Inflammatory pain hypersensitivity is associated with activation of primary afferent neurons. This study investigated the existence of the inflammasome in dorsal root ganglion (DRG) and the functional significance in the development of inflammatory pain hypersensitivity. Tissue inflammation was induced in male C57BL/6 mice with complete Freund's adjuvant (CFA) or ceramide injection into the hind paw. Behavioral testing was performed to investigate inflammation-induced pain hypersensitivity. Ipsilateral L5 DRGs were obtained for analysis. Expression of nucleotide oligomerization domain-like receptors (NLRs) was analyzed with real-time PCR. Cleaved interleukin (IL)-1β and NLRP2 expression was investigated with immunohistochemistry and western blotting. Caspase 1 activity was also measured. A caspase 1 inhibitor and NLRP2 siRNA were intrathecally administered to inhibit NLRP2 inflammasome signaling in DRG. Cleaved IL-1β expression was significantly increased after CFA injection in small-sized DRG neurons. The amount of cleaved IL-1β and caspase 1 activity were also increased. Among several NLRs, NLRP2 mRNA was significantly increased in DRG after CFA injection. NLRP2 was expressed in small-sized DRG neurons. Intrathecal injection of a caspase 1 inhibitor or NLRP2 siRNA reduced CFA-induced pain hypersensitivity and cleaved IL-1β expression in DRG. Induction of cleaved IL-1β and NLRP2 in DRG neurons was similarly observed after ceramide injection. NLRP2 siRNA inhibited ceramide-induced pain hypersensitivity. These results confirmed the existence of NLRP2 inflammasome in DRG neurons. Activation of the NLRP2 inflammasome leads to activation of DRG neurons and subsequent development of pain hypersensitivity in various types of tissue inflammation.

BackgroundIntense nociceptive signaling arising from ongoing injury activates primary afferent nociceptive systems to generate peripheral sensitization. ERK1/2 phosphorylation in dorsal root ganglion can be used to visualize intracellular signal activity immediately after noxious stimulation. The aim of this study was to investigate spatiotemporal characteristics of ERK1/2 phosphorylation against tissue injury in the primary afferent neurons.MethodsPlantar incisions were made in the hind paws of Sprague-Dawley rats (n =150). Levobupivacaine was injected into the plantar aspect of the paws and ankles, Mitogen-activated protein kinase kinase (MEK) inhibitor was injected into the paw, and carbenoxolone, dual inhibitor of the gap junction and pannexin channel, was intraperitoneally injected. Pain hypersensitivity was investigated by a behavioral study, while phosphorylated ERK1/2 was detected in dorsal root ganglion and hind paw using immunohistochemistry and Western blot.ResultsPhosphorylated ERK1/2 was induced in dorsal root ganglion (26.8 ± 2.9% at baseline, 65.6 ± 3.6% at 2 min, and 26.3 ± 3.4% at 2 h) after the incision. NF-200 positive A-fiber neurons and satellite glial cells were positive for phosphorylated ERK1/2. Injury-induced pain hypersensitivity was abolished by MEK inhibitor. Levobupivacaine treatment inhibited phosphorylated ERK1/2 induction, carbenoxolone treatment inhibited glial phosphorylated ERK1/2 at 2 min after the injury, and carbenoxolone inhibited pain hypersensitivity and neuronal phosphorylated ERK1/2 at 1 h after the injury.ConclusionERK1/2 phosphorylation in A-fiber neurons and satellite glial cells immediately after injury contributes to the generation of pain hypersensitivity. Signal communication between neurons and satellite glial cells expands the duration of neuronal ERK1/2 phosphorylation and pain hypersensitivity at 1 h after tissue injury.

No abstract

BackgroundAdvances in medical technology have resulted in an increased life expectancy in pediatric patients with congenital heart diseases. Assessment of health‐related quality of life is crucial to improving their healthcare status. We aimed to assess post‐surgical pain prevalence and its impact on health‐related quality of life in pediatric patients who underwent cardiac surgery during childhood.MethodsThis cross‐sectional study recruited patients aged 4 years or older who underwent cardiac surgery for congenital heart disease at least 1 year prior, during the age of 0‐10 years, and were admitted for post‐surgical follow‐up at our institute. The prevalence, intensity, and location of pain and health‐related quality of life were assessed in an interview. Perioperative information was collected from the patients’ medical records. Health‐related quality of life was assessed using the Pediatric quality of life inventory 4.0 (PedsQL).ResultsPain was reported by 24 (17%) of the 141 participants. One‐third of them reported moderate to severe pain that required medical intervention. After adjustment for several confounding factors, multivariable linear regression analysis demonstrated that the presence of pain and the number of surgeries were associated with lower total PedsQL scores.ConclusionsPain was present in 17% of the patients who underwent cardiac surgery during childhood. Presence of pain had a negative impact on long‐term health‐related quality of life after pediatric cardiac surgery.

BackgroundPain assessment is highly recommended in patients receiving mechanical ventilation. However, pain intensity and its impact on outcomes in these patients remain obscure. We collected the results of routine pain assessments, utilizing the behavioral pain scale (BPS), from 151 patients receiving mechanical ventilation. Risk factors associated with a pain event, defined as BPS of >5, and its impact on patient outcomes were investigated.MethodsA total of 151 consecutive adult patients receiving mechanical ventilation for more than 24 h in a single 10-bed ICU were enrolled in this study. The highest BPS within 48 h after the initiation of mechanical ventilation was collected, as well as information about the patients’ characteristics and medication received. We also recorded patient outcomes, including time to successful weaning from mechanical ventilation, time to successful ICU discharge, and 30-day in-hospital mortality. Multivariate logistic regression analysis was used to determine factors independently associated with patients with a BPS of >5. Clinical outcomes were also assessed using multivariate logistic regression analysis, correcting for risk factors.ResultsWe analyzed 151 patients. The median highest BPS was 4. The percentage of patients who recorded a BPS of >5 was 19.9% (n = 30). Multivariate logistic regression analysis revealed that the disuse of fentanyl and inotropic support was an independent predictor of pain event. Multivariable Cox regression analysis suggested that the development of a BPS of >5 was associated with increased mortality and a not statistically significant trend towards prolonged mechanical ventilation.ConclusionsA significant proportion of ventilated patients experienced a BPS of >5 soon after the initiation of mechanical ventilation. Disuse of fentanyl and use of inotropic agents increased the risk of developing a BPS of >5 during mechanical ventilation. An association between adequate analgesia and improved patient outcomes provides a rationale for the assessment of pain during mechanical ventilation, with subsequent intervention if necessary.Pain events were common among ventilated patients. In critical care settings, appropriate and adequate pain management is warranted, given the association with improved patient outcomes.