mass index and blood pressure, lower heart rate variability), and impaired inhibition of spinal nociception partly mediated the pain inequity. The present study examined mechanisms of chronic pain at the 5-year follow-up for OK-SNAP. Results found that the NA pain inequity worsened-NAs were 4x more likely to develop chronic pain (OR = 4.025; CI = 1.966, 8.239), even after controlling for baseline age, sex assigned at birth, income, and education. Moreover, serial mediation models replicated paths from the 2-year follow-up that linked psychosocial variables, cardiometabolic load, and impaired inhibition of spinal nociception to chronic pain onset. Further, 2 new significant paths were observed. One linked discrimination, stress, sleep problems, and facilitated pain perception to increased pain risk. The other linked discrimination with higher spinal nociceptive threshold and pain risk. These results provide further evidence for a NA pain inequity and identify multiple psychosocial, cardiometabolic, and pronociceptive targets for primary interventions.

Abstract: Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders.

Abstract: Evidence linking adverse childhood experiences and chronic pain in adulthood is largely cross-sectional, potentially subject to recall bias and does not allow exploration of mediating pathways. We analysed a large population-based cohort (UK Biobank) using a causal framework, to determine if childhood maltreatment is related to chronic "all over" body pain in adulthood. We used doubly robust estimation with inverse probability weights to estimate the difference in risk of chronic pain "all over" between those exposed/not exposed to childhood maltreatment (abuse or neglect). In addition, we looked at interaction with adult stressful life events and examined mediation using inverse odds weighting in a generalized linear model. Using cases with complete data (n = 118,347), the risk of chronic "all over" body pain was higher in the exposed (6.3%, 95% confidence interval [CI] 6.0%-6.5%) than in the unexposed (4.0%; 95% CI 3.8%-4.2%). This difference remained in analyses stratified by sex. Conversely, when analyses were repeated with a negative control exposure, childhood sunburn, risk differences were 0.8% in women (95% CI 0.3%-1.3%) and 0.5% in men (95% CI 0.1%-0.9%). Childhood maltreatment and adult life events had similar effects, and there was a supra-additive risk (1.2%; 95% CI 0.6-1.7) when experiencing both. In mediation analyses, the total effect was a relative risk of 1.57 (95% CI 1.49-1.66), while the estimated indirect effect via all mediators was relative risk 1.16 (95% CI 1.14-1.18). Reducing childhood maltreatment would likely prevent cases of chronic widespread pain in adulthood. Stressful adult events and mediators may offer opportunities for intervention.

Abstract: Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.

Abstract: Prevention of chronic pain is a major challenge in this area of clinical practice. To do this, we must be able to understand who is most at risk of developing chronic pain after an injury. In this study, we aimed to identify risk factors of chronic pain onset, disability, and pain interference after a lower limb musculoskeletal injury in children and adolescents between 8 to 16 years of age. We assessed biopsychosocial factors including age, sex, pubertal status, anxiety, depression, fear of pain, pain worry, adverse life events, and sleep in children. We also assessed risk factors in parents including parent anxiety, depression, parent pain catastrophising, and protective behaviours. Logistic and hierarchical linear regressions identified risk factors assessed immediately postinjury for outcomes assessed at 3 months postinjury. Fourteen percent (17/118 children) reported chronic pain 3 months after injury. There were significant between-group differences in children with and without chronic pain at baseline. Children with chronic pain reported higher pain intensity, disability, pain interference, child depression, fear of pain, and catastrophic thinking about their pain. Regressions showed child depression and fear of pain at baseline independently predicted chronic pain onset at 3 months, parent protectiveness predicted child pain interference at 3 months, and child depression, poor sleep, parent anxiety and pain catastrophising predicted disability. Most children recover after a lower limb injury, but a minority develop chronic pain predicted by important psychosocial risk factors, which could be addressed to prevent the onset of treatment-resistant chronic pain and disability.