Pain Pathways Research Articles

Pain Pathways: Linking Environmental Pollutants with Migraine-Associated Pain Signaling.

Using human cells and a mouse study, researchers found that pesticides, phthalates, hormone-like compounds, and other chemicals affected the TRPA1 channel-which is also implicated in migraine.

Acupuncture-Related Therapy for Knee Osteoarthritis: A Narrative Review of Neuroimaging Studies.

Acupuncture has been widely applied for treating knee osteoarthritis (KOA). Numerous studies have found that acupuncture can effectively alleviate KOA symptoms. With the advancement of neuroimaging techniques, integrating neuroimaging with in-depth investigations of acupuncture mechanisms has emerged as a hot topic in traditional Chinese medical neuroscience research. This review aimed to analyze the study design and main findings from neuroimaging studies of acupuncture-related therapy for KOA to provide a reference for future research. Original studies were sourced from English databases (PubMed, Embase, and Cochrane Library) and Chinese databases (Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, the Chongqing VIP database, and Wanfang database). As a result, thirteen articles were ultimately included in this review. Functional magnetic resonance imaging was the most frequently used neuroimaging technique to explore cerebral responses to acupuncture-related therapy for KOA. Findings suggested that acupuncture-related therapy could regulate some brain regions in patients with KOA. Specifically, for acupuncture, it showed that the medial pain pathway and the limbic system were involved in the regulation of KOA. Meanwhile, moxibustion induced a wide range of functional activity throughout the entire brain.

Chronic Morphine Treatment and Antiretroviral Therapy Exacerbate HIV-Distal Sensory Peripheral Neuropathy and Induce Distinct Microbial Alterations in the HIV Tg26 Mouse Model.

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.

Efek Antinyeri Ekstrak Etanol Buah Belimbing Wuluh (Averrhoa bilimbi L) pada Mencit yang Diinduksi Asam Asetat

Pain is an unpleasant combination of sensory and emotional experience linked to the potential or actual of tissue damage. Typically, pain arises from stimulation of peripheral receptors, which send impulses through pain pathways to the brain. Starfruit is a medicinal plant that is used empirically as an analgesic. This study aims to determine the analgesic effect of starfruit extract on the stretch index and pain protection ratio against acetic acid-induced mice. This study used 25 mice divided into three test groups: one control group (Na-CMC) and one comparison group (Mefenamic acid). The results showed that starfruit can reduce the pain stretch index and have a pain protection ratio compared to the control group. A dose of 250 mg/kg has an analgesic protection ratio of 75.75%, and a dose of 500 mg/kg has a protection ratio of 85.14%. Thus, based on the results of this study, it can be seen that starfruit has the ability to act as an anti-pain.

The deconstruction of chronic orofacial pain and a hiding inhibition pathway of orofacial pain: the trigeminal proprioceptive mesencephalic periaqueductal gray pathway.

Chronic orofacial pain has a significant negative impact that influences individuals' quality of life and our society. The prevalence is around 11.2% to 33.2% and remains high in females. Currently, there are two main diagnostic classification systems that are used internationally for chronic pain: the International Classification of Diseases, 11th Revision (ICD-11), which was published by the World Health Organization (WHO) in 2018, and the International Classification of Orofacial Pain, which was published by the International Association for the Study of Pain (IASP) in 2020. Deficits in ascending and descending pain modulation pathways may be involved in the chronic pain pathophysiology. A newly described "trigeminal proprioceptive mesencephalic periaqueductal gray pathway" is considered to be the mechanism of action of occlusal appliance in managing orofacial pain. The genetic basis of chronic orofacial pain is not yet fully understood, but a genetic susceptibility involving multiple genes among the peripheral nerves, brainstem and higher brain regions to regulate and suppress the transmission of pain signals, thereby modulating the perception of pain, is likely.

Different vulnerability of fast and slow cortical oscillations to suppressive effect of spreading depolarization: state-dependent features potentially relevant to pathogenesis of migraine aura

BackgroundSpreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect.MethodsSpectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia.ResultsIn wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity.ConclusionSlow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura.

Substance P-Botulinum Mediates Long-term Silencing of Pain Pathways that can be Re-instated with a Second Injection of the Construct in Mice

Chronic pain presents an enormous personal and economic burden and there is an urgent need for effective treatments. In a mouse model of chronic neuropathic pain, selective silencing of key neurons in spinal pain signalling networks with botulinum constructs resulted in a reduction of pain behaviours associated with the peripheral nerve. However, to establish clinical relevance it was important to know how long this silencing period lasted. Now, we show that neuronal silencing and the concomitant reduction of neuropathic mechanical and thermal hypersensitivity lasts for up to 120d following a single injection of botulinum construct. Crucially, we show that silencing and analgesia can then be reinstated with a second injection of the botulinum conjugate. Here we demonstrate that single doses of botulinum-toxin conjugates are a powerful new way of providing long-term neuronal silencing and pain relief. PerspectiveThis research demonstrates that botulinum-toxin conjugates are a powerful new way of providing long-term neuronal silencing without toxicity following a single injection of the conjugate and have the potential for repeated dosing when silencing reverses.

A Comparative Study of Duloxetine with Pregabalin as a Preemptive Analgesic in Lumbar Spine Surgery: A Prospective Randomized Study

Abstract Background: Preemptive analgesia is a method of administration of drugs prior to surgery involving blocking noxious stimuli across the perioperative period. It involves blocking the pain pathway preemptively before injury-induced hypersensitivity manifests. Objective: To compare the analgesic efficacy of duloxetine with pregabalin as preemptive analgesic in lumbar spine surgeries. Design: Randomised, double-blinded, prospective study. Methods: Fifty patients of both sexes between 18-55yrs undergoing elective lumbar spine surgery were randomly allocated into two groups, group P and group D of twenty-five patients each. Group P received 75 mg pregabalin once daily for three days, followed by 150 mg pregabalin daily for the next four days till the day of surgery. Group D received 20 mg duloxetine once daily for three days, followed by 40 mg duloxetine twice daily for the next four days till the day of surgery. Outcome Measure: Both the groups were primarily evaluated in terms of time for request of 1st rescue analgesic and total intraoperative analgesic requirement in terms of fentanyl boluses required; among other parameters. Results: The time for request of 1st rescue analgesic postoperatively was significantly longer in the pregabalin group (396 ± 267.77 min) than in the duloxetine group (218.4 ± 96.9 min), P = 0.003. Pregabalin recipients required considerably less rescue analgesics in terms of dosage, P = 0.006. Also, pregabalin exhibited better postoperative pain control than duloxetine as reflected by NRS comparative scores. No statistical difference was appreciated in terms of intraoperative fentanyl requirement, intraoperative hemodynamic control; nausea and sleepiness. Conclusion: Pregabalin is more efficacious as a preemptive analgesic than duloxetine in lumbar spine surgery.

Association Between Cannabis Use and Opioid Consumption, Pain, and Respiratory Complications After Surgery: A Retrospective Cohort Analysis.

Cannabis is a widely used illicit drug with effects on different pain pathways. However, interactions between cannabis and postoperative pain are unclear. Cannabis smoking also affects the lungs, but the impact of cannabis use on postoperative pulmonary complications is unknown. We hypothesized that preoperative cannabis use in adults having elective surgery is associated with higher postoperative opioid consumption. Secondarily, we tested the hypothesis that cannabis use is associated with higher pain scores, hypoxemia (oxygen saturation [Sp o2 ]/fraction of inspired oxygen [F io2 ] ratio), and higher postoperative pulmonary complications compared to nonuse of cannabis. In this retrospective study, we included adult patients who had elective surgeries at Cleveland Clinic Main Campus between January 2010 and December 2020. The exposure was use of cannabis within 30 days before surgery, and the control group never used cannabis. Patients who had regional anesthesia or chronic pain diagnosis were excluded. The primary outcome was postoperative opioid consumption; 3 secondary outcomes were time-weighted average (TWA) postoperative pain score, TWA Sp o2 /F io2 ratio, and composite of pulmonary complications after surgery. We assessed the association between cannabis use and opioid consumption during the first 24 postoperative hours using linear regression on log-transformed opioid consumption with a propensity score-based method (inverse probability of treatment weighting [IPTW]) adjusting for confounders. We further adjusted for imbalanced confounding variables after IPTW was applied. In total, 1683 of 34,521 patients were identified as cannabis users. Cannabis use was associated with increased opioid consumption, with an adjusted ratio of geometric means (95% confidence interval [CI]) of 1.30 (1.22-1.38; P < .0001) for cannabis users versus nonusers. Secondarily, (1) cannabis use was associated with increased TWA pain score, with a difference in means of 0.57 (95% CI, 0.46-0.67; P < .0001); (2) cannabis use was not associated with TWA Sp o2 /F io2 , with an adjusted difference in means of 0.5 (95% CI, -3.1 to 4.2; P = .76); and (3) cannabis use was not associated with a collapsed composite of pulmonary complications, with estimated odds ratio of 0.90 (95% CI, 0.71-1.13; P = .34). Adult cannabis users undergoing surgeries were found to have significantly higher postoperative opioid consumption and pain scores than nonusers. Cannabis use did not have a clinically meaningful association with hypoxia or composite pulmonary complications.

Model-Based Meta-Analysis Supporting the Combination of Acetaminophen and Topical Diclofenac in Acute Pain: A Therapy for Mild-to-Moderate Osteoarthritis Pain?

Acetaminophen and topical diclofenac (AtopD) have complementary mechanisms of action and are therefore candidates for combination use in osteoarthritis (OA) pain. However, an evidence gap exists on their combination use in OA pain. This study aimed to assess the effects of this combination and compare its performance relative to monotherapies on pain score reduction and opioid-sparing effect by leveraging evidence from acute pain setting using a model-based meta-analysis (MBMA). A literature search was conducted using the MEDLINE database to identify randomized controlled trials (RCTs) studying the combination for acute pain. Subsequently, an MBMA of RCTs was implemented in conjunction with extrapolation principles to infer efficacy in the population of interest. Pain score reduction and opioid-sparing effect (OSE) were selected as the measures of efficacy. A total of 11 RCTs encompassing 1396 patients were included. Exploratory evaluation revealed AtopD combination to show greater pain score reduction versus acetaminophen monotherapy. However, pain score reduction was more susceptible to confounding by opioid patient-controlled analgesia (PCA) than OSE. Therefore, a parsimonious MBMA evaluating OSE was developed from 5 of the 11 RCTs (n = 353 patients). The analysis revealed a statistically significant interaction coefficient, suggesting a reduction of 32% in opioid use with the combination versus acetaminophen monotherapy. Differences in the effect size of the combination were less conclusive versus diclofenac monotherapy. Our results indicate greater pain reduction and opioid-sparing efficacy for the AtopD combination versus acetaminophen monotherapy. Given the similar pain pathways and mechanisms of action of the two drugs in acute and mild-to-moderate OA pain, comparable beneficial effects from the combination therapy may be anticipated following extrapolation to chronic OA pain. Prospective RCTs and real-world studies in OA pain are needed to confirm the differences in the efficacy of the combination treatment observed in our study.

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF's pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder.

Introduction: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity, inattention, and impulsivity that often persist until adulthood. Frequent comorbid disorders accompany ADHD and two thirds of children diagnosed with ADHD also suffer from behavioural disorders and from alteration of sensory processing. We recently characterized the comorbidity between ADHD-like symptoms and pain sensitisation in a pharmacological mouse model of ADHD, and we demonstrated the implication of the anterior cingulate cortex and posterior insula. However, few studies have explored the causal mechanisms underlying the interactions between ADHD and pain. The implication of inflammatory mechanisms has been suggested but the signalling pathways involved have not been explored. Methods: We investigated the roles of purinergic signalling, at the crossroad of pain and neuroinflammatory pathways, by using a transgenic mouse line that carries a total deletion of the P2X4 receptor. Results: We demonstrated that P2X4 deletion prevents hyperactivity in the mouse model of ADHD. In contrast, the absence of P2X4 lowered thermal pain thresholds in sham conditions and did not affect pain sensitization in ADHD-like conditions. We further analysed microglia reactivity and the expression of inflammatory markers in wild type and P2X4KO mice. Our results revealed that P2X4 deletion limits microglia reactivity but at the same time exerts proinflammatory effects in the anterior cingulate cortex and posterior insula. Conclusion: This dual role of P2X4 could be responsible for the differential effects noted on ADHD-like symptoms and pain sensitization and calls for further studies to investigate the therapeutic benefit of targeting the P2X4 receptor in ADHD patients.

CELL-DERIVED EXTRACELLULAR MATRIX TAILORING FOR INTERVERTEBRAL DISC REGENERATION

Intervertebral disc (IVD) degeneration is characterized by tissue loss of function and major structural changes, which can lead to Low Back Pain. Current treatments fail to tackle the disc's hindered function and degenerative alterations. Our goal is to promote IVD regeneration, through the recapitulation of a fetal-like microenvironment based on a tailored cell-derived matrix (CDM), rich in two fetal exclusive collagens – COLXII and COLXIV. We hypothesize that this engineered CDM will have a pro-regenerative potential and allow IVD functional restoration. Immortalized mesenchymal stromal/stem cells (iMSCs) were transduced with the CRISPR/dCas9-VP64 lentiviral system, targeting COL12A1 or COL14A1. Gene and protein expression were evaluated by qRT-PCR, Western Blot and immunofluorescence. Simultaneously, optimization of CDM decellularization protocol was performed. Process efficacy was validated by immunofluorescence. DNA content was quantified using the Quant-iT™ PicoGreen™ Kit. Successful iMSCs engineering was confirmed by an average increase of mRNA relative expression for both collagens (2.12-fold for COL12A1 and 11.7-fold for COL14A1). Protein level assessment by western blot and immunofluorescence confirmed increased COLXII and COLXIV. Decellularized CDM production was optimized. Cell removal was demonstrated by nuclear and actin staining reduction, when compared with the non-decellularized control. DNA content showed a marked decrease in both NH4OH- and SDS-based protocols. Matrix preservation after decellularization was confirmed by fibronectin staining only in the NH4OH-based decellularization. Preliminary proteomic characterization data of engineered iMSCs as shown some functional impact namely on Sonic Hedgehog (Shh) pathway and repression of pain by DREAM (Downstream regulator element antagonist modulator). In conclusion, we were able to establish a CRISPR activating system for COL12A1 and COL14A1, allowing the use of iMSCs as biofactories for a IVD fetal-tailored CDM. The use of a customized ECM and fetal microenvironment recapitulations is an innovative strategy for IVD functional restoration, and its versatility opens new avenues in the tissue regeneration field.

Correlatos Neurais da Dor, Resiliência e Empatia

Currently, pain is understood as a complex phenomenon infl uenced by biopsychosocial factors, as evidenced by the growing body of research in the “new science of pain.” The neurobiology of pain reveals a complex brain network associated with pain perception, with clear implications for emotional and cognition disorders. Empathy and resilience are crucial behavioral skills observed in both humans and animals, with neurobiological bases related to understanding others’ emotions and adapting to adverse situations. However, the association between neural processes related to resilience and empathy with pain pathways still needs to be clarifi ed. To this end, a systematic review was conducted in two databases (PubMed and Lilacs), including English articles without date limitations to achieve broader coverage. Initially, 3,649 studies were identifi ed, and after inclusion and exclusion criteria were applied, 72 relevant articles exploring this interrelation were identifi ed, highlighting neurobiological convergences in pain modulation by empathy and resilience. Empathy activates brain areas linked to understanding others’ emotions, while resilience is associated with adapting to stressful situations, both sharing neurobiological convergences in pain processing. Therapeutic interventions such as mindfulness and psychotherapy show promise in promoting empathy and resilience, off ering new perspectives for chronic pain management. These fi ndings underscore the importance of a multidimensional approach in chronic pain treatment, integrating biopsychosocial considerations to enhance patient outcomes.Keywords: Empathy, resilience, pain, neural pathways

Targeting the JAK2/STAT3 signaling pathway for chronic pain.

Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and minimal side effects remain unidentified. Substantial evidence indicates that the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a distinct and critical role in different stages of chronic pain. Aberrant activation of the JAK2/STAT3 signaling pathway is evident in multiple chronic pain models. Moreover, an increasing number of studies have demonstrated that the downregulation of JAK2/STAT3 can attenuate chronic pain in different animal models. In this review, we investigated the mechanism and role of the JAK2/STAT3 signaling pathway in modulating chronic pain. The aberrant activation of JAK2/STAT3 can trigger chronic pain by interacting with microglia and astrocytes, releasing proinflammatory cytokines, inhibiting anti-inflammatory cytokines, and regulating synaptic plasticity. We also retrospectively reviewed current reports on JAK2/STAT3 pharmacological inhibitors that demonstrated their significant therapeutic potential in different types of chronic pain. In summary, our results provide strong evidence that the JAK2/STAT3 signaling pathway is a promising therapeutic target for chronic pain.

Systematic review of translational insights: Neuromodulation in animal models for Diabetic Peripheral Neuropathy.

Diabetic Peripheral Neuropathy (DPN) is a prevalent and debilitating complication of diabetes, affecting a significant proportion of the diabetic population. Neuromodulation, an emerging therapeutic approach, has shown promise in the management of DPN symptoms. This systematic review aims to synthesize and analyze the current advancements in neuromodulation techniques for the treatment of DPN utilizing studies with preclinical animal models. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Web of Science. Inclusion criteria were focused on studies utilizing preclinical animal models for DPN that investigated the efficacy of various neuromodulation techniques, such as spinal cord stimulation, transcranial magnetic stimulation, and peripheral nerve stimulation. The findings suggest that neuromodulation significantly alleviated pain symptoms associated with DPN. Moreover, some studies reported improvements in nerve conduction velocity and reduction in nerve damage. The mechanisms underlying these effects appeared to involve modulation of pain pathways and enhancement of neurotrophic factors. However, the review also highlights the variability in methodology and stimulation parameters across studies, highlighting the need for standardization in future research. Additionally, while the results are promising, the translation of these findings from animal models to human clinical practice requires careful consideration. This review concludes that neuromodulation presents a potentially effective therapeutic strategy for DPN, but further research is necessary to optimize protocols and understand the underlying molecular mechanisms. It also emphasizes the importance of bridging the gap between preclinical findings and clinical applications to improve the management of DPN in diabetic patients.

Adolescent medicine. Explaining chronic functional pain to teenagers

There is a growing body of scientific understanding surrounding the topic of functional chronic pain. Numerous studies have highlighted a persistent low-grade inflammation within the fascial and central nervous systems, coupled with detrimental neuroplasticity involving substantial remodeling of pain pathways in the spinal cord and brain. These findings provide a more concrete basis for explaining functional chronic pain to adolescents, simplifying the establishment of trust and the justification of proposed treatments in the process.

Deciphering Authentic Nociceptive Thalamic Responses in Rats.

The thalamus and its cortical connections play a pivotal role in pain information processing, yet the exploration of its electrophysiological responses to nociceptive stimuli has been limited. Here, in 2 experiments we recorded neural responses to nociceptive laser stimuli in the thalamic (ventral posterior lateral nucleus and medial dorsal nucleus) and cortical regions (primary somatosensory cortex [S1] and anterior cingulate cortex) within the lateral and medial pain pathways. We found remarkable similarities in laser-evoked brain responses that encoded pain intensity within thalamic and cortical regions. Contrary to the expected temporal sequence of ascending information flow, the recorded thalamic response (N1) was temporally later than its cortical counterparts, suggesting that it may not be a genuine thalamus-generated response. Importantly, we also identified a distinctive component in the thalamus, i.e., the early negativity (EN) occurring around 100 ms after the onset of nociceptive stimuli. This EN component represents an authentic nociceptive thalamic response and closely synchronizes with the directional information flow from the thalamus to the cortex. These findings underscore the importance of isolating genuine thalamic neural responses, thereby contributing to a more comprehensive understanding of the thalamic function in pain processing. Additionally, these findings hold potential clinical implications, particularly in the advancement of closed-loop neuromodulation treatments for neurological diseases targeting this vital brain region.

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics.

The altered activity generated by corneal neuronal injury can result in morphological and physiological changes in the architecture of synaptic connections in the nervous system. These changes can alter the sensitivity of neurons (both second-order and higher-order projection) projecting pain signals. A complex process involving different cell types, molecules, nerves, dendritic cells, neurokines, neuropeptides, and axon guidance molecules causes a high level of sensory rearrangement, which is germane to all the phases in the pathomechanism of corneal neuropathic pain. Immune cells migrating to the region of nerve injury assist in pain generation by secreting neurokines that ensure nerve depolarization. Furthermore, excitability in the central pain pathway is perpetuated by local activation of microglia in the trigeminal ganglion and alterations of the descending inhibitory modulation for corneal pain arriving from central nervous system. Corneal neuropathic pain may be facilitated by dysfunctional structures in the central somatosensory nervous system due to a lesion, altered synaptogenesis, or genetic abnormality. Understanding these important pathways will provide novel therapeutic insight.

Stem cells and pain.

Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.