Changes In Pain Sensitivity Research Articles

Epigenetic modifications associated to diabetic peripheral neuropathic pain (Review).

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

The Relationship Between Age and The Incidence of Post Dural Puncture Headache in Post Sectio Caesarea Patients with Spinal Anesthesia

Background: Caesarean Section (CS) is a surgical procedure involving incisions in the abdominal wall and uterus. Spinal anesthesia is the preferred method due to the lower maternal morbidity and mortality risks compared to general anesthesia. However, the most common complication associated with spinal anesthesia is Post Dural Puncture Headache (PDPH), caused by a dural puncture. Age is a significant factor influencing PDPH occurrence. Patients aged 20-40 are at a higher risk, while those over 50 years have a reduced risk due to the decrease in cranial elasticity and pain sensitivity with age. Purpose: This study aims to assess the correlation between age and the incidence of PDPH following spinal anesthesia in CS patients. Methods: This study employed a cross-sectional analytic correlation design. The sample included all CS patients who received spinal anesthesia and met the study criteria, totaling 35 respondents. Data were analyzed using univariate and bivariate analysis, with the correlation significance tested at 0.05 (2-tailed). Findings: The study revealed that 14.3% of respondents experienced PDPH, while 85.7% did not. A significant correlation was found between age and PDPH incidence, with a p-value of 0.05. The highest incidence of PDPH was observed in the 20-40 age group, decreasing notably in individuals aged 50 and above. Conclusion: This study highlights that PDPH risk is highest in patients aged 20-40 and significantly decreases in patients older than 50. Age-related changes in cranial structure and pain sensitivity likely contribute to this decreased risk.

The Efficacy of Ketogenic Diets (Low Carbohydrate; High Fat) as a Potential Nutritional Intervention for Lipedema: A Systematic Review and Meta-Analysis.

Lipedema is a frequently misdiagnosed condition in women, often mistaken for obesity, which significantly deteriorates both quality of life and physical health. Recognizing the necessity for holistic treatment strategies, research has increasingly supported the integration of specific dietary approaches, particularly ketogenic diets focusing on low-carbohydrate and high-fat intake. to evaluate the impact of ketogenic diets on women with lipedema through a systematic review and meta-analysis. A systematic review and meta-analysis were conducted by reviewing published, peer-reviewed studies addressing the implications of a low-carbohydrate, high-fat (LCHF) ketogenic diet in managing lipedema following comprehensive scrutiny of digital medical databases, such as PubMed, PubMed Central, Science Direct, and the Web of Science. This research was governed by specified parameters, including an established search string composed of search terms and an eligibility criterion (PICO) as denoted by the principal authors. Statistical analysis was carried out using RevMan 5.4.1 software with the Newcastle-Ottawa Scale utilized for quality appraisal of the included studies. Seven studies reporting statistical outcomes were included in the systematic review and meta-analysis following a rigorous quality appraisal and data identification process. Three hundred and twenty-nine female participants were diagnosed with lipedema and treated using a low-carbohydrate, high-fat diet. Data analysis identified the high-fat diet with a mean study duration of 15.85 weeks. Mean Differences (MDs) on changes pre- and post-intervention showed significant reductions in BMI and total body weight [4.23 (95% CI 2.49, 5.97) p < 0.00001 and 7.94 (95% CI 5.45, 10.43) p < 0.00001 for BMI and body weight, respectively]. Other anthropometric measurements, such as changes in waist/hip circumferences and waist/hip ratios, showed a significant reduction in these parameters, with an MD of 8.05 (95% CI 4.66, 11.44) p < 0.00001 and an MD of 6.67 (95% CI 3.35, 9.99) p < 0.0001 for changes in waist and hip circumferences from baseline, respectively. Lastly, changes in pain sensitivity were statistically significant post-intervention [MD 1.12 (95% CI, 0.44, 1.79) p = 0.001]. All studies scored fair on the Newcastle-Ottawa Scale. despite the limited studies and low number of study participants, the review observed a significant reduction in anthropometric and body composition metrics, indicating a potentially beneficial association between LCHF ketogenic diets and lipedema management.

Pressure Pain Hyperalgesia Expressed by Topographical Pressure Pain Sensitivity after Cardiac Surgery.

We aim to evaluate changes in pressure pain sensitivity before and after cardiac surgery using topographical sensitivity maps utilizing a pressure algometer. Pressure pain thresholds over 17 thoracic points and 4 distant pain-free points were assessed in 70 patients (women: 29, age: 67.5 years), before and at 1, 3, and 7 postoperative days. Thoracic topographical pressure pain sensitivity maps were calculated at all follow-ups. Postoperative pain was recorded at each follow-up on a numerical pain rate scale. Postoperative pain intensity decreased from 6.4 (SD 1.0) on the first postoperative day to 5.5 (SD 1.9) on the third and to 4.5 (SD 1.7) on the seventh day (p < 0.001). The mixed-model ANOVA revealed that the lowest pressure pain thresholds were observed one day after surgery, increased slightly during follow-up, and were lower at the xiphoid process. Significant negative correlations between postoperative pain intensity and pressure pain thresholds were observed at each time point in thoracic measures (all, p < 0.01), but not with pressure pain thresholds from distant pain-free areas. Postoperative pain after cardiac surgery can be objectively quantified using algometry. Pressure pain hyperalgesia was associated with the intensity of postoperative pain.

Determinants of perceived pain relief from acute alcohol intake in a laboratory setting

BackgroundStudies of alcohol analgesia often assume that changes in pain sensitivity reflect the negative reinforcing effects of alcohol in pain self-management. However, factors that may influence perceived pain relief due to alcohol use remain incompletely characterized. Thus, the primary aim of this study was to identify which factors are most strongly related to self-reported pain relief in individuals with and without chronic pain after alcohol consumption. MethodsThis study combined data from two studies of alcohol analgesia in individuals who regularly consume alcohol with and without chronic pain. Alcohol analgesia expectancies were assessed during screening. In laboratory sessions, participants received an alcohol-containing (.08g/dL target BrAC) or placebo beverage and rated subjective intoxication and subjective response (positive/negative aspects of stimulation/sedation). Participants underwent quantitative sensory testing to measure pain intensity, pain threshold, and relief. Paired sample t-tests determined effects of alcohol on pain measures. Hierarchical linear models determined factors associated with pain relief ratings in the alcohol condition. ResultsPain relief and pain threshold were higher in the alcohol session relative to placebo, but pain intensity did not differ. In a 4-step hierarchical linear model, expectancy of pain relief, subjective intoxication, and high positive affect, but not pain threshold or pain intensity, were significantly and uniquely associated with perceived relief. ConclusionsTaken together, results suggest the negative-reinforcing effects of alcohol for pain-management are not completely reflected by changes in pain sensitivity in a laboratory setting. Expectancies and subjective response may be important in determining an individual’s evaluation of alcohol’s efficacy for pain self-management.

Features of pain sensitivity during premedication with xenon in patients before outpatient dental interventions

BACKGROUND: Premedication in outpatient dental interventions normalizes pain sensitivity and emotional state of patients. Inhalation of xenon-oxygen mixture can be an effective means for it. AIM: To study the effect of xenon premedication on pain sensitivity in patients with outpatient dental interventions. MATERIALS AND METHODS: Twenty patients were studied. Emotional and personal characteristics of patients were determined using the Eysenck test, Spielberger–Khanin personal anxiety scale, and hospital scale of anxiety and depression. Pain sensitivity was assessed using pain thresholds and somatosensory evoked potentials of the brain before and after inhalation of xenon-oxygen mixture at a concentration of 30/70 for 3 minutes. RESULTS: According to the results of psychological testing, all examined patients were characterized by a stable psychological sphere and predominantly lowered anxiety and constituted a group with insignificantly different emotional and personal characteristics. Before inhalation, pain sensitivity in patients varied significantly. After inhalation, multidirectional changes in pain sensitivity occurred, which were expressed in a decrease and an increase in pain sensitivity thresholds and the degree of activation of brain structures. CONCLUSION: Preoperative stress can both exacerbate and reduce pain sensitivity in patients. The use of inhalation of a xenon-oxygen mixture at a concentration of 30/70 for 3 minutes as a premedication causes multidirectional changes in the sensitivity of tissues and organs in the maxillofacial region in patients before outpatient dental interventions, which may be caused by a change in the activity of endogenous antinociceptive (analgesic) system.

Widespread Pressure Pain Hyperalgesia Is Not Associated With Morphological Changes of the Wrist Extensor Tendon in Unilateral Lateral Epicondylalgia: A Case-Control Study.

The aims of the current study were to investigate the presence of widespread pressure hyperalgesia, the presence of structural changes in the wrist extensor tendon and muscle, and their association in people with lateral epicondylalgia (LE). Thirty-seven patients with LE (43% women; mean age = 45.5 [SD = 9.5] years) and 37 controls matched for age and sex and free of pain participated in this study. Pressure pain thresholds (PPTs) were assessed bilaterally over the symptomatic area (elbow), 2 segment-related areas (C5-C6 joint, second intermetacarpal space), and 1 remote area (tibialis anterior) in a blinded design. Ultrasound measurements (eg, cross-sectional area, thickness, and width) of the common wrist extensor tendon and extensor carpi radialis brevis muscle as well as the thickness of the supinator muscle were assessed. Patients with LE exhibited lower PPTs bilaterally at all points and lower PPTs at the lateral epicondyle and second intermetacarpal space on the symptomatic side as compared to the nonsymptomatic side (η2 from 0.123-0.369; large effects). Patients exhibited higher cross-sectional area and width of the common wrist extensor tendon (η2 from 0.268-0.311; large effects) than controls bilaterally, whereas tendon thickness was also higher (η2 = 0.039; small effects) on the painful side than on the nonpainful side. This study reported bilateral widespread pressure pain hyperalgesia and morphological changes in the tendon, but not the muscle, in LE. Pressure pain sensitivity and morphological changes were not associated in individuals with LE. Management of LE should consider altered nociceptive pain processing and structural tendon changes as 2 different phenomena in patients with LE.

The effects of neck exercise in comparison to passive or no intervention on quantitative sensory testing measurements in adults with chronic neck pain: A systematic review.

Previous systematic reviews have identified the benefits of exercise for chronic neck pain on subjective reports of pain, but not with objective measures such as quantitative sensory testing (QST). A systematic review was conducted to identify the effects of neck specific exercise on QST measures in adults with chronic neck pain to synthesise existing literature and provide clinical recommendations. The study protocol was registered prospectively with PROSPERO (PROSPERO CRD42021297383). For both randomised and non-randomised trials, the following databases and trial registries were searched: AMED, CINAHL, Embase, Google Scholar, Medline, PEDro, PubMed, Scopus, SPORTDiscus, Science Citation Index and Social Science Citation Index from Web of Science Core Collection, clinicaltrials.gov, GreyOpen, and ISRCTN registry. These searches were conducted from inception to February 2022 and were updated until September 2023. Reference lists of eligible studies were screened. Study selection was performed independently by two reviewers, with data extraction and quality appraisal completed by one reviewer and independently ratified by a second reviewer. Due to high heterogeneity, narrative synthesis was performed with results grouped by exercise type. Three trials were included. Risk of bias was rated as moderate and the certainty of evidence as low or moderate for all studies. All exercise groups demonstrated statistically significant improvement at an intermediate-term follow-up, with progressive resistance training combined with graded physical training demonstrating the highest certainty of evidence. Fixed resistance training demonstrated statistically significant improvement in QST measures at a short-term assessment. Fixed resistance training is effective for short-term changes in pain sensitivity based on low-quality evidence, whilst moderate-quality evidence supports progressive resistance training combined with graded physical training for intermediate-term changes in pain sensitivity.

To allow or avoid pain during shoulder rehabilitation exercises for patients with chronic rotator cuff tendinopathy-Study protocol for a randomized controlled trial (the PASE trial)

BackgroundRotator cuff (RC) tendinopathy is the most reported shoulder disorder in the general population with highest prevalence in overhead athletes and adult working-age population. A growing body of evidence support exercise therapy as an effective intervention, but to date there are no prospective randomized controlled trials addressing pain as an intervention variable.MethodsA single-site, prospective, pragmatic, assessor-blinded randomized controlled superiority trial. Eighty-four patients aged 18–55 years with chronic (symptom duration over 3 months) RC tendinopathy are randomized 1:1 to receive shoulder exercise during which pain is either allowed or avoided. The intervention period lasts 26 weeks. During that period, participants in both groups are offered 8 individual on-site sessions with an assigned sports physiotherapist. Participants perform home exercises and are provided with a pain and exercise logbook and asked to report completed home-based exercise sessions and reasons for not completing sessions (pain or other reasons). Patients are also asked to report load and the number of sets and repetitions per sets for each exercise session. The logbooks are collected continuously throughout the intervention period. The primary and secondary outcomes are obtained at baseline, 6 weeks, 26 weeks, and 1 year after baseline. The primary outcome is patient-reported pain and disability using the Shoulder PAin and Disability Index (SPADI). Secondary outcomes are patient-reported pain and disability using Disability Arm Shoulder and Hand short-form (Quick DASH), and shoulder pain using Numeric Pain Rating Scale. Objective outcomes are shoulder range of motion, isometric shoulder muscle strength, pain sensitivity, working ability, and structural changes in the supraspinatus tendon and muscle using ultrasound.DiscussionThe results of this study will contribute knowledge about the treatment strategies for patients with RC tendinopathy and help physiotherapists in clinical decision-making. This is the first randomized controlled trial comparing the effects of allowing pain versus avoiding pain during shoulder exercises in patients with chronic RC tendinopathy. If tolerating pain during and after exercise proves to be effective, it will potentially expand our understanding of “exercising into pain” for this patient group, as there is currently no consensus.Trial registrationClinicalTrials.gov NCT05124769. Registered on August 11, 2021.

Agomelatine alleviates pain-related behaviour in ovariectomized rats

Aim: Menopause is a physiological process that results in the cessation of ovarian follicle activity. Research suggests that postmenopausal women may experience changes in pain sensitivity. Ovariectomized (Ovx) rats are commonly used to mimic postmenopausal pain symptoms in research. Agomelatine is a unique antidepressant that acts as both a melatonergic receptor agonist and a 5-HT2C receptor antagonist. Preclinical studies have suggested potential analgesic effects associated with Agomelatine. This study aims to investigate the influence of agomelatine on pain behavior in Ovx rats. Materials and Methods: Forty female Sprague Dawley rats were divided into four groups: Sham, Ovx, Ago20 and Ago40. The Ovx, Ago20 and Ago40 groups underwent bilateral ovariectomy, while the Sham group underwent all surgical procedures except ovarian ligation. After four months, the Sham and Ovx groups received vehicle, while the Ago20 (20mg/kg) and Ago40 (40mg/kg) groups received agomelatine by oral gavage for two months. Pain sensitivity assessments were conducted using electronic von Frey, hot plate, tail flick, and tail immersion methods after the final drug administration. Results: In the Ovx group, there was an increase in pain sensitivity observed in the hot plate, electronic von Frey, tail flick, and tail immersion tests (p &lt; 0.05). Agomelatine treatment significantly reduced the heightened nociceptive response (p &lt; 0.05). Conclusion: Agomelatine effectively attenuates the increased sensitivity to pain observed in Ovx rats.

Examining Changes in Pain Sensitivity Following 8 Minutes of Cycling at Varying Exercise Intensities

Examining Changes in Pain Sensitivity Following 8 Minutes of Cycling at Varying Exercise Intensities

Physiological and clinical effects of low-intensity blood-flow restricted resistance exercise compared to standard rehabilitation in adults with knee osteoarthritis–Protocol for a randomized controlled trial

Introduction Osteoarthritis (OA) is a common disease with high socioeconomical costs. In Denmark, standard rehabilitation (SR) consists of a combination of patient education and supervised physical exercise involving a standardized neuromuscular training program. As an evidence-based alternative, high–load (&gt;70% 1RM) resistance training (HIRT) has shown positive rehabilitation effects in knee-OA but may not be tolerated in all patients (~25%) due to knee joint pain. However, low-load resistance training (20–40% 1RM) with concurrent partial blood-flow restriction (BFR) appears to produce effects similar to HIRT yet involving reduced joint pain during and after exercise. The aim is to examine the effect of low-load BFR training compared to SR on pain, thigh muscle mass and muscle function in adults with knee-OA. We hypothesize that 12 weeks of BFR will lead to superior improvements in pain, muscle mass and mechanical muscle function compared to SR. Methods and analysis 90 participants diagnosed with radiographic knee-OA will be randomized to either BFR or SR twice a week for 12 weeks. BFR will consist of two selected lower limb strength exercises performed with an inflated pneumatic occlusion cuff. Intervention procedures in SR consist of a full 8 weeks GLA:D course followed by 4 weeks of team group training. Primary outcome variable is the change in KOOS-Pain subscale from baseline to 12 weeks. Secondary outcome variables are changes in pain sensitivity, functional performance, muscle mass and mechanical muscle function. Intention-to-treat and per-protocol analyses will be conducted. One-way analysis of variance will be performed to evaluate between-group changes. Pre-to-post intervention comparisons will be analyzed using a mixed linear model. Regression analysis will be performed to evaluate potential associations between selected outcome variables.

Diurnal Pain Classification in Critically Ill Patients using Machine Learning on Accelerometry and Analgesic Data.

Quantifying pain in patients admitted to intensive care units (ICUs) is challenging due to the increased prevalence of communication barriers in this patient population. Previous research has posited a positive correlation between pain and physical activity in critically ill patients. In this study, we advance this hypothesis by building machine learning classifiers to examine the ability of accelerometer data collected from daily wearables to predict self-reported pain levels experienced by patients in the ICU. We trained multiple Machine Learning (ML) models, including Logistic Regression, CatBoost, and XG-Boost, on statistical features extracted from the accelerometer data combined with previous pain measurements and patient demographics. Following previous studies that showed a change in pain sensitivity in ICU patients at night, we performed the task of pain classification separately for daytime and nighttime pain reports. In the pain versus no-pain classification setting, logistic regression gave the best classifier in daytime (AUC: 0.72, F1-score: 0.72), and CatBoost gave the best classifier at nighttime (AUC: 0.82, F1-score: 0.82). Performance of logistic regression dropped to 0.61 AUC, 0.62 F1-score (mild vs. moderate pain, nighttime), and CatBoost's performance was similarly affected with 0.61 AUC, 0.60 F1-score (moderate vs. severe pain, daytime). The inclusion of analgesic information benefited the classification between moderate and severe pain. SHAP analysis was conducted to find the most significant features in each setting. It assigned the highest importance to accelerometer-related features on all evaluated settings but also showed the contribution of the other features such as age and medications in specific contexts. In conclusion, accelerometer data combined with patient demographics and previous pain measurements can be used to screen painful from painless episodes in the ICU and can be combined with analgesic information to provide moderate classification between painful episodes of different severities.

Pressure pain sensitivity, thermographic changes, function, life and sleep quality in patients with unilateral rotator cuff injury: A case-control study

Introduction-AimThis study aimed to assess pressure pain sensitivity, thermographic changes, functional status, quality of life, and sleep in individuals with unilateral shoulder pain due to rotator cuff tear and compare these parameters with the unaffected side and asymptomatic individuals. Material-methodThirty-two patients with unilateral rotator cuff injury and 32 volunteers without shoulder problems were included. Pain was evaluated using a visual analogue scale, pressure pain sensitivity with a digital algometer, thermographic changes with a thermal camera, upper extremity function through the Disabilities of the Arm, Shoulder, and Hand Disability Questionnaire, sleep quality using the Pittsburgh Sleep Quality Index, and quality of life using SF-36. ResultsPressure pain sensitivity of the deltoideus, supraspinatus, and subscapularis muscles in the affected limb was lower than in the unaffected limb (p = 0.027, p = 0.005, p < 0.001). Conversely, pressure sensitivity of the deltoideus, biceps brachii, and subscapularis muscles was higher in the patient group (p = 0.008, p = 0.042, p < 0.001). Furthermore, a decrease in temperature was observed in all patients, except for the trapezius muscles of the affected side (p < 0.05). ConclusionThis study sheds light on altered pressure pain sensitivity and thermographic changes in individuals with unilateral shoulder pain due to rotator cuff tear. Additionally, the study highlights impairments in functional status, quality of life, and sleep in these individuals, emphasizing the broader impact of such injuries. Targeted interventions based on these findings have the potential to enhance overall well-being and functional outcomes for affected individuals. Level of evidenceLevel III, Case-control study, prognosis study.

Employing the sustained-release properties of poly(lactic-co-glycolic acid) nanoparticles to reveal a novel mechanism of sodium-hydrogen exchanger 1 in neuropathic pain

Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain.

Комплексный миофасциальный болевой синдром

Myofascial pain syndrome is one of the most common manifestations of musculoskeletal pain, and it is manifested not only by the pain syndrome but also by localized highly sensitive areas of pain sensitivity changes. Clinical manifestations of isolated trigger zones have been described in the literature. However, in practice, one has to deal with the myofascial pain syndrome caused by multiple trigger zones in the muscles of one or several neighboring regions. In this case, pain patterns overlap and change the clinical picture and, in some cases, lead to misdiagnosis. In order to illustrate such a course of the myofascial pain syndrome, the article presents a clinical case. As a matter of discussion, it is suggested to designate myofascial pain syndrome with multiple active trigger zones in several muscles with interference ofthe referred pain zones as “complex myofascial pain syndrome”.

Toxicological Evaluation and Pain Assessment of Four Minor Cannabinoids Following 14-Day Oral Administration in Rats.

Introduction: Despite growing consumer interest and market availability, the safety of minor cannabinoids, generally present in low concentrations in Cannabis sativa L., is not well understood. Materials and Methods: Cannabichromene (CBC; 3.2, 10, 17, 22, 32, or 100 mg/kg-bw/day), cannabinol (CBN; 1, 3.2, 10, 17, 32, or 100 mg/kg-bw/day), delta-8-tetrahydrocannabinol (D8-THC; 0.32, 1, 3.2, or 10 mg/kg-bw/day), tetrahydrocannabivarin (THCV; 3.2, 10, 17, 22, 32, or 100 mg/kg-bw/day), and vehicle (medium-chain triglyceride oil) preparations were administered via oral gavage once daily for 14 days to Sprague Dawley rats. Changes in behavior, body weight, food consumption, clinical pathology, organ weights, body temperature, and thermal pain sensitivity (tail flick assay) were assessed. Select organ tissues were collected at terminal necropsy and fixed for histopathological examination. Results: No treatment-related deaths were observed throughout the study, and cannabinoids were generally well tolerated. While some significant trends in body weight differences from controls (increases and decreases) were observed, these occurred independently of food consumption. Overall, differences in serum chemistry and hematology parameters between cannabinoid groups and their respective control groups were considered to occur due to biological variation among rats. No treatment-related gross abnormalities were observed in examined organs. Significant changes in absolute and relative organ weights occurred primarily in males and were generally of negligible magnitude. There were no biologically significant histopathological observations. While pain tolerance was significantly improved in animals treated with D8-THC (3.2 and 10 mg/kg-bw/day, day 14), results across minor cannabinoids were inconsistent and warrant further study. Conclusion: Minor cannabinoids were well tolerated across 14 days of daily oral administration at the doses assessed. Modest, dose-dependent trends in relative organ weights and serum chemistry parameters warrant exploration at higher oral doses. These data will assist in dose selection for future studies investigating the long-term safety and effects of CBC, CBN, D8-THC, and THCV.

Descending mechanism by which medial prefrontal cortex endocannabinoid signaling controls the development of neuropathic pain and neuronal activity of dorsal root ganglion.

Although regulation of nociceptive processes in the dorsal horn by deep brain structures has long been established, the role of cortical networks in pain regulation is minimally explored. The medial prefrontal cortex (mPFC) is a key brain area in pain processing that receives ascending nociceptive input and exerts top-down control of pain sensation. We have shown critical changes in mPFC synaptic function during neuropathic pain, controlled by endocannabinoid (eCB) signaling. This study tests whether mPFC eCB signaling modulates neuropathic pain through descending control. Intra-mPFC injection of cannabinoid receptor type 1 (CB1R) agonist WIN-55,212-2 (WIN) in the chronic phase transiently alleviates the pain-like behaviors in spared nerve injury (SNI) rats. By contrast, intra-mPFC injection of CB1R antagonist AM4113 in the early phase of neuropathic pain reduces the development of pain-like behaviors in the chronic phase. Spared nerve injury reduced the mechanical threshold to induce action potential firing of dorsal horn wide-dynamic-range neurons, but this was reversed in rats by WIN in the chronic phase of SNI and by mPFC injection of AM4113 in the early phase of SNI. Elevated dorsal root ganglion neuronal activity after injury was also diminished in rats by mPFC injection of AM4113, potentially by reducing antidromic activity and subsequent neuronal inflammation. These findings suggest that depending on the phase of the pain condition, both blocking and activating CB1 receptors in the mPFC can regulate descending control of pain and affect both dorsal horn neurons and peripheral sensory neurons, contributing to changes in pain sensitivity.

Pain sensitivity after Roux-en-Y gastric bypass- associations with chronic abdominal pain and psychosocial aspects.

The aims of this study were to investigate modifications in pain sensitivity after RYGB and to explore associations between pain sensitivity and weight loss, chronic abdominal pain, total body pain, anxiety, depression, and pain catastrophizing. In total, 163 patients with obesity were examined with a cold pressor test for pain sensitivity before and two years after RYGB. Two aspects of pain sensitivity were registered: Pain intensity (numeric rating scale, range 0-10) and pain tolerance (seconds). Associations between pain sensitivity and the explanatory variables were assessed with linear regression. Two years after RYGB the pain intensity increased (mean±SD 0.64±1.9 score units, p<0.001). Pain tolerance decreased (7.2±32.4 s, p=0.005). A larger reduction in body mass index was associated with increased pain intensity, β=-0.090 (95 % CI-0.15 to-0.031, p=0.003), and decreased pain tolerance β=1.1 (95 % CI 0.95 to 2.2, p=0.03). Before surgery, participants with chronic abdominal pain reported 1.2±0.5 higher pain intensity (p=0.02) and had 19.2±9.3 s lower pain tolerance (p=0.04) than those without abdominal pain. No differences in pain sensitivity were observed between participants who did or did not develop chronic abdominal pain after RYGB. Pain sensitivity was associated with symptoms of anxiety but not with pain catastrophizing, depression or bodily pain. The pain sensitivity increased after RYGB and was associated with larger weight loss and anxiety symptoms. Changes in pain sensitivity were not associated with development of chronic abdominal pain after RYGB in our study.

Chronic corticosterone exposure evokes itch hypersensitivity and sexual dysfunction in male rats: Relationship between the two distinct gastrin-releasing peptide systems in the spinal cord

In today’s society, people are subjected to many social stressors, and excessive chronic stress causes functional disruption of the neuroendocrine system and many diseases. Although the exacerbation of atopic dermatitis with symptoms of itching and erectile dysfunction is induced by chronic stress, the details of the mechanisms are unknown. Here, we examined the effects of chronic stress on itch sensation and male sexual function at the behavioral and molecular levels, focusing on two distinct gastrin-releasing peptide (GRP) systems that independently regulate itch transmission, i.e., the somatosensory GRP system, and male sexual function, i.e., the lumbosacral autonomic GRP system, in the spinal cord. In a rat model of chronic stress induced by chronic corticosterone (CORT) administration, we observed increased plasma CORT concentrations, decreased body weight, and increased anxiety-like behavior, similar to that observed in humans. Chronic CORT exposure induced hypersensitivity to itch and increased the Grp mRNA level in the spinal somatosensory system, but there was no change in pain or tactile sensitivity. Antagonists of the somatosensory GRP receptor, an itch-specific mediator, suppressed itch hypersensitivity induced by chronic CORT exposure. In contrast, chronic CORT exposure decreased male sexual behavior, ejaculated semen volume, vesicular gland weight, and plasma testosterone levels. However, there were no effects on the expression of Grp mRNA or protein in the lumbosacral autonomic GRP system, which regulates male sexual function. In summary, chronic stress model rats showed itch hypersensitivity and impaired sexual function in males, and the involvement of the spinal GRP systems was apparent in itch hypersensitivity.