Nociceptive Signals Research Articles

Metabolite-Sensing Receptors: Emerging Targets for Modulating Chronic Pain Pathways.

Chronic pain is a debilitating condition affecting millions worldwide, often resulting from complex interactions between the nervous and immune systems. Recent advances highlight the critical role of metabolite-sensing G protein-coupled receptors (GPCRs) in various chronic pain types. These receptors link metabolic changes with cellular responses, influencing inflammatory and degenerative processes. Receptors such as free fatty acid receptor 1 (FFAR1/GPR40), free fatty acid receptor 4 (FFAR4/GPR120), free fatty acid receptor 2 (FFAR2/GPR43), and Takeda G protein-coupled receptor 5 (TGR5/GPR131/GPBAR1) are key modulators of nociceptive signaling. GPR40, activated by long-chain fatty acids, exhibits strong anti-inflammatory effects by reducing cytokine expression. Butyrate-activated GPR43 inhibits inflammatory mediators like nitric oxide synthase-2 and cyclooxygenase-2, mitigating inflammation. TGR5, activated by bile acids, regulates inflammation and cellular senescence through pathways like NF-κB and p38. These receptors are promising therapeutic targets in chronic pain, addressing the metabolic and inflammatory factors underlying nociceptive sensitization and tissue degeneration. This review explores the molecular mechanisms of metabolite-sensing receptors in chronic pain, their therapeutic potential, and challenges in clinical application. By uncovering these mechanisms, metabolite-sensing receptors could lead to safer, more effective pain management strategies.

Mechanisms of Cancer-Induced Bone Pain.

Bone is a common site of advanced cancer metastasis, second only to the lungs and liver. Cancer-induced bone pain (CIBP) is a persistent and intense pain that is caused by a combination of inflammatory and neuropathic factors. As CIBP progresses, the degree of pain intensifies. Despite advancements in medical technology, the treatment outcomes of patients with CIBP remain unsatisfactory, and severe pain can typically only be controlled with opioid medications. However, patients treated with opioid medications often develop tolerance. Therefore, they may require dose increases, which can increase the severity of opioid-induced side effects, in turn influencing quality of life. The peripheral mechanisms of CIBP primarily involve bone tissue damage, tumor microenvironment formation, and changes in the dorsal root ganglion. The central mechanisms usually involve biochemical and electrophysiological changes in the spinal cord and brain. The spinal cord is the main processing center for nociceptive signals. When tumor cells produce inflammatory mediators that acidify the microenvironment or damage nerve endings, the spinal cord becomes excessively stimulated, resulting in increased or prolonged pain signals that propagate to the higher central nervous system through the ascending pathway. There are substantial differences in the pain generation mechanisms between CIBP and common inflammatory and neuropathic pain. Therefore, understanding the mechanisms underpinning CIBP development at the level of the spinal cord is crucial for optimizing pain management. This study explores the pathogenesis of CIBP at the level of the spinal cord and describes recently proposed treatment methods for CIBP.

Postcolitis Alterations in Dose-Dependent Effects of 5-HT1A Agonist Buspirone on Nociceptive Activity of the Raphe Magnus and Dorsal Raphe Neurons in Rats.

The serotonergic raphe magnus (RMg) and dorsal raphe (DR) nuclei are crucial pain-regulating structures, which nociceptive activity is shown to be altered in gut pathology, but the underlying neuroplastic changes remain unclear. Considering the importance of 5-HT1A receptors in modulating both pain and raphe neuronal activity, in this study, we aimed to determine whether 5-HT1A-dependent visceral and somatic nociceptive processing within the RMg and DR is modified in postcolitis conditions. In anaesthetised male Wistar rats, healthy control and recovered from TNBS-induced colitis, the microelectrode recordings of RMg and DR neuron responses to noxious colorectal distension (CRD) or tail squeezing (TS) were performed prior and after intravenous administration of 5-HT1A agonist, buspirone. In postcolitis animals, 5-HT1A autoreceptor- and heteroreceptor-activating high doses of buspirone (2 and 4 mg/kg) lost normally occurring ability to facilitate CRD- and TS-evoked activation of RMg neurons, causing inhibition of the local nociceptive signalling similar to 5-HT1A autoreceptor-activating low doses (0.1 and 0.5 mg/kg). Conversely, the normally inherent property of buspirone at all doses to reduce visceral and somatic pain-related neuronal excitation in the DR was weakened after colitis. These phenomena were associated with a loss of normally occurring inhibitory effect of the compound's high doses on hemodynamic reactions to CRD and TS, revealing deficient antinociceptive action at a systemic level. The data suggest postcolitis changes in buspirone-dependent 5-HT1A autoreceptor- and heteroreceptor-mediated signalling, which can directly or indirectly lead to reduced RMg pain-related activity and increased DR nociceptive excitation, impairing their functioning in the visceral and somatic pain control.

Macrophage to neuron communication via extracellular vesicles in neuropathic pain conditions.

Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons. Indeed, bone marrow-derived macrophages (BMDMs) release EVs containing microRNA-155 (miR-155) which are taken up by cultured sensory neurons. EV-mediated transfer of miR-155 suppresses phosphatase Ship1 expression and increases cytokine interleukin-6 (IL-6) contents. Intrathecal-injected BMDM-derived EVs accumulate in lumbar DRG and EVs containing miR-155 antagomir result in Ship1 upregulation, Il6 downregulation in neurons in concomitance to attenuation of neuropathic mechanical hypersensitivity. These data suggest that, under neuropathic conditions, pro-inflammatory macrophages shuttle EV-containing miR-155 to neurons and contribute to the expression of pronociceptive IL-6 in DRG.

Identifying the Brain Circuits that Regulate Pain-Induced Sleep Disturbances.

Pain therapies that alleviate both pain and sleep disturbances may be the most effective for pain relief, as both chronic pain and sleep loss render the opioidergic system, targeted by opioids, less sensitive and effective for analgesia. Therefore, we first studied the link between sleep disturbances and the activation of nociceptors in two acute pain models. Activation of nociceptors in both acute inflammatory (AIP) and opto-pain models led to sleep loss, decreased sleep spindle density, and increased sleep fragmentation that lasted 3 to 6 hours. This relationship is facilitated by the transmission of nociceptive signals through the spino-parabrachial pathways, converging at the wake-active PBelCGRP (parabrachial nucleus expressing Calcitonin Gene-Related Peptide) neurons, known to gate aversive stimuli. However, it has never been tested whether the targeted blocking of this wake pathway can alleviate pain-induced sleep disturbances without increasing sleepiness. Therefore, we next used selective ablations or optogenetic silencing and identified the key role played by the glutamatergic PBelCGRP in pain-induced sleep disturbances. Inactivating the PBelCGRP neurons by genetic deletion or optogenetic silencing prevented these sleep disturbances in both pain models. Furthermore, to understand the wake pathways underlying the pain-induced sleep disturbances, we silenced the PBelCGRP terminals at four key sites in the substantia innominata of the basal forebrain (SI-BF), the central nucleus of Amygdala (CeA), the bed nucleus of stria terminalis (BNST), or the lateral hypothalamus (LH). Silencing of the SI-BF and CeA also significantly reversed pain-induced sleep loss, specifically through the action on the CGRP and NMDA receptors. This was also confirmed by site-specific blockade of these receptors pharmacologically. Our results highlight the significant potential for selectively targeting the wake pathway to effectively treat pain and sleep disturbances, which will minimize risks associated with traditional analgesics.

Clinical proof-of-concept results with a novel TRPA1 antagonist (LY3526318) in 3 chronic pain states.

Transient receptor potential ankyrin 1 (TRPA1) is implicated in physiological and pathological nociceptive signaling, but the clinical benefit of TRPA1 antagonists in chronic pain is not clearly demonstrated. LY3526318 is an oral, potent, and selective novel TRPA1 antagonist. The Chronic Pain Master Protocol was used to evaluate the safety and efficacy of LY3526318 in 3 randomized, placebo-controlled, proof-of-concept studies in knee osteoarthritis pain (OA), chronic low back pain (CLBP), and diabetic peripheral neuropathic pain (DPNP). Participants were randomized (1:2, placebo:LY3526318, 250 mg daily) into an 8-week double-blinded period. At 4 weeks, participants treated with LY3526318 transitioned to a placebo. The primary endpoint was the self-reported daily pain intensity measured using a Numerical Rating Scale (NRS) at 4 weeks. All endpoints were collected for up to 8 weeks. Change from baseline in average weekly NRS was analyzed using Bayesian mixed model repeated measures in the OA (N = 160), CLBP (N = 159), and DPNP (N = 154) studies. Baseline characteristics were balanced between treatment arms. Mean NRS change from baseline to week 4 did not differ significantly between placebo and LY3526318; however, a numerical improvement was observed in the CLBP, not in the OA or DPNP populations. Safety analysis integrated across studies enhanced understanding of the safety profile of LY3526318. LY3526318 showed a potential drug-induced hepatotoxic effect posing a risk for clinical development. No other safety signals were identified. LY3526318 showed potential for different responses among chronic pain indications and patient subpopulations, highlighting challenges in developing TRPA1 antagonists but supporting their value as a target in managing chronic pain.

N-methyl-D-aspartate receptor activation is downstream coupled to pannexin 1 opening by Src kinase in dorsal horn neurons: an essential link for mechanical hyperalgesia in nerve-injured rats.

A well-recognized molecular entity involved in pain-related neuroplasticity is the N-methyl-D-aspartate receptor (NMDAR), which is crucial for developing chronic pain. Likewise, the pannexin 1 (Panx1) channel has been described as necessary for initiating and maintaining neuropathic pain, driving nociceptive signals dependent on spinal NMDAR through several possible mechanisms. Through behavioral, pharmacological, and molecular approaches, our study in male rats has revealed several key findings: (1) neurons located in spinal cord laminae I and II express functional Panx1 channels in both neuropathic and sham rats. These channels can open (indicated by YOPRO-1 uptake) through the stimulation of NMDARs with intrathecal NMDA; (2) intrathecal NMDA leads to increased expression of pSrc and pPanx1 in dorsal horn neurons. This elevation exacerbates existing mechanical hyperalgesia in nerve-injured rats; (3) inhibition of Src with intrathecal PP2 or blockade of Panx1 with intrathecal 10Panx effectively mitigates NMDA-induced effects and reduces the spontaneous mechanical hyperalgesia of nerve-injured rats. Notably, while 10Panx successfully alleviates hyperalgesia, it does not alter pSrc expression; and (4) NMDA-stimulated YOPRO-1 uptake in neurons of laminae I-II of spinal cord slices were prevented by the NMDAR antagonist D-AP5, the Src inhibitor PP2 (but not PP3), as well as with the 10Panx and carbenoxolone. Therefore, NMDAR activation in dorsal horn neurons triggers an NMDAR-Src-Panx1 signaling pathway, where Panx1 acts as an enhancing effector in neuropathic pain. This implies that disrupting the NMDAR-Panx1 communication (eg, through Src inhibitors and/or Panx1 blockers) may offer a valuable strategy for managing some forms of chronic pain.

Distinct Roles of Astrocytes and GABAergic Neurons in the Paraventricular Thalamic Nucleus in Modulating Diabetic Neuropathic Pain

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain (NP). The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 days after streptozotocin (STZ) injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.Significance StatementSome studies have focused on the role of paraventricular thalamic nucleus (PVT) glutamatergic neurons in neuropathic pain (NP) and anxiety. However, the role of PVT astrocytes and GABAergic neurons in diabetic neuropathic pain (DNP) has not been studied. We used chemogenetic techniques to bidirectionally regulate the activity of PVT astrocytes or GABAergic neurons and found that PVT astrocyte activation promotes NP, while PVT GABAergic neuron activation may mediate antinociceptive effects. These findings clarify the critical roles of PVT astrocytes and GABAergic neurons in modulating DNP, providing insight for the development of new strategies for the prevention and treatment of DNP and revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.

Repetitive Transcranial Magnetic Stimulation: Is it an Effective Treatment for Cancer Pain?

Cancer is a major public health issue, with an estimated 20 million new cases and 9.7 million cancer-related deaths worldwide in 2022. Approximately 44.5% of patients experience cancer pain, significantly impacting their quality of life and causing physical and psychological burdens. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, shows potential in managing cancer pain. This review summarizes current research on rTMS for cancer pain, focusing on pain directly caused by tumors, pain from cancer treatments, postoperative pain, and cancer-related symptoms. Additionally, rTMS shows promise in improving cancer-related fatigue, anxiety, depression, and cognitive dysfunction, which can indirectly reduce cancer pain. The analgesic mechanisms of rTMS include inhibiting nociceptive signal transmission in the spinal cord, modulating hemodynamic changes in brain regions, and promoting endogenous opioid release. High-frequency stimulation of the primary motor cortex (M1) has shown significant analgesic effects, improving patients' emotional and cognitive functions and overall quality of life. rTMS has a favorable safety profile, with most studies reporting no severe adverse events. In conclusion, rTMS holds substantial potential for cancer pain management, offering a non-invasive and multifaceted therapeutic approach. Continued research and clinical application are expected to establish rTMS as an essential component of comprehensive cancer pain treatment strategies, significantly enhancing the overall well-being of patients with cancer.

Deciphering pain: molecular mechanisms and neurochemical pathways-challenges and future opportunities.

This review delves into the intricate biological underpinnings of pain perception. It encompasses nociceptive signaling pathways, the molecular mechanisms involved, and the subjective experience of discomfort in humans. The initial focus is on nociceptor transduction, where specialized neurons transform noxious stimuli into electrical impulses. Subsequently, the review explores the central nervous system, elucidating how these signals are processed and modulated by critical elements such as ion channels, receptors, and neurotransmitters (e.g., substance P, glutamate, GABA). Shifting gears toward chronic pain, the review examines the concept of neuroplasticity, highlighting its potential to induce maladaptive responses through alterations in neural networks. The burgeoning field of pain genomics, alongside established genetic research, offers valuable insights that could pave the way for a framework of personalized pain management strategies. Finally, the review emphasizes the significance of these molecular insights in facilitating accurate therapeutic interventions. The overarching objective is to establish an integrative framework for precision medicine in pain management by incorporating this information alongside biopsychosocial models. This framework serves to translate the heterogeneous landscape of pain mechanisms into a coherent roadmap for the development of effective therapies.

A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing

Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS–LPB–PVT–PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS–LPB–PVT–PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.

The Influence of Regional Anesthesia on the Systemic Stress Response

Background: The systemic stress response to surgery is a complex physiological process characterized by neuroendocrine, sympathetic, and inflammatory activation. While necessary for survival, this response can lead to adverse outcomes such as hyperglycemia, immune suppression, cardiovascular complications, and delayed recovery. Regional anesthesia (RA) has been shown to modulate this stress response more effectively than general anesthesia (GA) by blocking nociceptive signaling and attenuating the release of stress mediators. Objectives: This review aims to elucidate how RA influences the systemic stress response, highlighting its clinical benefits in reducing postoperative pain, improving hemodynamic stability, minimizing inflammatory responses, and preserving immune function. Additionally, this review examines evidence from clinical trials supporting using RA to improve surgical outcomes, particularly in high-risk populations. Methods: A comprehensive narrative review of the literature was conducted to explore the physiological impact of RA on the systemic stress response and its associated clinical outcomes. Studies comparing RA to GA across various surgical procedures were evaluated, focusing on neuroendocrine modulation, sympathetic inhibition, inflammatory attenuation, and the implications for pain management, cardiovascular and pulmonary function, and immune preservation. Results: RA significantly attenuates the neuroendocrine response by reducing the release of cortisol and catecholamines, thereby improving hemodynamic stability and reducing myocardial oxygen consumption. RA also inhibits the sympathetic nervous system, leading to improved cardiovascular outcomes. Furthermore, RA mitigates the inflammatory response by reducing pro-inflammatory cytokine levels, reducing the risk of systemic inflammatory response syndrome (SIRS), sepsis, and pulmonary complications. Clinical studies and meta-analyses consistently demonstrate that RA reduces postoperative pain, opioid consumption, and the incidence of cardiovascular and pulmonary complications, particularly in elderly and high-risk patients. Conclusions: RA offers a significant advantage in modulating the systemic stress response to surgery, improving postoperative outcomes by reducing pain, enhancing cardiovascular stability, and preserving immune function. Its benefits are particularly pronounced in high-risk populations such as the elderly or those with pre-existing comorbidities. Given the growing evidence supporting its efficacy, RA should be considered a critical component of multimodal perioperative care strategies aimed at minimizing the systemic stress response and improving recovery. Future research should optimize RA techniques and identify patient-specific factors to enhance therapeutic benefits.

When thinking about pain contributes to suffering: the example of pain catastrophizing.

The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)- appraisals of pain as threatening, overwhelming, and unmanageable- and review the evidence that these thoughts are learned in childhood through experience and observation of others, particularly caretakers and parents. For children who have learned pCAT, repeated exposures to pain over time activate pCAT and likely contribute to further amplification of pain through changes in the neurobiological pain regulatory systems, which overlap with those regulating the stress response. We propose that repeated pain and stress exposures throughout childhood, adolescence, and into adulthood alter the neurobiology of pain via a repetitive positive feedback loop that increases risk for heightened pain sensitivity over time with repeated exposures. At some point, often precipitated by an acute episode of pain and possibly influenced by allostatic load, pCAT contributes to persistence of episodic or acute pain and exacerbates pain-related suffering. This developmental trajectory is not inevitable, as the impact of pCAT on pain and pain-related suffering can be influenced by various factors. We also present future directions for work in this area.

Natural Products with Potential for the Treatment of Pain: Global Evidence from the NAPRALERT Database.

Natural products (NPs) continue to inform the discovery and development of a diversity of drugs, both marketed and investigational. Pain, one of the most common of human experiences and profound challenges in medicine and biology, has emerged at the core of an urgent societal problem, in the United States and globally. The present study employs a retrospective analysis of an extensive set of published literature curated in the NAPRALERT database to identify NPs with experimental evidence of bioactivity supporting the selection and prioritization of NP leads with promise in pain management. The NAPRALERT pain data set currently documents >38,000 pain-relevant experiments reported in >1,750 distinct journals. The evidence presented here was annotated from >10,000 distinct scientific publications identifying NP extracts and isolates with experimental biological data indicating positive mitigation of pain, inflammation, and/or modulation of nociceptive signaling targets. Correlation of ethnomedical uses with experimental data represents a value-added approach to the selection and prioritization of leads. Dissemination of this unique NP/pain data set, with experimental data and information applicable to basic, translational, and clinical science stakeholders alike, furnishes practical evidence in support of a rational selection of NPs for directed pain research. A large portion of the NAPRALERT pain-relevant data set, along with a set of query tools designed to assist user-directed selection and prioritization of leads, are presented as Supporting Information in order to mitigate the limitations inherent in presenting such a large data set in (print) format. To support user efforts, this report involves explication of NAPRALERT data organization and the articulation of rational approaches to user-guided selection of evidence-based NP leads.

Unraveling the Molecular Reason of Opposing Effects of α-Mangostin and Norfluoxetine on TREK-2 at the Same Binding Site.

TWIK-related K+ channel (TREK)-2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK-2 is of significance for the development of new analgesics. Recent studies have shown that α-Mangostin (α-MG) activates TREK-2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK-2, α-MG is also observed to share a same binding site with NFx, and this implies that TREK-2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK-2 is activated by α-MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α-MG and NFx exhibit opposing effects at the same binding site of TREK-2. These findings will broaden our understanding of TREK-2 modulation, providing clues for designing novel analgesic drugs.

Short Lysine-Containing Tripeptide as Analgesic Substance: The Possible Mechanism of Ligand–Receptor Binding to the Slow Sodium Channel

A possible molecular mechanism of the ligand–receptor binding of Ac-Lys-Lys-Lys-NH2 (Ac-KKK-NH2) to the NaV1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon Ac-KKK-NH2 application at 100 nM, a significant decrease in the effective charge carried by the NaV1.8 channel activation gating system Zeff is demonstrated in the patch-clamp experiments. A strong Ac-KKK-NH2 analgesic effect at both the spinal and supraspinal levels is detected in vivo in the formalin test. The distances between the positively charged amino groups in the Ac-KKK-NH2 molecule upon binding to the NaV1.8 channel are 11–12 Å, as revealed by the conformational analysis. The blind docking with the NaV1.8 channel has made it possible to locate the Ac-KKK-NH2 binding site on the extracellular side of the voltage-sensing domain VSDI. The Ac-KKK-NH2 amino groups are shown to form ionic bonds with Asp151 and Glu157 and a hydrogen bond with Thr161, which affects the coordinated movement of the voltage sensor up and down, thus modulating the Zeff value. According to the results presented, Ac-KKK-NH2 is a promising candidate for the role of an analgesic medicinal substance that can be applied for pain relief in humans.

Роль ванілоїдного рецептора типу 1 та глутаматних рецепторів у синаптичній активності нейронів пластинки X спинного мозку щурів

This study is aimed at understanding the mechanisms of nociceptive signaling in lamina X of the spinal cord, which are involved in the regulation of pain sensations. First, tetrodotoxin, which blocks action potentials, was applied to the system, which made it possible to isolate miniature synaptic activity (mEPSCs). After that, they added pidal, an agonist of TRPV1 receptors, which caused a significant increase in the frequency and amplitude of mEPSCs. Against the background of tetrodotoxin, the effect of capsaicin was biphasic: at first, the frequency of events increased sharply, after which it gradually decreased, but the amplitude increased. A control, without tetrodotoxin, application of capsaicin also caused an increase in synaptic activity, but this effect was not biphasic. Additional blockade of NMDA receptors (AP-5) partially reduced capsaicin-induced activity, while an AMPA receptor blocker (CNQX) almost completely abolished it, suggesting a critical role of glutamate receptors in maintaining this activity. The obtained results emphasize the importance of TRPV1 receptors in central sensitization and the possibility of its regulation, which opens new ways of modulation of chronic pain.

Investigating the effects of artificial baroreflex stimulation on pain perception: A comparative study in no-pain and chronic low back pain individuals.

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, where acute pain triggers ANS responses, whereas resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by 'top-down' processes occurring in the brain, brainstem and spinal cord, known as 'descending modulation'. By employing the conditioned pain modulation (CPM) paradigm, we previously revealed a connection between reduced low-frequency heart rate variability and CPM. Individuals with chronic pain often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and heart rate variability regulation, may play a significant role in this relationship, although their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In the present study, we combined artificial 'baroreceptor stimulation' in both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. In total, 22 individuals with chronic low back pain (CLBP) and 29 individuals with no-pain (NP) took part in the present study. We identified a differential modulation of baroreceptor stimulation on pressure pain between the groups of NP and CLBP participants. Specifically, NP participants perceived less pain in response to baroreflex activation, whereas CLBP participants exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex sensitivity in both CLBP and NP participants. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the ANS and descending pain modulation. KEY POINTS: Baroreflex stimulation has different effects on pressure pain in participants with chronic pain compared to matched individuals with no-pain. Baroreceptor activation decreases pain in participants with no-pain but increases pain perception in participants with chronic pain. Baroreflex sensitivity is associated with conditioned pain modulation in both groups of chronic pain and no-pain participants. The reactivity of the baroreflex during autonomic stress demonstrated a positive correlation with Pain Trait scores in participants with chronic back pain.

Recent advances in acupuncture for pain relief.

Acupuncture therapy has achieved global expansion and shown promise for health promotion and treatment of acute/chronic pain. To present an update on the existing evidence base for research and clinical practice supporting acupuncture analgesia. This Clinical Update elaborates on the 2023 International Association for the Study of Pain Global Year for Integrative Pain Care "Factsheet Acupuncture for Pain Relief" and reviews best evidence and practice. Acupuncture is supported by a large research evidence base and growing utilization. Mechanisms of acupuncture analgesia include local physiological response at the needling site, suppression of nociceptive signaling at spinal and supraspinal levels, and peripheral/central release of endogenous opioids and other biochemical mediators. Acupuncture also produces pain relief by modulating specific brain networks, integral for sensory, affective, and cognitive processing, as demonstrated by neuroimaging research. Importantly, acupuncture does not just manage pain symptoms but may target the sources that drive pain, such as inflammation, partially by modulating autonomic pathways. Contextual factors are important for acupuncture analgesia, which is a complex multifaceted intervention. In clinical practice, historical records and many providers believe that acupuncture efficacy depends on specific acupoints used, the technique of needle placement and stimulation, and the person who delivers the procedure. Clinical research has supported the safety and effectiveness of acupuncture for various pain disorders, including acupuncture as a complementary/integrative therapy with other pain interventions. Although the quality of supportive evidence is heterogeneous, acupuncture's potential cost-effectiveness and low risk profile under standardized techniques suggest consideration as a neuromodulatory and practical nonpharmacological pain therapy.

The Effect of Mesenchymal Stem Cell Administration on the Expression of Nuclear Factor Kappa Beta, Neural Growth Factor Expression, and Prostaglandin E2 Concentration as Determinants of Pain in a Mouse Model of Endometriosis

Endometriosis is a significant reproductive health issue with pain being the primaru symptom. The complex pain in endometriosis involves the activation of macrophages, inflammatory activators such as NF-kB, neural growth factors (NGF), cytokines, adhesive molecules (ICAM-1), and mediators (PGE2) which they are stimulate sensory nerve fibers and produce nociceptive signals. This study is aim for investigate the effect of Mesenchymal Stem Cell (MSC) administration on the expression of NF-kB, NGF, and PGE2 concentration in a mouse model of endometriosis. Thirty-three mices were randomly divided into 3 groups consist non-endometriosis (P0), endometriosis without treatment (P1), and endometriosis with MSC administration (P2). The results showed MSC administration significantly reduced the expression of NF-kB by found scoring 2 groups (P1: 6.96 ± 0.13 and P2: 4.446 ± 0.228) and NGF (P1: 7.118 ± 0.629 and P2: 4.927 ± 1.187) also PGE2 (P1:1005.862 ± 176.656 and P2: 891.218 ± 54.031. In onclusion, this study demonstrates that MSC administration can able reduce the expression of NF-kB and NGF, but not to PGE2. The suggestion we can said is the MSC have potential therapeutic value in managing endometriosis-asssosciated pain by modulating inflammatory and neurotrophic factors. HIGHLIGHTS Pain in endometriosis, which is driven by inflammatory factors like NF-kB, NGF, cytokines, and PGE2, stimulating sensory nerve fibers and producing nociceptive signals. Investigate the effects of mesenchymal stem cell (MSC) administration on the expression of NF-kB, NGF, and PGE2 in a mouse model of endometriosis. Mesenchymal stem cell (MSC) administration was shown to reduce the expression of key inflammatory and neurotrophic factors—NF-kB and NGF—in a mouse model of endometriosis. Limited effect on reducing PGE2 concentration. These findings suggest that MSCs may have therapeutic potential for managing pain associated with endometriosis by modulating inflammatory and neurotrophic pathways. GRAPHICAL ABSTRACT