Increased Pain Sensitivity Research Articles

TCHis mitigate oxidative stress and improve abnormal behavior in a prenatal valproic acid-exposed rat model of autism.

Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. The VPA was administered to pregnant rats on gestational day 12.5 to induce a model of autism. The offspring were given the treatment of TCHis on postnatal day (PND) 21-50. On PND 43-50, the behavioral analysis of offspring was performed after the treatment of TCHis for 1 h. On PND 50, the offspring were harvested and the brains were collected. The hippocampus and prefrontal cortex were isolated for relevant biochemical detections. The administration of TCHis increased pain sensitivity and improved abnormal social behaviors in prenatal VPA-exposed rats. Prenatal exposure of VPA induced neuronal loss and apoptosis, enhanced reactive oxygen species (ROS) production, and promoted oxidative stress in hippocampus and prefrontal cortex, whereas these effects were reversed by the postnatal treatment of TCHis. In addition, postnatal administration of TCHis ameliorated mitochondrial function in hippocampus and prefrontal cortex of prenatal VPA-exposed rats. This study concluded that postnatal treatment of TCHis reduced oxidative stress and ameliorated abnormal behavior in a prenatal VPA-induced rat model of autism.

Posttraumatic Stress Symptoms and Pain Sensitization After Whiplash Injury: A Longitudinal Cohort Study With Quantitative Sensory Testing.

Posttraumatic stress symptoms (PTSS) are common after whiplash injury and are associated with poor recovery. The acute stress response may lead to pain sensitization and widespread pain, thereby compromising recovery. To our knowledge, no longitudinal study has assessed the associations between early PTSS and pain sensitization over time using quantitative sensory testing (QST). The aim of this study was to compare participants with different levels of PTSS, as measured by the impact of event scale (IES; subclinical 0–8, mild 9–25, and clinical ≥ 26) at baseline (<10-day post-injury) and at a follow-up of 1, 3, 6, and 12-month post-injury on pain sensitivity, neck mobility, pain distribution, and pain intensity. In total, 740 participants were recruited from emergency units or general practitioners with acute neck pain after a whiplash injury. The clinical PTSS group showed increased pain sensitivity on all QSTs at all time points compared to the subclinical PTSS group. Also, the clinical PTSS group showed significantly lower neck mobility at all time points except for a 3-month follow-up compared to the subclinical PTSS group. Moreover, the clinical PTSS group showed more widespread pain and self-reported headache and neck pain intensity at all time points compared to the subclinical PTSS group. This study emphasizes that participants with clinical levels of PTSS constitute a high-risk group that is sensitized to pain early after the injury. Hence, screening for PTSS within the 1st week after whiplash injury for those who experience high levels of pain intensity and distress may be an important clinical procedure in the assessment and treatment of whiplash-associated disorders (WAD).

24-LB: Guanfacine Normalizes Presynaptic Alpha-2 Adrenoceptors Enrichment and Ameliorates Neuropathic Pain in Type 1 Diabetic Rats

Diabetes is associated with several complications, including neuropathic pain, which is challenging to manage with currently available drugs. Descending noradrenergic neurons possess anti-nociceptive activity; however their involvement in diabetic neuropathic pain remains to be explored. To infer the regulatory role of this system, we examined in the pons, a part of the brainstem, lumbar nerves of the spinal cord and dorsal root ganglia of streptozotocin (STZ) -treated rats, a model for type 1 diabetes (T1D) , the localization (immunofluorescence) and the mRNA (qRT-PCR) and protein (Western blotting) expression of alpha-2A adrenoceptor (ADRA2A) . The data revealed that presynaptic SNAP-25 labeled ADRA2A in the central and peripheral nervous system of STZ diabetic rats were up-regulated both at the mRNA and protein levels. Interestingly, the levels of PSD-95 labeled postsynaptic neuronal ADRA2A remain unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of hyperalgesia and cold/mechanical allodynia. The latter pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective ADRA2A agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic ADRA2A and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight ADRA2A, a key component of the descending neuronal autoinhibitory pathway as a potential therapeutic target in the treatment of diabetic neuropathic pain. Disclosure N. Munawar: None. A. Al madhoun: None. J. Nader: None. W. Al-ali: None. W. Masocha: None. F. Al-mulla: None. M. S. Bitar: None. Funding Grant YM05/19 from Kuwait University Research Sector.

0454 Response to Lemborexant in Older Subjects with Insomnia Disorder and Comorbid Pain at Baseline

Abstract Introduction The reciprocal relationship between pain and poor sleep has been well established. Pain interferes with sleep, and insomnia increases pain sensitivity, thus reducing quality of life. Therefore, it is of clinical importance to evaluate whether a sleep-promoting drug such as the dual orexin receptor antagonist, lemborexant (LEM; approved in multiple countries to treat adults with insomnia) can improve sleep in older patients, in whom both sleep and ongoing pain are prevalent. Methods Study 304 (NCT02783729), was a 1-month, double-blind, PBO- and active-controlled study in subjects age ≥55y with insomnia (full analysis set [FAS]=1006). Those who also endorsed some/severe pain at baseline on the pain/discomfort dimension of the EuroQual-5 Dimension-3 Level scale (EQ-5D-3L; no problems/some problems/extreme problems) at baseline were eligible for these post-hoc analyses. Medical history of pain conditions and/or ongoing therapy were not required for eligibility and were not evaluated. Subjects were randomized to bedtime doses of placebo, LEM 5mg (LEM5),10mg (LEM10) or zolpidem tartrate extended release (not reported here). Changes from baseline (CFB) in objective sleep parameters assessed by polysomnography (latency to persistent sleep [LPS]; wake after sleep onset [WASO]) were analyzed by mixed-effect repeated measures analyses adjusted for relevant factors. Results Approximately 18% of the FAS reported some or extreme pain at baseline (PBO=55; LEM5=78; LEM10=50). For LPS, baseline median values (minutes) were 31.0, 29.4 and 42.1 for PBO, LEM5 and LEM10, respectively. Median CFB for LPS were larger and statistically significantly different for both LEM doses compared with PBO at the beginning of treatment (mean of Nights 1/2: +2.5; -8.4, -15.8; P&amp;lt;0.005); and were (mean of Nights 29/30: -7.1,-9.9, -9.0) at the end of treatment LEM5 (P=0.031), LEM10 (P=0.054). For WASO, baseline median values (minutes) were 101.0, 103.6 and 111.1 for PBO, LEM5 and LEM10, respectively. Median CFB for WASO were larger and statistically significantly different (P&amp;lt;0.001) for both LEM doses compared with PBO at the beginning (Nights 1/2; -1.5; -41.5, -64.4) and end of treatment (Nights 29/30; -1.1, -37.9, -52.5). Conclusion These data suggest that lemborexant can effectively treat insomnia in older adults with concomitant painful conditions. Support (If Any) Eisai Inc.

Obesity by High-Fat Diet Increases Pain Sensitivity by Reprogramming Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia.

Obesity is a significant health concern as a result of poor-quality diet, for example, high-fat diet (HFD). Although multiple biological and molecular changes have been identified to contribute to HFD-induced pain susceptibility, the mechanisms are not fully understood. Here, we show that mice under 8 weeks of HFD were sensitive to mechanical and thermal stimuli, which was coupled with an accumulation of branched-chain amino acids (BCAAs) in lumbar dorsal root ganglia (DRG) due to local BCAA catabolism deficiency. This HFD-induced hyperalgesic phenotype could be exacerbated by supply of excessive BCAAs or mitigated by promotion of BCAA catabolism via BT2 treatment. In addition, our results suggested that HFD-related pain hypersensitivity was associated with a pro-inflammatory status in DRG, which could be regulated by BCAA abundance. Therefore, our study demonstrates that defective BCAA catabolism in DRG facilitates HFD-induced pain hypersensitivity by triggering inflammation. These findings not only reveal metabolic underpinnings for the pathogenesis of HFD-related hyperalgesia but also offer potential targets for developing diet-based therapy of chronic pain.

Increased Pain Sensitivity Is Associated with Reduced REM Sleep in Females with Temporomandibular Joint Disorder (TMD)

Previous evidence demonstrates that the incidence of chronic sleep disturbance is high in patients with temporomandibular joint disorder (TMD). However, there has been little examination of whether heightened daytime pain sensitivity in this population is associated with alter sleep architecture at night. We aimed to test the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST) is associated with objective markers of sleep physiology, including sleep architecture and power spectral density bands, in patients with TMD. Female participants (n=149) with insomnia and TMD were recruited as part of a randomized-controlled trial. Pre-randomization, we performed a quantitative sensory testing (QST) battery to measure General Pain Sensitivity, a Central Sensitization Index, and Masseter Pressure Pain Threshold, and performed polysomnography (PSG) that night to calculate sleep architecture parameters (N1%, N2%, SWS%, REM%) and derive relative power in the Delta (0.5-3.5 Hz), Theta (3.5-8.0 Hz), Alpha (8.0-15.0 Hz), and Beta (15-30.0 Hz) spectral bands during sleep. We fit linear regression models with sleep parameters as the outcome, and pain sensitivity as the predictor, controlling for age, depressive symptom severity, and race. Higher Central Sensitization (B = -2.863, P = <0.01) and General Pain Sensitivity Indices (B = -3.069, P = <0.01) were significantly associated with lower REM% both before after controlling for covariates, however masseter pressure pain threshold was not significantly associated with REM% (B = -0.0259, P = 0.0743). Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands, or with any other sleep architectural stages. Heightened pain sensitivity, measured using QST is associated with objective features of sleep architecture in TMD patients, potentially due to heightened pain interfering with sleep. These findings may contribute to understanding of physiological mechanisms through which acute and chronic pain result in sleep disruption. Grant support from NIH Grant R01 DE019731. Previous evidence demonstrates that the incidence of chronic sleep disturbance is high in patients with temporomandibular joint disorder (TMD). However, there has been little examination of whether heightened daytime pain sensitivity in this population is associated with alter sleep architecture at night. We aimed to test the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST) is associated with objective markers of sleep physiology, including sleep architecture and power spectral density bands, in patients with TMD. Female participants (n=149) with insomnia and TMD were recruited as part of a randomized-controlled trial. Pre-randomization, we performed a quantitative sensory testing (QST) battery to measure General Pain Sensitivity, a Central Sensitization Index, and Masseter Pressure Pain Threshold, and performed polysomnography (PSG) that night to calculate sleep architecture parameters (N1%, N2%, SWS%, REM%) and derive relative power in the Delta (0.5-3.5 Hz), Theta (3.5-8.0 Hz), Alpha (8.0-15.0 Hz), and Beta (15-30.0 Hz) spectral bands during sleep. We fit linear regression models with sleep parameters as the outcome, and pain sensitivity as the predictor, controlling for age, depressive symptom severity, and race. Higher Central Sensitization (B = -2.863, P = <0.01) and General Pain Sensitivity Indices (B = -3.069, P = <0.01) were significantly associated with lower REM% both before after controlling for covariates, however masseter pressure pain threshold was not significantly associated with REM% (B = -0.0259, P = 0.0743). Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands, or with any other sleep architectural stages. Heightened pain sensitivity, measured using QST is associated with objective features of sleep architecture in TMD patients, potentially due to heightened pain interfering with sleep. These findings may contribute to understanding of physiological mechanisms through which acute and chronic pain result in sleep disruption. Grant support from NIH Grant R01 DE019731.

Structural Brain Changes Are Associated with Pain Sensitivity in New Daily Persistent Headache

New daily persistent headache (NDPH) is a rare form of chronic daily headache with poorly understood pathophysiology. The aim of this study was to investigate for the first time the presence of possible brain changes in pediatric NDPH and their associations with pain-related measures. Structural images were acquired for 13 patients with NDPH and 13 pain-free, healthy controls using magnetic resonance imaging (20 females, 12-18 years old, mean age=16.1, SD=1.6). In patients, brain changes were correlated with disease duration, pain intensity ratings, pain sensitivity, and functional disability. Deceased cortical thickness was found in the bilateral superior temporal gyrus, left superior frontal gyrus, and left middle frontal gyrus areas in patients with NDPH compared to controls (cluster-wise threshold of p<0.05, Monte Carlo corrected). In addition, decreased cortical thickness in the left superior frontal gyrus was associated with elevated pain sensitivity in NDPH. Our results might represent abnormal pain modulation in NDPH including increased pain sensitivity through cognitive control processes in the developing brain. The detected brain changes could help understand the underlying mechanisms of NDPH that could guide future investigations and personalized therapeutic interventions. This study was primarily supported by Migraine Research Foundation (NCT03447782).

KATP Channels Function in the Peripheral and Central Nervous Systems in a Mouse Model of Type 2 Diabetes

Over 50% of individuals with type 2 diabetes eventually develop diabetic neuropathy. There is a need for increased knowledge in how diabetes affects structural and molecular changes in the nervous system, and how current diabetes interventions affect the progression of chronic pain. Loss of KATP channel activity or function could cause nerve fiber hypersensitivity and consequently increased pain sensitivity due to neuron depolarization. Diabetic neuropathy was induced in male and female C57Bl6 mice over a total of 16 weeks by feeding the animals a high-fat diet (HFD) or corresponding control diet (12330 and 12328, Research Diets Inc., New Brunswick, NJ) for over 16 weeks. Mice on the HFD for at longer than 8 weeks have significantly lower mechanical thresholds and compared to control diet mice. Decreased expression of KATP channel subunits in the spinal cord, and dorsal root ganglia were correlated with decreased mechanical paw withdrawal thresholds. Mice fed a HFD also have decreased analgesia to systemic morphine (0-20 mg/kg, s.c.), which is exacerbated after systemic treatment with glyburide or nateglinide for four weeks, (KATP channel antagonist, glyburide or nateglinide, 50 mg/kg/day, IP or vehicle, 5% DMSO + 0.5% Tween). Upregulation of KATP channels using a viral vector strategy increased paw withdrawal thresholds to systemic morphine. Diabetes affects many adults including those with prediabetes and new-onset diabetes. It is clear that novel biomarkers and pharmaceutical targets are needed in order to (1) confront the demand for new treatments that better manage and (2) identify patients that may develop diabetic neuropathy. Further investigation of KATP channel expression and function during chronic pain syndromes, including diabetic neuropathy, may help to find sufficient treatment options for patients. This work was supported through a University of Minnesota Academic Health Center Faculty Development Grant to AHK and MLG. Funding also provided by the NIH: K01 DA042902, R01 DA051876, and UL1TR002494 (AHK).

Generation of an in vitro model for peripheral neuropathy in Fabry disease using CRISPR-Cas9 in the nociceptive dorsal root ganglion cell line 50B11

Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the lysosomal enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). As a result, the glycolipid substrate, globotriaosylceramide (Gb3) accumulates in various cell types throughout the body producing a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. A hallmark of this disorder is neuropathic pain that occurs in up to 80% of Fabry patients and has been characterized as a small fiber neuropathy. The molecular mechanism by which changes in AGA activity produce neuropathic pain is not clear, in part due to a lack of relevant model systems. Using 50B11 cells, an immortalized dorsal root ganglion neuron with nociceptive characteristics derived from rat, we used CRISPR-Cas9 gene editing of the galactosidase alpha (GLA) gene for AGA to create two stable knock-out clones that have the phenotypic characteristics of Fabry cells. The cell lines show severely reduced lysosomal AGA activity in homogenates as well as impaired degradation of Gb3 in cultured cells. This phenotype is stable over long-term culture. Similar to the unedited 50B11 cell line, the clones differentiate in response to forskolin and extend neurites. Flow cytometry experiments demonstrate that the gene-edited cells express TRPV1 pain receptor at increased levels compared to control, suggesting a possible mechanism for increased pain sensitization in Fabry patients. Our 50B11 cell lines show phenotypic characteristics of Fabry disease and grow well under standard cell culture conditions. These cell lines can provide a convenient model system to help elucidate the molecular mechanism of pain in Fabry patients.

Hedgehog signaling plays a crucial role in hyperalgesia associated with neuropathic pain in mice.

Neuropathic pain is a debilitating chronic syndrome of the nervous system caused by nerve injury. In Drosophila, the Hedgehog (Hh) signaling pathway is related to increased pain sensitivity (hyperalgesia) but does not affect the baseline nociceptive threshold. In general, the contribution of the Hh signaling pathway to neuropathic pain in vertebrates is a highly debated issue. Alternatively, we investigated the potential role of Hh signaling in mechanical allodynia using a mouse model of neuropathic pain. Seven days after spinal nerve-transection (SNT) surgery, microglial activation increased in the ipsilateral spinal dorsal horn compared with that in the sham group; however, 21 days after surgery, microglial activation decreased. Contrastingly, astrocyte activation in the spinal cord did not differ between the groups. On day 21 of postsurgery, the SNT group showed marked upregulation of sonic hedgehog expression in peripheral glial cells but not in dorsal root ganglion (DRG) neurons. Intrathecal administration of the Hh signaling inhibitor vismodegib attenuated the mechanical allodynia observed on day 21 postsurgery. Conversely, intrathecal treatment with the Hh signaling activator smoothened agonist in naive mice induced mechanical allodynia, which was abolished by the ATP transporter inhibitor clodronate. Moreover, inhibition of Hh signaling by pretreatment with vismodegib significantly reduced ATP secretion and the frequency/number of spontaneous elevations of intracellular calcium ion levels in cultured DRG cells. Thus, the Hh signaling pathway appears to modulate the neural activity of DRG neurons via ATP release, and it plays an important role in sustaining mechanical allodynia and hypersensitivity in a mouse model of neuropathic pain.

Central sensitization and adult attention deficit hyperactivity disorder in medical students with chronic back pain: a cross-sectional study

BackgroundChronic back pain is a common health complaint among university students. A subset of chronic back pain patients suffer from increased pain sensitivity, a process termed central sensitization. Chronic pain is also associated with cognitive dysfunction, involving attention, memory, and learning. Those are key features of adult attention deficit hyperactivity disorder. This study aimed to assess the associations between adult attention deficit hyperactivity disorder and central sensitization in students with chronic back pain.ResultsTwo hundred twenty-seven students completed the survey, and 90 (39.6%) had back pain for more than 3 months. Students with back pain had significantly higher central sensitization (P<0.01) and higher attention deficit scores (P=0.05). Significant positive correlations were found between scores of the two questionnaires (r= 0.55, P<0.01). Regression analysis adjusted for age and gender showed that higher attention deficit scores were associated with back pain (odd’s ratio:1.025, P=0.05). The odd’s ratio was attenuated after adding central sensitization to the model (odd’s ratio: 0.99, P=0.70).ConclusionsThe findings of this study suggest that attention deficit hyperactivity disorder is associated with elevated central sensitization in patients with chronic back pain. Our results support the hypothesis that central sensitization mediates the effect of attention deficit on back pain.

Skin conductance levels and responses in Asian and White participants during fear conditioning✰

Fear conditioning paradigms are frequently used in the translational study of anxiety and fear-related disorders. Accordingly, it is important to understand whether the measurement of fear conditioning responses is systematically influenced by an individual's race. Studies have found increased pain sensitivity and smaller physiological startle responses in Asian individuals, compared to White individuals; to our knowledge, no studies have evaluated whether skin conductance response (SCR) outcomes differ between Asian and White individuals. In a series of secondary data analyses, we investigated potential differences in skin conductance level (SCL), orienting SCR, unconditioned SCR, SCR to CS+ and CS-, differential SCR, and differential SCR non-responder status. In sample 1, Asian participants (n = 97) demonstrated a significantly smaller mean differential SCR compared to White participants (n = 86). No other between group differences were observed. In sample 2, there was no difference in mean differential SCR between Asian (n = 52) and White (n = 62) participants, although more Asian participants failed to show adequate skin conductance levels for study entry. To our knowledge, this is the first study to evaluate differences between Asian and White samples using skin conductance outcomes in a fear conditioning paradigm. We detected only subtle evidence for SCR differences between Asian and White samples, unlikely to reach significance outside large studies.

292 Fibromyalgianess and Glucocorticoid Persistence Among Patients with Rheumatoid Arthritis

OBJECTIVES/GOALS: Over 30% of patients with rheumatoid arthritis (RA) exhibit fibromyalgianess, a symptom cluster associated with increased pain sensitivity. Up to half of RA patients use oral glucocorticoids (GCs) long-term despite their known, dose-dependent toxicity. We examined the association between fibromyalgianess and oral GC persistence in RA patients. METHODS/STUDY POPULATION: We used data from the Central Pain in Rheumatoid Arthritis (CPIRA) cohort to follow participants with active RA on oral prednisone who initiated a new disease-modifying anti-rheumatic drug. We measured fibromyalgianess using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key fibromyalgia features often superimposed upon RA. We stratified fibromyalgianess severity as follows: FSQ&lt;8 low, 8-10 moderate, &gt;10 high/very high. We defined GC persistence as GC use at 3 month followup visit. We assessed the association between baseline fibromyalgianess (exposure) and GC persistence at followup (outcome) using multiple logistic regression, adjusted for demographics, RA duration, serostatus, and inflammatory activity measured by swollen joint count and C reactive protein. RESULTS/ANTICIPATED RESULTS: Of 97 participants on prednisone at baseline, 65% were taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent GC use, compared to 84% with high or very high fibromyalgianess. After adjustment as outlined above, participants with high/very high baseline fibromyalgianess remained more likely to be on prednisone at follow-up, relative to those with low fibromyalgianess (OR 4.99 [95% CI 1.20 – 20.73]). DISCUSSION/SIGNIFICANCE: In this cohort of patients with active RA, high fibromyalgianess is associated with persistent GC use, independent of inflammatory activity. This finding suggests non-inflammatory pain related to fibromyalgianess may be misclassified as inflammatory pain related to RA disease activity.

Opioid abuse and perioperative care: a new medical disease.

This review article aims to describe the perioperative clinical implications of opioid use or opioid use disorder (OUD) and to provide recommendations related to analgesia, anesthesia, and postoperative care for patients with this 'new medical disease'. Evidence suggest that 1 in 4 surgical patients will be using opioids preoperatively. Management of these patients, or those with OUD, can be challenging given their opioid tolerance, hyperalgesia, decreased pain tolerance, and increased pain sensitivity. Therefore, an individualized plan that considers how to manage OUD treatment medications, the risk of relapse, multimodal analgesia, and postoperative monitoring requirements is highly important. Fortunately, recent publications provide both insight and guidance on these topics. Postoperatively, persistent opioid utilization appears higher in patients currently using opioids and even for those with a prior history. Although numerous other adverse outcomes are also associated with opioid use or abuse, some may be modifiable with cessation. A coordinated, evidence-based, multidisciplinary team approach is critical when caring for patients with OUD to ensure safety, provide adequate analgesia, and reduce the risk of relapse. Enhanced postoperative monitoring, multimodal analgesia, and a plan for preoperative opioid management may help to modify the risks of adverse postoperative outcomes.

Contextual control of conditioned pain tolerance and endogenous analgesic systems.

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment. To answer this question, we conditioned mice to associate distinct contexts with either repeated administration of a mild visceral pain stimulus (intraperitoneal injection of acetic acid) or vehicle injection over the course of 3 days. On the final day of experiments, animals received either an acid injection or vehicle injection prior to being placed into both contexts. In this way, contextual control of pain sensitivity and pain expectation could be tested respectively. When re-exposed to the noxious stimulus in a familiar environment, both male and female mice exhibited context-dependent conditioned analgesia, a phenomenon mediated by endogenous opioid signaling. However, when expecting the presentation of a painful stimulus in a given context, males exhibited conditioned hypersensitivity whereas females exhibited endogenous opioid-mediated conditioned analgesia. These results are evidence that pain perception and engagement of endogenous opioid systems can be modified through their psychological association with environmental cues. Successful determination of the brain circuits involved in this sexually dimorphic anticipatory response may allow for the manipulation of pain memories, which may contribute to the development of chronic pain states.

Characteristics of clusters with contrasting relationships between central sensitization-related symptoms and pain

The central sensitization inventory (CSI) evaluates the central sensitization (CS)-related symptoms associated with increased pain sensitivity. However, the CSI includes items that are not directly related to pain. In this study, 146 patients with pain were classified into subgroups by k-means cluster analysis based on the short form of the central sensitization inventory (CSI9) and pain scores. In addition, inter-group and multiple comparisons were performed to examine the characteristics of each group. As a result of this study, there were three subgroups (clusters 1, 2, and 3) in which the CSI9 and pain intensity were both low, moderate, and high, and one subgroup (cluster 4) in which only CSI9 was high and pain intensity was low. Two subgroups with high CSI9 scores but contrasting pain intensities (clusters 3 and 4) were extracted; the pattern of CS-related symptoms in these two groups was very similar, with no differences in most of the non-pain factors. It is necessary to consider these points when interpreting the clinical condition of a patient with pain when using the assessment of CS-related symptoms.

Use of virtual reality in managing paediatric procedural pain and anxiety: An integrative literature review.

This integrative review aimed to identify, analyse and synthesise studies investigating the clinical efficacy of virtual reality (VR) distraction for children undergoing varying painful and anxiety-inducing medical procedures across different hospital settings and to identify implications for research and clinical practice. Virtual reality has been leveraged as a distraction tool in the healthcare setting to help patients manage procedural pain and anxiety. Initial studies in the burn wound care setting using VR as a non-pharmacological analgesia led to the use of VR during other medical procedures. An integrative review of the literature was conducted following the PRISMA guidelines across four electronic databases. Published studies between 2000 and 2020 investigating the clinical efficacy of VR in managing paediatric procedural pain or anxiety were included for review. Reviewed studies collectively included 2,174 patients aged 6months-18years used VR during burn wound care, post-burn physiotherapy, dental, needle-related and other procedures. Additionally, ten studies included samples with adults, for which paediatric data could not be isolated (n=507). Overall, studies supported the efficacy of VR in managing procedural pain and anxiety in the paediatric setting. Virtual reality is redefining pain management by immersing children in a virtual world, reducing pain and anxiety at the hospital. A notable gap was the neglected use of VR in children with chronic conditions receiving orthopaedic procedures as part of their standard care. Ultimately, VR distraction will reduce the fear associated with medical interventions, preventing increased pain sensitivity, exacerbated anxiety and healthcare avoidance in adulthood. Nurses will play an important role in ensuring the smooth integration of VR in clinical practice by championing the technology and transferring evidence-based methods for VR use.

Curcumin induces peripheral antinociception by opioidergic and cannabinoidergic mechanism: Pharmacological evidence

BackgroundCurcumin is one of the compounds present in plants of the genus Curcuma sp., being very used not only as condiment but also with medicinal purposes. As an analgesic, papers highlight the efficacy of curcumin in the treatment of various types of pain. AimsIn this study we evaluated the peripheral antinociceptive effect of curcumin and by which mechanisms this effect is induced. Main methodsThe mice paw pressure test was used on animals which had increased pain sensitivity by intraplantar injection of carrageenan. All the drugs were administered in the right hind paw. Key findingsCurcumin was administered to the right hind paw animals induced antinociceptive effect. Non -selective antagonist of opioid receptors naloxone reverted the antinociceptive effect induced by curcumin. Selective antagonists for μ, δ and κ opioid receptors clocinnamox, naltrindole and nor- binaltorphimine, respectively, reverted the antinociceptive effect induced by curcumin. Bestatin, enkephalinases inhibitor that degrade peptides opioids, did not change the nociceptive response. Selective antagonists for CB1 and CB2 cannabinoid receptors, AM251 and AM630, respectively, reversed the antinociceptive effect induced by curcumin. The MAFP inhibitor of the enzyme FAAH which breaks down anandamide, JZL184, enzyme inhibitor MAGL which breaks down the 2-AG, as well as the VDM11 anandamide reuptake inhibitor potentiated the antinociceptive effect of curcumin. SignificanceThese results suggest that curcumin possibly peripheral antinociception induced by opioid and cannabinoid systems activation and possibly for endocannabinoids and opioids release.

Different genes may be involved in distal and local sensitization: A genome-wide gene-based association study and meta-analysis.

BackgroundNeuropathic pain symptoms and signs of increased pain sensitization in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitization and neuropathic‐like pain phenotypes could be clinically important in identifying targets for early intervention.MethodsWe performed a genome‐wide gene‐based association study (GWGAS) using pressure pain detection thresholds (PPTs) from distal pain‐free sites (anterior tibia), a measure of distal sensitization, and from proximal pain‐affected sites (lateral joint line), a measure of local sensitization, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene‐based fixed‐effects meta‐analysis of PPTs and a neuropathic‐like pain phenotype using genome‐wide association study (GWAS) data from KPIC and from an independent cohort of 613 post‐TJR participants, respectively.ResultsThe most significant genes associated with distal and local sensitization were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain‐associated genes—KCNA1, MTOR, ADORA1 and SCN3B—associated with PPT at the anterior tibia and an inflammatory pain gene—PTAFR—associated with PPT at the lateral joint line. Meta‐analysis results of anterior tibia and neuropathic‐like pain phenotypes revealed genes associated with bone morphogenesis, neuro‐inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function.ConclusionsOverall, our results suggest that different biological processes might be involved in distal and local sensitization, and common genetic mechanisms might be implicated in distal sensitization and neuropathic‐like pain. Future studies are needed to replicate these findings.SignificanceTo the best of our knowledge, this is the first GWAS for pain sensitization and the first gene‐based meta‐analysis of pain sensitization and neuropathic‐like pain. Higher pain sensitization and neuropathic pain symptoms are associated with persistent pain after surgery hence, identifying genetic biomarkers and molecular pathways associated with these traits is clinically relevant.

Boric acid improves the behavioral, electrophysiological and histological parameters of cisplatin-induced peripheral neuropathy in rats

Boric acid (BA) has been used in many diseases because it increases the amount of reduced glutathione in the body and reduces oxidative damage. This study aims to investigate the effects of boric acid in cisplatin-induced neuropathy, in which oxidative stress is also effective in its pathophysiology.In this study, 8–10 weeks old, 170−190 g Wistar Albino rats were used. Each group contained seven rats (n = 35). Experimental groups consist of control, sham, neuropathy, treatment, and boric acid groups. For the neuropathy model, a single dose of cisplatin (3 mg/kg, i.p) was administered once a week for five weeks, and for the treatment group, boric acid was administered daily (100 mg/kg, intragastric) for five weeks. After drug administration, the rotarod test to evaluate motor performance, the tail-flick and hot/cold plate tests to evaluate sensory conduction states, the von Frey filament test to evaluate the mechanical allodynia, and the adhesive removal test to assess sensorimotor function were performed. The sciatic nerve's motoric conduction velocity was also assessed electrophysiologically. Oxidative stress parameters were also assessed biochemically in sciatic nerve tissue and serum. Hematoxylin and eosin staining was used to evaluate the sciatic nerve tissue histopathologically.The motor conduction velocity of the sciatic nerve, impaired by cisplatin, was increased considerably by boric acid (p < 0.05). It also reduced the latency time of the compound muscle action potential (CMAP), which was increased by cisplatin. (p < 0.05). The von Frey filament test results demonstrated increased pain sensitivity of the cisplatin group increased, and mechanical allodynia was observed. Boric acid significantly alleviated this condition (p < 0.05). In the cold plate, adhesive removal, and rotarod tests, boric acid attenuated the adverse effects of cisplatin (p < 0.05). Biochemically, BA reduced the level of MDA, which was raised by cisplatin, and significantly increased the level of SOD, which was lowered by cisplatin (p < 0.05). Histopathologically; BA reduced neuronal degeneration and vacuolization caused by cisplatin.As a consequence, it has been determined that boric acid alleviates the adverse effects of cisplatin. BA reduced the destructive effect of cisplatin by reducing oxidative stress, and this effect was verified electrophysiologically, behaviorally, and histopathologically.