Pain Conditions Research Articles

Biphasic Hormetic-like Effect of Lebecetin, a C-type Lectin of Snake Venom, on Formalin-induced Inflammation in Mice.

Integrins, important extracellular matrix (ECM) receptor proteins, are affected by inflammation and can participate in the maintenance of many painful conditions. Although they are ubiquitous and changeable across all cell types, the roles of these cell adhesion molecules in pathological pain have not been fully explored. We evaluated the effects of the subcutaneous injection of lebecetin, a C-type lectin isolated from Macrovipera lebetina snake venom, previously reported to inhibit α5β1 and αv integrin activity, on different components of inflammation induced by the formalin administration in the hind paw of mice. The formalin-induced nocifensive behavior, edema, and histopathological changes in the hind paw associated with cytokine, iNOS, and COX2 expression, nociceptive-specific neuron activity, and microglial activation analysis in the spinal cord were evaluated in mice receiving vehicle or lebecetin pretreatment. Lebecetin inhibited the nocifensive responses in the formalin test, related edema, and cell infiltration in the injected paw in a biphasic, hormetic-like, and dose-dependent way. According to that hormetic trend, a reduction in pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha and upregulation of the anti-inflammatory cytokine IL-10 in the spinal cord were found with the lowest doses of lebecetin. Moreover, COX2 and iNOS expression in serum and spinal cord followed the same biphasic pattern of cytokines. Finally, nociceptive neurons sensitization and activated microglia were normalized in the dorsal horn of the spinal cord by lebecetin. These findings implicate specific roles of integrins in inflammation and tonic pain, as well as in the related central nervous system sequelae.

Prevalence and burden of pain across the entire spectrum of Huntington’s disease

BackgroundPain is an important symptom in Huntington’s disease (HD), however, not systematically studied and understood. The objective of the current study is to assess the prevalence of pain, pain interference...

Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Translation, cross-cultural adaptation, and measurement properties of the Arabic version of the fear avoidance components scale

Purpose This study aimed to translate, validate, and cross-culturally adapt the original FACS into the Arabic language. Methods The English version of the FACS was translated and culturally adapted into Arabic following international guidelines. The psychometric properties of the final version of the FACS-Arabic (FACS-A) were tested among 119 patients with different musculoskeletal (MSK) pain disorders. Results The Cronbach’s α for the FACS-A was 0.86. The test-retest reliability, measured with intraclass correlation coefficient, was 0.80. The FACS-A showed positive significant correlations with other psychological patient-reported measures, including the pain catastrophizing scale (PCS) (r = 0.545); p ≤ 0.01), Brief Pain Inventory (BPI)-pain score (r = 0.546; p ≤ 0.01), BPI-pain interference score (r = 0.511; p ≤ 0.01), and Hospital Anxiety and Depression Scale (HADS) (r = 0.451, 0.336, respectively; p ≤ 0.01). Confirmatory factor analysis of the FACS-A confirmed the two-factor structure found in the original English version. Conclusion This study determined the FACS-A to be a reliable and valid tool for the assessment of the fear-avoidance beliefs in Arabic-speaking individuals with MSK pain disorders.

Rates and Predictors of Pain Reduction With Intracranial Stimulation for Intractable Pain Disorders.

Intracranial modulation paradigms, namely deep brain stimulation (DBS) and motor cortex stimulation (MCS), have been used to treat intractable pain disorders. However, treatment efficacy remains heterogeneous, and factors associated with pain reduction are not completely understood. We performed an individual patient review of pain outcomes (visual analog scale, quality-of-life measures, complications, pulse generator implant rate, cessation of stimulation) after implantation of DBS or MCS devices. We evaluated 663 patients from 36 study groups and stratified outcomes by pain etiology and implantation targets. Included studies comprised primarily retrospective cohort studies. MCS patients had a similar externalized trial success rate compared with DBS patients (86% vs 81%; P = .16), whereas patients with peripheral pain had a higher trial success rate compared with patients with central pain (88% vs 79%; P = .004). Complication rates were similar for MCS and DBS patients (12% vs 15%; P = .79). Patients with peripheral pain had lower likelihood of device cessation compared with those with central pain (5.7% vs 10%; P = .03). Of all implanted patients, mean pain reduction at last follow-up was 45.8% (95% CI: 40.3-51.2) with a 31.2% (95% CI: 12.4-50.1) improvement in quality of life. No difference was seen between MCS patients (43.8%; 95% CI: 36.7-58.2) and DBS patients (48.6%; 95% CI: 39.2-58) or central (41.5%; 95% CI: 34.8-48.2) and peripheral (46.7%; 95% CI: 38.9-54.5) etiologies. Multivariate analysis identified the anterior cingulate cortex target to be associated with worse pain reduction, while postherpetic neuralgia was a positive prognostic factor. Both DBS and MCS have similar efficacy and complication rates in the treatment of intractable pain. Patients with central pain disorders tended to have lower trial success and higher rates of device cessation. Additional prognostic factors include anterior cingulate cortex targeting and postherpetic neuralgia diagnosis. These findings underscore intracranial neurostimulation as an important modality for treatment of intractable pain disorders.

Impact of neighborhood disadvantage on posttrauma outcomes after sexual assault.

In the United States, 8,000,000 people seek emergency care for traumatic injury annually. Motor vehicle collisions (MVCs) and sexual assault are two common sources of trauma, with evidence that reduced neighborhood-level socioeconomic characteristics increase posttraumatic pain and stress after an MVC. We evaluated whether neighborhood disadvantage was also associated with physical and mental posttrauma outcomes after sexual assault in a sample of adult women (N = 656) who presented for emergency care at facilities in the United States following sexual assault and were followed for 1 year. Neighborhood characteristics were assessed via the Area Deprivation Index, and self-reported pain, anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms were collected at 6 weeks posttrauma. Adjusted log-binomial regression models examined the association between each clinical outcome and neighborhood disadvantage. Women in more disadvantaged neighborhoods were more likely to be non-White and have lower annual incomes. At 6 weeks posttrauma, the prevalence of clinically significant pain, anxiety, and depressive symptoms more than doubled from baseline (41.7% vs.18.8%,62.4% vs.23.9%, and 55.2% vs.22.7%, respectively); 40.7% of women also reported PTSD symptoms. Black, Hispanic, and lower-income participants were more likely to report pre- and postassault pain, anxiety, and depression. After adjusting for race, ethnicity, and income, no significant association existed between neighborhood disadvantage and any outcome, ps =.197 -.859. Although neighborhood disadvantage was not associated with posttrauma outcomes, these findings highlight the need for continued research in diverse populations at high risk of adverse physical and mental health symptoms following sexual assault.

Opioid Use Prior to Adult Spine Deformity Correction Surgery is Associated With Worse Pre- and Postoperative Back Pain and Prolonged Opioid Demands.

Prospective multicenter database post-hoc analysis. Opioids are frequently prescribed for painful spinal conditions to provide pain relief and to allow for functional improvement, both before and after spine surgery. Amidst a current opioid epidemic, it is important for providers to understand the impact of opioid use and its relationship with patient-reported outcomes. The purpose of this study was to evaluate pre-/postoperative opioid consumption surrounding ASD and assess patient-reported pain outcomes in older patients undergoing surgery for spinal deformity. Patients ≥60 years of age from 12 international centers undergoing spinal fusion of at least 5 levels and a minimum 2-year follow-up were included. Patient-reported outcome scores were collected using the Numeric Rating Scale for back and leg pain (NRS-B; NRS-L) at baseline and at 2 years following surgery. Opioid use, defined based on a specific question on case report forms and question 11 from the SRS-22r questionnaire, was assessed at baseline and at 2-year follow-up. Of the 219 patients who met inclusion criteria, 179 (81.7%) had 2-year data on opioid use. The percentages of patients reporting opioid use at baseline (n = 75, 34.2%) and 2 years after surgery (n = 55, 30.7%) were similar (P = .23). However, at last follow-up 39% of baseline opioid users (Opi) were no longer taking opioids, while 14% of initial non-users (No-Opi) reported opioid use. Regional pre- and postoperative opioid use was 5.8% and 7.7% in the Asian population, 58.3% and 53.1% in the European, and 50.5% and 40.2% in North American patients, respectively. Baseline opioid users reported more preoperative back pain than the No-Opi group (7.0 vs 5.7, P = .001), while NRS-Leg pain scores were comparable (4.8 vs 4, P = .159). Similarly, at last follow-up, patients in the Opi group had greater NRS-B scores than Non-Opi patients (3.2 vs 2.3, P = .012), but no differences in NRS-Leg pain scores (2.2 vs 2.4, P = .632) were observed. In this study, almost one-third of surgical ASD patients were consuming opioids both pre- and postoperatively world-wide. There were marked international variations, with patients from Asia having a much lower usage rate, suggesting a cultural influence. Despite both opioid users and nonusers benefitting from surgery, preoperative opioid use was strongly associated with significantly more back pain at baseline that persisted at 2-year follow up, as well as persistent postoperative opioid needs.

Select Minor Cannabinoids from Cannabis sativa are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between labs or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. Significance Statement Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study we evaluated 5 minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that 4 of the 5 minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.

Ultrasound-Guided Off-Plan Lumbar Seated Erector Spinae Plane Blocks : Are There Advantages?

The erector spinae plane block (ESPB) has been widely used as a treatment strategy for a variety of acute and chronic painful conditions. ESPBs are typically performed under ultrasound guidance [USG] in an in-plane long axis approach, targeting the tip of the lumbar transverse process while the patient lies prone. Off-Plane Seated Injection Technique-ESPB [OPSIT-E] represents a useful alternative in situations where a standard prone spine injection would be technically challenged by circumstances which may include morbid obesity, orthopnoea, recent upper limbs surgeries, chest pain from recent pacemaker implant, and in a subjects were in-plane approaches may be complicated by skin lesions. A seated forward flexed off-plane injection position, may also flatten the lumbar lordosis, shift adipose tissue more anteriorly, lessening skin to target distance and facilitating bony landmark identification, in high BMI and hyperlordotic subjects. The relatively larger curved transverse arc radius of the curvilinear probe [GE G1-5] in comparison to its transverse arc, also appears to offer improved central field of skin-transducer contact, earlier needle visualization, improved acute angle trajectory visualization of deep structures, which may be due to less crepuscular beam dispersion in comparison to transverse probe orientation. Even with a linear probe, the orthogonal technique facilitates a more perpendicular vector, lessening needle transit to target distance, which may in turn decrease procedure time, and improve patient comfort. The OPSITE, may also be easier to teach, learn, and master, as other studies have generally reported a higher rate of off-lane injection success among novice vascular interventionists.

Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade

There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

Nociceptors are functionally male or female: from mouse to monkey to man.

The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.

Noise or signal? Spontaneous activity of dorsal horn neurons: patterns and function in health and disease.

Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or "noise" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment.

Introduction. Functional neurosurgery for pain and movement disorders with a special emphasis on spasticity.

Introduction. Functional neurosurgery for pain and movement disorders with a special emphasis on spasticity.

Do Spiritual Well-Being and Pain Intensity Predict Physical or Mental Components of Health-Related Quality-of-Life Scale in Patients With Multiple Myeloma?

BackgroundMultiple myeloma is a complex disease and supportive care is important for improving quality of life. Management of disease treatment symptoms, bone disease, renal dysfunction, infection, anemia, pain, and coagulation disorder are specific issues. Spirituality, or spiritual well-being, is one of the most fundamental and essential concepts for coping with the difficulties and stress caused by cancer. AimsThis study explores whether spiritual well-being, pain, and other demographic factors predict the physical and mental components of quality of life in MM subjects. MethodsThis cross-sectional descriptive study was conducted with 92 multiple myeloma patients registered with the Cancer Warriors Association in Turkey. The data were collected using the Personal Information Form, The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale-12, the Numeric Rating Scale for Pain, and the Short Form-12 Health-Related Quality of Life Scale. ResultsThe mean age of the patients was 54.4 ± 10.7 years. It was found that the mean total pain score in the previous week was 3.9 ± 2.6, while the mean total The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale-12 score was 28.1 ± 9.8. Their mean Short Form-12 total physical component score was 39.1 ± 25.4; whereas the Short Form-12 total mental component score was 45.5 ± 24.8. According to this model, 56.7% of the physical component score was explained by vertebroplasty, The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale-12 total score and subscale of peace and the pain intensity experienced in the previous week. According to multiple linear regression analysis, bone-sparing therapy and FACIT-Sp-12-Total and subscale peace significantly predicted the Mental component score (p < .05). ConclusionsCancer pain remains undertreated, and patients with myeloma are no exception. Pain and spiritual well-being scores were significant predictors of physical and mental component scores of quality of life in this group of patients. According to this result, pain-reducing practices should be implemented to improve the quality of life in MM patients and the spiritual needs of the patients should be met.

Widespread Vascularization and Correlation of Glycosaminoglycan Accumulation to Tendon Pain in Human Plantar Fascia Tendinopathy

Background: Plantar fasciitis is a painful tendinous condition (tendinopathy) with a high prevalence in athletes. While a healthy tendon has limited blood flow, ultrasound has indicated elevated blood flow in tendinopathy, but it is unknown if this is related to a de facto increase in the tendon vasculature. Likewise, an accumulation of glycosaminoglycans (GAGs) is observed in tendinopathy, but its relationship to clinical pain is unknown. Purpose: To explore to what extent vascularization, inflammation, and fat infiltration were present in patients with plantar fasciitis and if they were related to clinical symptoms. Study Design: Descriptive laboratory study. Methods: Biopsy specimens from tendinopathic plantar fascia tissue were obtained per-operatively from both the primary site of tendon pain and tissue swelling (“proximal”) and a region that appeared macroscopically healthy at 1 to 2 cm away from the primary site (“distal”) in 22 patients. Biopsy specimens were examined with immunofluorescence for markers of blood vessels, tissue cell density, fat infiltration, and macrophage level. In addition, pain during the first step in the morning (registered during an earlier study) was correlated with the content of collagen and GAGs in tissue. Results: High vascularization (and cellularity) was present in both the proximal (0.89%) and the distal (0.96%) plantar fascia samples, whereas inconsistent but not significantly different fat infiltration and macrophage levels were observed. The collagen content was similar in the 2 plantar fascia regions, whereas the GAG content was higher in the proximal region (3.2% in proximal and 2.8% in distal; P = .027). The GAG content in the proximal region was positively correlated with the subjective morning pain score in the patients with tendinopathy (n = 17). Conclusion: In patients with plantar fasciitis, marked tissue vascularization was present in both the painful focal region and a neighboring nonsymptomatic area. In contrast, the accumulation of hydrophilic GAGs was greater in the symptomatic region and was positively correlated with increased clinical pain levels in daily life. Clinical Relevance: The accumulation of GAGs in tissue rather than the extent of vascularization appears to be linked with the clinical degree of pain symptoms of the disease.

Evaluating the Potential of Green Light Exposure on Nociception-A Mini Review.

The capacity of animals to react to unpleasant stimuli that might endanger their integrity is known as nociception. Pharmacological treatments do not show satisfactory results in response to nociception. In the recent era, light therapy emerged as a potential non-pharmacological approach for treating various diseases, including seasonal affective disorders, migraine, pain, and others. Evaluating the potential of green light exposure on nociception involves studying its effects on different types of pain and pain-related conditions and determining the optimal exposure methods. This review provides the beneficial effects of green light on the reduction in the frequency of pain. The green light exposure on nociception changes the activity of pain-related genes and proteins in cells. This review could provide insights into the underlying mechanisms by which green light modulates pain. Overall, evaluating the potential of green light exposure on nociception requires a multidisciplinary approach and should consider the safety, efficacy, optimal dose, and duration of green light exposure and the type of pain. However, few studies have been reported so far; therefore, light therapy for treating migraines require more studies on animal models to provide precise results of light effects on nociception.

Development and Evaluation of Celecoxib Emulgel by Using Natural Oil.

Emulgel combines the qualities of an emulsion with those of a gel. In order to create an emulgel w/o or o/w, emulsions have to be formulated, which are then combined with a gelling agent, resulting in a dual-control drug release. Celecoxib exhibits analgesic, antipyretic and anti-inflammatory activities and is used to treat osteoarthritis, severe pain, rheumatoid arthritis, and other medical conditions. Celecoxib Emulgel was developed and evaluated by using natural oil and carbopol-940 as a gelling agent in different concentrations. The screening of various oils, co-surfactants and surfactants was performed to determine the solubility. The essential oils (eucalyptus oil and turpentine oil) were used as penetration modifiers. Studies on compatibility with polymers have been conducted, and the results indicate that there should be no physical or chemical interactions between the polymers and the drug substance. For the preparation of emulgel, various emulsions were prepared with Smix (cosurfactant and surfactant) ratios (1:1, 2:1 and 3:1). The selection of a gelling agent was done by incorporating the selected emulsion system ratio of 1:1 with the combinations of polymers carbapol 940, carbapol 934, and HPMC (0:1:0, 0:0.5:1, 0:0:3, 0.5:0:1, 1:0:0) gel base to make a homogenous emulgel. The emulgel was examined visually to see if it had any phase behaviour, feel, spread-ability, and grittiness by applying its thin layer to a slide. Then, all six formulations of emulgel were prepared with the selected gelling agent. All emulgels were evaluated for pH, physical properties (consistency, homogeneity, colour, texture), drug content, spreadability, extrudability, swelling index, viscosity, stability and centrifugation. A Franz diffusion cell and an egg membrane were used to perform in-vitro drug release. Among all prepared formulations, EG1 had a better release, higher viscosity, higher drug content, and a higher swelling index than the others. The formulation EG1 showed higher drug release (91.25%) within 8 hours.

SIRT1 mediates the excitability of spinal CaMKIIα-positive neurons and participates in neuropathic pain by controlling Nav1.3.

Neuropathic pain is a common chronic pain disorder, which is largely attributed to spinal central sensitization. Calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) activation in the spinal dorsal horn (SDH) is a major contributor to spinal sensitization. However, the exact way that CaMKIIα-positive (CaMKIIα+) neurons in the SDH induce neuropathic pain is still unclear. This study aimed to explore the role of spinal CaMKIIα+ neurons in neuropathic pain caused by chronic constriction injury (CCI) and investigate the potential epigenetic mechanisms involved in CaMKIIα+ neuron activation. CCI-induced neuropathic pain mice model, Sirt1loxP/loxP mice, and chemogenetic virus were used to investigate whether the activation of spinal CaMKIIα+ neurons is involved in neuropathic pain and its involved mechanism. Transcriptome sequence, western blotting, qRT-PCR, and immunofluorescence analysis were performed to assay the expression of related molecules and activation of neurons. Co-immunoprecipitation was used to observe the binding relationship of protein. Chromatin immunoprecipitation (ChIP)-PCR was applied to analyze the acetylation of histone H3 in the Scn3a promoter region. The expression of sodium channel Nav1.3 was increased and the expression of SIRT1 was decreased in the spinal CaMKIIα+ neurons of CCI mice. CaMKIIα neurons became overactive after CCI, and inhibiting their activation relieved CCI-induced pain. Overexpression of SIRT1 reversed the increase of Nav1.3 and alleviated pain, while knockdown of SIRT1 or overexpression of Nav1.3 promoted CaMKIIα+ neuron activation and induced pain. By knocking down spinal SIRT1, the acetylation of histone H3 in the Scn3a (encoding Nav1.3) promoter region was increased, leading to an increased expression of Nav1.3. The findings suggest that an aberrant reduction of spinal SIRT1 after nerve injury epigenetically increases Nav1.3, subsequently activating CaMKIIα+ neurons and causing neuropathic pain.

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia

Abstract Introduction: Patients with chronic pain frequently report cognitive symptoms that affect memory and attention, which are functions attributed to the hippocampus. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysmal attacks of unilateral orofacial pain. Given the stereotypical nature of TN pain and lack of negative symptoms including sensory loss, TN provides a unique model to investigate the hippocampal implications of chronic pain. Recent evidence demonstrated that TN is associated with macrostructural hippocampal abnormalities indicated by reduced subfield volumes; however, there is a paucity in our understanding of hippocampal microstructural abnormalities associated with TN. Objectives: To explore diffusivity metrics within the hippocampus, along with its functional and structural subfields, in patients with TN. Methods: To examine hippocampal microstructure, we utilized diffusion tensor imaging in 31 patients with TN and 21 controls. T1-weighted magnetic resonance images were segmented into hippocampal subfields and registered into diffusion-weighted imaging space. Fractional anisotropy (FA) and mean diffusivity were extracted for hippocampal subfields and longitudinal axis segmentations. Results: Patients with TN demonstrated reduced FA in bilateral whole hippocampi and hippocampal body and contralateral subregions CA2/3 and CA4, indicating microstructural hippocampal abnormalities. Notably, patients with TN showed significant correlation between age and hippocampal FA, while controls did not exhibit this correlation. These effects were driven chiefly by female patients with TN. Conclusion: This study demonstrates that TN is associated with microstructural hippocampal abnormalities, which may precede and potentially be temporally linked to volumetric hippocampal alterations demonstrated previously. These findings provide further evidence for the role of the hippocampus in chronic pain and suggest the potential for targeted interventions to mitigate cognitive symptoms in patients with chronic pain.

Perceived Stress and Life Stressors in Adults with and without Fibromyalgia.

Chronic medical conditions (i.e., chronic widespread pain) may contribute to accelerated/accentuated aging, such that middle-aged individuals with comorbidities may actually show increased declines in physical, cognitive, and mental health compared to normal aging adults. We examined perceived stress, life stressors, and depression in adults with and without fibromyalgia, a chronic pain condition. Ninety-four participants (52% with fibromyalgia, 78% female) aged 50 to 93 were administered the Perceived Stress Scale, Social Readjustment Rating Scale, and Beck Depression Inventory. Hierarchical regression analyses were conducted: the predictor variables were age, gender, fibromyalgia status, depression, and fibromyalgia-depression interaction. The interaction term significantly predicted perceived stress, but not life stressors. Depression significantly predicted stress for Social Readjustment Rating Scale measures after controlling for covariates. Significant associations were found between perceived stress and life stressors in all participants. In addition, those with fibromyalgia were significantly more likely to report higher levels of stress above standardized scores on both the Perceived Stress Scale and the Social Readjustment Rating Scale. Finally, depressive symptoms played a more significant role than fibromyalgia status in predicting life stressors. Conclusions: These findings emphasize the importance of assessing different types of stress and stressors in individuals with chronic widespread pain and/or depression in mid-life and beyond to better treat individuals with these conditions.