Pain Mediators Research Articles

A Structural Model of Cognitive Reactivity and Early Life Experiences with Suicide Resiliency: The Mediation of Psychological Pain

Background: Suicide resiliency has gained increasing attention from researchers because it can serve as a protective factor against suicide, although it has not been thoroughly studied in adolescents. Objectives: This study examined the structural relationship between cognitive reactivity and early life experiences with suicide resiliency, with psychological pain serving as a mediator. Methods: The statistical population for this descriptive-correlational study, utilizing structural equation modeling, included all adolescents aged 15 to 19 years in Lorestan province. A total of 300 high school students were selected through cluster sampling. To collect data, the following tools were used: The Leiden Index of Depression Sensitivity-Revised, the Early Life Experiences Scale (ELES), the Suicide Resilience Inventory (SRI-25), and the Orbach & Mikulincer Mental Pain Scale (OMMP). Structural equation modeling was employed to evaluate the proposed model using AMOS version 24 and SPSS version 26. Results: Correlation results indicated a positive relationship between cognitive reactivity (CR) and early life experiences with psychological pain. Additionally, there was a significant negative relationship between cognitive reactivity, early life experiences, and psychological pain with suicide resiliency. Findings showed that the proposed model adequately fit the data. The results of structural equation modeling revealed that 74% of the variance in psychological pain was explained by CR and early life experiences. Furthermore, 79% of the variance in the Suicide Resilience Inventory (SRI) was explained by CR, early life experiences, and psychological pain. Conclusions: These findings represent a preliminary step toward clarifying the role of cognitive reactivity, early life experiences, and psychological pain in suicide resiliency. These factors should be considered in psychotherapeutic interventions aimed at reducing suicide attempts.

Neurobiological Correlates of Rheumatoid Arthritis and Osteoarthritis: Remodelling and Plasticity of Nociceptive and Autonomic Innervations in Synovial Joints.

Swelling, stiffness, and pain in synovial joints are primary hallmarks of osteoarthritis and rheumatoid arthritis. Hyperactivity of nociceptors and excessive release of inflammatory factors and pain mediators play a crucial role, with emerging data suggesting extensive remodelling and plasticity of joint innervations. Herein, we review structural, functional, and molecular alterations in sensory and autonomic axons wiring arthritic joints and revisit mechanisms implicated in the sensitization of nociceptors, leading to chronic pain. Sprouting and reorganization of sensory and autonomic fibers with the invasion of ectopic branches into surrounding inflamed tissues are associated with the upregulation of pain markers. These changes are frequently complemented by a phenotypic switch of sensory and autonomic profiles and activation of silent axons, inferring homeostatic adjustments and reprogramming of innervations. Identifying critical molecular players and neurobiological mechanisms underpinning the rewiring and sensitization of joints is likely to elucidate causatives of neuroinflammation and chronic pain, assisting in finding new therapeutic targets and opportunities for interventions.

Posterior-superior insula repetitive transcranial magnetic stimulation reduces experimental tonic pain and pain-related cortical inhibition in humans.

High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterior-superior insula (PSI) may produce analgesic effects. However, the alterations in cortical activity during PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended 2 sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10 Hz, 100 pulses per train, 15 trains) ∼50 minutes postcapsaicin administration. Transcranial magnetic stimulation-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found after active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak ∼45 ms (N45) TEP relative to baseline. After active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, after sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain numerical rating scale scores after active vs sham rTMS was correlated with and partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia. This study demonstrates that high-frequency rTMS targeting the posterior-superior insula reduces capsaicin-induced pain and alters cortical activity, with changes in the N45 TMS-evoked potential peak mediating the analgesic effects.

The Impact of Pleasure and Pain on Frequent Substance Use During Receptive Anal Intercourse

ABSTRACT Sexualized drug use (SDU) describes use of any psychoactive substance before or during planned sexual activity to facilitate, intensify, or prolong intercourse. The impact of pain, pleasure, and other mediators on SDU is not well characterized. This study aimed to distinguish the motivations behind different classes and frequencies of substance use during receptive anal intercourse (RAI). Data were from an internet-based survey conducted between July 2022-January 2023. We measured the frequency of SDU for five substances: poppers, alcohol, marijuana, methamphetamine, and nicotine. Satisfaction with pleasurable sensations during RAI and any type of pain bother during RAI were assessed on a 5-point scale. Multivariable logistic regression was performed for 1,119 respondents. Our results showed a strong association between bothersome pain during RAI and frequent alcohol (aOR 2.1), marijuana (aOR 2.4), nicotine (aOR 3.1), and meth (aOR 5.9) use. None of the five substance classes studied was correlated with dissatisfaction with pleasure during RAI. Frequent popper use was associated with increasing lifetime RAI experience and number of sexual partners. The mechanism behind SDU during RAI is substance-specific and multifactorial. Bothersome pain during RAI is highly associated with frequent SDU. Inquiring about pain during RAI may offer avenues for intervention.

Unraveling TRPV1's Role in Cancer: Expression, Modulation, and Therapeutic Opportunities with Capsaicin.

Cancer is a global health challenge with rising incidence and mortality rates, posing significant concerns. The World Health Organization reports cancer as a leading cause of death worldwide, contributing to nearly one in six deaths. Cancer pathogenesis involves disruptions in cellular signaling pathways, resulting in uncontrolled cell growth and metastasis. Among emerging players in cancer biology, Transient Receptor Potential (TRP) channels, notably TRPV1, have garnered attention due to their altered expression in cancer cells and roles in tumorigenesis and progression. TRPV1, also known as the capsaicin receptor, is pivotal in cancer cell death and pain mediation, offering promise as a therapeutic target. Activation of TRPV1 triggers calcium influx and affects cell signaling linked to growth and death. Additionally, TRPV1 is implicated in cancer-induced pain and chemo-sensitivity, with upregulation observed in sensory neurons innervating oral cancers. Also, when capsaicin, a compound from chili peppers, interacts with TRPV1, it elicits a "hot" sensation and influences cancer processes through calcium influx. Understanding TRPV1's multifaceted roles in cancer may lead to novel therapeutic strategies for managing cancer-related symptoms and improving patient outcomes. The current review elucidates the comprehensive role of capsaicin in cancer therapy, particularly through the TRPV1 channel, highlighting its effects in various cells via different signaling pathways and discussing its limitations.

PENGUJIAN AKTIVITAS DAYA ANALGETIK EKSTRAK n-HEKSANA, ETIL ASETAT DAN ETANOL DAUN KANGKUNG PAGAR (Ipomoea carnea Jacq)

Pain is unpleasant symptom and feeling in of the organs, caused by tissue damage such as inflammatory conditions, infection, or related to muscle spasms. Previous research, is known that leaves Ipomoea carnea can inhibit prostaglandins which are pain mediators. This research aims to determine the activity of analgesic leaves Ipomoea carnea. The leaves Ipomoea carnea macerated with 96% ethanol and partitioned with n-hexane and ethyl acetate. The three extracts tested on male white mice (Mus musculus) with a weight of 25-30 g. The research method used is the writhing test. The test animals were divided into 11 groups. Group 1 (Na CMC 0.5% positive control), Group 2 (Paracetamol as a comparison), Group 3-5 (Ipomoea carnea ethanol extract doses of 50 mg, 100 mg and 200 mg/Kg BW), Groups 6-8 (ethyl acetate extract of Ipomoea carnea leaves doses of 50 mg, 100 mg and 200 mg/kb BW) and groups 9-11 (n-hexane extract of Ipomoea carnea leaves dose 50 mg, 100 mg and 200 mg/kb BW). The pain inducer 0.5% acetic acid intraperitoneally. Observations were carried out for 1 hour every 5 minutes and the percentage of analgesic power was calculated. Ethanol extract provides effect than ethyl acetate and n-hexane extracts, dose of 50 mg/Kg BW 62.4%; 100 mg/Kg BW 70.42% and 200 mg/Kg BW 69.15%. The significant value of the Mann-Whitney test is 0.008 from the test sample against the positive control so it can be concluded that there is analgesic activity from the ethanol extract of Ipomoea carnea leaves.

Update on the Role of β2AR and TRPV1 in Respiratory Diseases.

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies.

Edible cannabis for chronic low back pain: associations with pain, mood, and intoxication.

Cannabis, commonly known for both therapeutic and intoxicating effects, is gaining accessibility on legal markets and traction as a potential alternative therapy for pain mediation, particularly in those suffering from chronic low back pain. However, the effectiveness in this population of legal market forms of cannabis, particularly commonly used edibles, is unknown. Therefore, this study utilized a naturalistic prospective design where participants with chronic low back pain with intentions to initiate cannabis use for treatment were recruited and self-selected edible cannabis products containing varying amounts of delta- 9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Products were categorized as CBD-dominant, THC-dominant, or combined THC and CBD (THC + CBD). 249 participants [140 female (56.62%), mean (SD) age of 46.30 (16.02), 90% White] were tracked over 2weeks of ad libitum use and assessed during a naturalistic acute cannabis administration session on changes in pain, mood, and subjective drug effects. During acute administration, a significant correlation between THC dose and short-term pain relief was found, suggesting that higher THC doses were associated with greater pain reduction (p < .05). In addition, THC was associated with higher levels of subjective cannabis drug effects (p < .001), regardless of whether CBD was also in the edible product. Acute CBD dose was primarily associated with short-term tension relief (p < .05); however, there were no associations between CBD dose and acute pain. Over the 2-week ad libitum administration period results suggested pain reductions across participants using all forms of cannabis. However, trends suggested that more frequent use of CBD-dominant edible cannabis may be associated with greater reductions in perceived pain over the 2-week observation period (p = .07). These findings support the short-term analgesic effects of THC and anxiolytic effects of CBD and further suggest that orally-administered THC and CBD should continue to be evaluated for the potential to provide both acute and extended relief from chronic low back pain. https://clinicaltrials.gov/study/NCT03522324?locStr=Boulder,%20CO&country=United%20States&state=Colorado&city=Boulder&cond=chronic%20low%20back%20pain&intr=Cannabis&rank=1, identifier NCT03522324.

Mast cell-derived BH4 and serotonin are critical mediators of postoperative pain.

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

Effect of the novel anti-NGF monoclonal antibody DS002 on the metabolomics of pain mediators, cartilage and bone.

The anti-nerve growth factor antibody class of drugs interrupts signaling by blocking NGF binding to TrkA receptors for the treatment of pain; however, this target class of drugs has been associated with serious adverse effects in the joints during clinical trials. DS002 is a novel anti-nerve growth factor antibody drug independently developed by Guangdong Dashi Pharmaceuticals. The main purpose of this study is to explore the correlation between DS002 and pain as well as cartilage and bone metabolism with the help of metabolomics technology and the principle of enzyme-linked reaction, and to examine whether DS002 will produce serious adverse effects in joints caused by its same target class of drugs, in order to provide more scientific basis for the safety and efficacy of DS002. Our results showed that DS002 mainly affected the metabolism of aromatic amino acids and other metabolites, of which six metabolites, l -phenylalanine, 5-hydroxytryptophan, 5-hydroxytryptamine hydrochloride, 3-indolepropionic acid, kynuric acid, and kynurenine, were significantly altered, which may be related to the effectiveness of DS002 in treating pain. In addition, there were no significant changes in biological indicators related to cartilage and bone metabolism in vivo, suggesting that DS002 would not have a significant effect on cartilage and bone metabolism, so we hypothesize that DS002 may not produce the serious adverse effects in joints caused by its fellow target analogs. Therefore, the Anti-NGF analgesic drug DS002 has the potential to become a promising drug in the field of analgesia, providing pain patients with an efficient treatment option without adverse effects.

Is Chronic Tendon Pain Caused by Neuropathy? Exciting Breakthroughs may Direct Potential Treatment.

Tendinopathy significantly impacts the quality of life and imposes a high economic burden, accounting for a large proportion of sports and musculoskeletal injuries. Traditionally considered a collagen-related inflammatory disorder, emerging evidence suggests a critical role of neuropathic processes in chronic tendon pain. This review aims to evaluate the neuropathic mechanisms in tendinopathy and discuss innovative treatments targeting these pathways. We analyze recent studies highlighting the tendon innervation, pathological nerve sprouting neuronal ingrowth in tendinopathy, and the associated increase in pain and neuronal mediators. Chronic tendinopathy exhibits nociceptive sprouting from paratenon into the fibrous tendon proper. Innovative treatments such as Percutaneous Ultrasound-Guided Tenotomy (PUT) or high-frequency ultrasound interventions show promise in targeting these neuropathic components by paratenon separation. These approaches focus on disrupting the pathological innervation cycle. Chronic tendon pain may be predominantly neuropathic, driven by pathologic neuronal ingrowth from paratenon into the tendon proper. Interventions that accurately target and disrupt these nerve pathways could revolutionize the treatment of tendinopathy. Further research is required to validate these findings and refine treatment modalities to ensure safety and efficacy.

N-methyl-D-aspartate Receptor Subunits 2A and 2B Mediate Connexins and Pannexins in the Trigeminal Ganglion Involved in Orofacial Inflammatory Allodynia during Temporomandibular Joint Inflammation.

Temporomandibular joint osteoarthritis (TMJOA) is a severe form of temporomandibular joint disorders (TMD), and orofacial inflammatory allodynia is one of its common symptoms which lacks effective treatment. N-methyl-D-aspartate receptor (NMDAR), particularly its subtypes GluN2A and GluN2B, along with gap junctions (GJs), are key players in the mediation of inflammatory pain. However, the precise regulatory mechanisms of GluN2A, GluN2B, and GJs in orofacial inflammatory allodynia during TMJ inflammation still remain unclear. Here, we established the TMJ inflammation model by injecting Complete Freund's adjuvant (CFA) into the TMJ and used Cre/loxp site-specific recombination system to conditionally knock out (CKO) GluN2A and GluN2B in the trigeminal ganglion (TG). Von-frey test results indicated that CFA-induced mechanical allodynia in the TMJ region was relieved in GluN2A and GluN2B deficient mice. In vivo, CFA significantly up-regulated the expression of GluN2A and GluN2B, Gjb1, Gjb2, Gjc2 and Panx3 in the TG, and GluN2A and GluN2B CKO played different roles in mediating the expression of Gjb1, Gjb2, Gjc2 and Panx3. In vitro, NMDA up-regulated the expression of Gjb1, Gjb2, Gjc2 and Panx3 in satellite glial cells (SGCs) as well as promoted the intercellular communication between SGCs, and GluN2A and GluN2B knocking down (KD) altered the expression and function differently. NMDAR regulated Gjb1 and Panx3 through ERK1/2 pathway, and mediated Gjb2 and Gjc2 through MAPK, PKA, and PKC intracellular signaling pathways. These findings shed light on the distinct functions of GluN2A and GluN2B in mediating peripheral sensitization induced by TMJ inflammation in the TG, offering potential therapeutic targets for managing orofacial inflammatory allodynia.

Changes in contractile characteristics of rat skeletal muscles associated with P2-receptor activation after spinal cord transection

Introduction. Traumatic spinal cord and peripheral-nerve injury is associated with release of proinflammatory cytokines and chemokines, which may stimulate neuronal activity. Adenosine triphosphoric acid (ATP) is an important pain mediator involved in the acute and chronic neuropathic pain development. Its excessive release from primary injured tissue leads to activation of P2-receptors, which may further start secondary injury mechanisms. Although the effects of ATP on the peripheral nervous system are relatively well studied, the pathophysiological role of purinergic signaling after spinalization remains unclear. The study was aimed at assessing the post-spinalization effects of P2-receptors on the contractile characteristics of rat skeleton muscles. Materials and methods. The objects of the study were the soleus muscle, the extensor digitorum longus (EDL) muscle, and diaphragm in intact rats and spinalized rats. Seven days after laminectomy followed by spinal cord transection, animals were anesthetized, exsanguinated, and their muscles with nerve stumps were isolated. Contractile response parameters were recorded using mechanomyography (MMG). To study effects of ATP on ligand binding, ATP was added to a bath and mechanical responses in the rat muscles were assessed 7 min after. After washing with Krebs–Henseleit solution, the preparations were incubated with suramin solution for 20 min with subsequent ATP application. Then the mechanical responses in the muscles were again recorded. Statistical significance was assessed using Student's t-test for independent (unpaired) and paired samples. Results. We found a significant (p 0.05) decrease in the modulating activity of ATP, as the main endogenous signaling agent, in the cholinergic synapse of the soleus muscle from 32.4 to 5.8% and from 13.7 to 5.6% for the EDL muscle after the spinalization (spinal cord injury at the Th6–Th7 level) compared with intact animals. No such dramatic changes were observed in the diaphragm. Conclusions. Abnormal ATP-mediated modulation of neuromuscular transmission demonstrated in this study supports the involvement of purinergic signaling in the neurotrophic control and functioning of various motor units.

Clinical Conditions Targeted by OnabotulinumtoxinA in Different Ways in Medicine.

OnabotulinumtoxinA (BT-A) is used in different medical fields for its beneficial effects. BT-A, a toxin originally produced by the bacterium Clostridium botulinum, is widely known for its ability to temporarily paralyze muscles by blocking the release of acetylcholine, a neurotransmitter involved in muscle contraction. The literature continually reports new hypotheses regarding potential applications that do not consider blockade of acetylcholine release at the neuromuscular junction as a common pathway. In this opinion article, it is our aim to investigate the different pathway targets of BT-A in different medical applications. First of all, the acetylcholine effect of BT-A is used to reduce wrinkles for cosmetic purposes, in the treatment of urological problems, excessive sweating, temporomandibular joint disorders, obesity, migraine, spasticity in neurological diseases, and in various cases of muscle overactivity such as cervical dystonia, blepharospasm, and essential head tremor. In another potential pathway, glutamate A, CGRP, and substance P are targeted for pain inhibition with BT-A application in conditions such as migraine, trigeminal neuralgia, neuropathic pain, and myofascial pain syndrome. On the other hand, as a mechanism different from acetylcholine and pain mediators, BT-A is used in the treatment of hair loss by increasing oxygenation and targeting transforming growth factor-beta 1 cells. In addition, the effect of BT-A on the apoptosis of cancer cells is also known and is being developed. The benefits of BT-A applied in different doses to different regions for different medical purposes are shown in literature studies, and it is also emphasized in those studies that repeating the applications increases the benefits in the long term. The use of BT-A continues to expand as researchers discover new potential therapeutic uses for this versatile toxin.

Intergenerational associations between childhood maltreatment, post-traumatic stress symptoms, and chronic pain in young adult offspring and their parents.

Findings have revealed a strong link between exposure to child maltreatment (CM) and later chronic pain. Concurrently, other findings have been grounded in the understanding that CM consequences may not end with the exposed individual, rather, they extend to their offspring. However, little is known regarding the possible intergenerational transmission of chronic pain following CM. This study examines whether chronic pain among parents and their young adult offspring may be associated with parental exposure to CM. Three hundred ninety-three parent-offspring dyads (parents' mean age=58, SD=5.91years; offspring's mean age=27, SD=3.91years) completed self-report questionnaires, assessing CM (CTQ), posttraumatic stress (PTS) and disturbances in self-organisation (DSO) symptoms (ITQ), and chronic pain. CM was associated with chronic pain mediated by DSO symptoms among parents (indirect effect=0.77; p=0.007) and PTS symptoms among offspring (indirect effect=0.285; p=0.005). Offspring chronic pain was significantly associated with parental CM through two intergenerational paths: the mediation of parents' DSO symptoms and chronic pain (indirect effect=0.298; p=0.011), and through parents' PTS symptoms and offspring's PTS symptoms (indirect effect=0.077; p=0.004). This study's findings support the relevance of the intergenerational transmission of chronic pain following parental exposure to CM. Furthermore, the findings reveal complex PTS symptoms as a possible underlying mechanism for the intergenerational associations of chronic pain following CM.

Systematic Review and Metanalysis of the Expression of Blood-Based and Cerebrospinal Fluid-Based Biomarkers Related to Inflammatory Mediators in Neuropathic Pain.

The understanding of neuropathic pain remains incomplete, highlighting the need for research on biomarkers for improved diagnosis and treatment. This review focuses on identifying potential biomarkers in blood and cerebrospinal fluid for neuropathic pain in different neuropathies. Searches were performed in six databases: PubMed, Web of Science, Scopus, Cochrane Library, EMBASE, and CINAHL. Included were observational studies, namely cross-sectional, cohort, and case-control, that evaluated quantitative biomarkers in blood or cerebrospinal fluid. Data were qualitatively synthesized, and meta-analyses were conducted using R. The study is registered with PROSPERO under the ID CRD42022323769. The literature search resulted in 16 studies for qualitative and 12 for quantitative analysis, covering patients over 18 years of age with painful neuropathies. A total of 1403 subjects were analyzed, identifying no significant differences in levels of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) between patients with and without pain. Despite the high inter-rater reliability and adequate bias assessment, the results suggest negligible differences in inflammatory biomarkers, with noted publication bias and heterogeneity among studies, indicating the need for further research. Our review underscores the complex nature of neuropathic pain and the challenges in identifying biomarkers, with no significant differences found in CRP, IL-6, and TNF-alpha levels between patients with and without pain. Despite methodological robustness, the results are limited by publication bias and heterogeneity. This emphasizes the need for further research to discover definitive biomarkers for improved diagnosis and personalized treatment of neuropathic pain.

Tannic acid inhibits pain mediators, inflammation and oxidative stress in mice exposed to glyphosate-based herbicide.

Chronic exposure to glyphosate-based herbicide (Gly) has been associated with neurological disorders. Tannic acid (TA) is an antioxidant with attenuating action against neuroinflammation-associated conditions. This study evaluated the effect of Gly on pain perception alongside antinociceptive and anti-inflammatory actions of TA in Gly-exposed mice. Male Swiss mice were randomly divided into six groups (n=8): control (distilled water 0.2 ml/kg), Gly (Gly 500 mg/kg), Pre-TA + Gly (TA 50 mg/kg pre-treatment, afterwards Gly-administered), TA + Gly (TA 50 mg/kg and Gly co-administered), Pre-AA + Gly (ascorbic acid (AA) 10 mg/kg pre-treatment, afterwards Gly-administered), and AA + Gly (AA 10 mg/kg and Gly co-administered). Mechanical, thermal, and chemical pain were evaluated six weeks post vehicle/drugs administrations orally, followed by brain biochemical measurements. TA treatment alleviated Gly-induced hyperalgesia in similar version to the values of control and AA groups by increasing significantly (p < 0.05) nociceptive thresholds. Moreover, TA-treatment significantly decreased malondialdehyde (MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, significantly increased anti-inflammatory cytokines (IL-10, IL-4, and TGF-1β) levels, and antioxidant enzymes, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities compared to Gly-treated mice (p < 0.05). Conclusively, TA treatment exerted antinociceptive and anti-inflammatory actions, possibly through its antioxidant and anti-inflammatory actions in Gly-exposed mice. Notably, TA pre-treatment showed a better response than TA and Gly co-administration. We propose the potential neuroprotective and ameliorative functions of TA in Gly-induced hyperalgesia. This merits further clinical research into protective roles of TA against pesticide-related conditions.

Light-Inducible Activation of TrkA for Probing Chronic Pain in Mice.

Chronic pain is a prevalent problem that plagues modern society, and better understanding its mechanisms is critical for developing effective therapeutics. Nerve growth factor (NGF) and its primary receptor, Tropomyosin receptor kinase A (TrkA), are known to be potent mediators of chronic pain, but there is a lack of established methods for precisely perturbing the NGF/TrkA signaling pathway in the study of pain and nociception. Optobiological tools that leverage light-induced protein-protein interactions allow for precise spatial and temporal control of receptor signaling. Previously, our lab reported a blue light-activated version of TrkA generated using light-induced dimerization of the intracellular TrkA domain, opto-iTrkA. In this work, we show that opto-iTrkA activation is able to activate endogenous ERK and Akt signaling pathways and causes the retrograde transduction of phospho-ERK signals in dorsal root ganglion (DRG) neurons. Opto-iTrkA activation also sensitizes the transient receptor potential vanilloid 1 (TRPV1) channel in cellular models, further corroborating the physiological relevance of the optobiological stimulus. Finally, we show that opto-iTrkA enables light-inducible potentiation of mechanical sensitization in mice. Light illumination enables nontraumatic and reversible (<2 days) sensitization of mechanical pain in mice transduced with opto-iTrkA, which provides a platform for dissecting TrkA pathways for nociception in vitro and in vivo.

Substance P's Impact on Chronic Pain and Psychiatric Conditions-A Narrative Review.

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP's impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP's diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.

Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.