The large-caliber primary afferents innervating the spindles of the jaw-closing muscles have their cell bodies located centrally in the mesencephalic trigeminal nucleus (NVmes). We have shown, in an acid-induced jaw muscle chronic myalgia model, that these afferents exhibit increased excitability and ectopic discharges that emerge from subthreshold membrane oscillations (SMOs) supported by a persistent sodium current (I NaP) exquisitely sensitive to extracellular Ca2+-decreases. Here, we explore if the Ca2+-binding astrocytic protein, S100β, contributes to this hyperexcitability emergence and aim to localize the site where ectopic discharge arises using whole-cell patch-clamp recordings on mice brain slices. We found that astrocytes, by lowering [Ca2+]e at focal points along the axons of NVmes neurons through S100β, enhance the amplitude of the NaV1.6-dependent SMOs, leading to ectopic firing. These findings suggest a crucial role for astrocytes in excitability regulation and raise questions about this neuron-astrocyte interaction as a key contributor to hyperexcitability in several pathologies.

Chronic pain is a global health problem with major socioeconomic implications. Drug therapy for chronic pain is limited, prompting search for non-pharmacological treatments. One such approach is physical exercise, which has been found to be beneficial for numerous health issues. Research in recent years has yielded considerable evidence for the analgesic actions of exercise in humans and experimental animals, but the underlying mechanisms are far from clear. It was proposed that exercise influences the pain pathways by interacting with the immune system, mainly by reducing inflammatory responses, but the release of endogenous analgesic mediators is another possibility. Exercise acts on neurons and glial cells in both the central and peripheral nervous systems. This review focuses on the periphery, with emphasis on possible glia-neuron interactions. Key topics include interactions of Schwann cells with axons (myelinated and unmyelinated), satellite glial cells in sensory ganglia, enteric glial cells, and the sympathetic nervous system. An attempt is made to highlight several neurological diseases that are associated with pain and the roles that glial cells may play in exercise-induced pain alleviation. Among the diseases are fibromyalgia and Charcot-Marie-Tooth disease. The hypothesis that active skeletal muscles exert their effects on the nervous system by releasing myokines is discussed.

Fibromyalgia represents a chronic pain disorder characterized by musculoskeletal pain, fatigue, and cognitive impairments. The exact mechanisms underlying fibromyalgia remain undefined; as a result, diagnosis and treatment present considerable challenges. On the other hand, the endogenous opioid system is believed to regulate pain intensity and emotional responses; hence, it might be expected to play a key role in the enhanced sensitivity experienced by fibromyalgia patients. One explanation for the emergence of disrupted pain modulation in individuals with fibromyalgia is a significant reduction in opioid receptor activity or an imbalance in the levels of endogenous opioid peptides. Further research is essential to clarify the complex details of the mechanisms underlying this abnormality. This complexity arises from the notion that an improved understanding could contribute to the development of innovative therapeutic strategies aimed at targeting the endogenous opioid system in the context of fibromyalgia. Although progress is being made, a complete understanding of these complexities remains a significant challenge. This paradigm has the potential to revolutionize the complex management of fibromyalgia, although its implementation may experience challenges. The effectiveness of this approach depends on multiple factors, but the implications could be profound. Despite the challenges involved in this transformation, the potential for improving patient care is considerable, as this condition has long been inadequately treated.

Background: Low back pain (LBP) is a leading cause of disability worldwide, often driven by distinct pain mechanisms: nociceptive, neuropathic, and central sensitization. Accurate classification of these mechanisms is critical for guiding effective, targeted treatments. Methods: A scoping review was conducted following the Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. A comprehensive literature search was performed in MEDLINE, Cochrane CENTRAL, Scopus, PEDro, and Web of Science. Eligible studies included adults with LBP and focused on clinical criteria for classifying pain mechanisms. Data on study methods, population characteristics, and outcomes were extracted and synthesized. Results: Nine studies met the inclusion criteria. Nociceptive pain was characterized by localized symptoms proportional to mechanical triggers, with no neurological signs. Neuropathic pain was associated with burning sensations, dysaesthesia, and a positive neurodynamic straight leg raise (SLR) test. Central sensitization featured widespread pain, hyperalgesia, and disproportionate symptoms. Tools such as painDETECT, DN4, and the Central Sensitisation Inventory (CSI) were validated for neuropathic and central sensitization pain. Central sensitization and neuropathic pain were linked to greater disability and psychological distress compared to nociceptive pain. Conclusions: This review aims to provide a historical perspective on pain mechanism classifications and to explore how previous frameworks have influenced current diagnostic concepts in physiotherapy practice. By synthesizing key clinical criteria used to differentiate between nociceptive, neuropathic, and central sensitization pain, this review proposes a practical framework to improve the accuracy of pain classification in clinical settings.

Neuropathic pain, a chronic condition resulting from somatosensory system damage, remains a significant clinical challenge due to its complex pathophysiology and inadequate response to traditional therapies. Oxidative stress, characterized by an imbalance between free radicals production and antioxidant defenses, plays a pivotal role in the development and maintenance of neuropathic pain. Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to differentiate into various cell types and possess immunomodulatory, anti-inflammatory, and regenerative properties, making them promising candidates for novel pain management strategies. Preclinical studies demonstrate that MSCs can reduce inflammation, scavenge reactive oxygen species (ROS), promote nerve regeneration, and modulate pain signaling pathways. Various administration routes, including intravenous and intrathecal, have been investigated to optimize MSC delivery and efficacy. Additionally, MSC-derived extracellular vesicles (EVs) represent a cell-free alternative with substantial therapeutic potential. Despite encouraging preclinical findings, further research is needed to refine MSC-based therapies, including the exploration of combination treatments and rigorous clinical trials, to translate these promising results into effective clinical applications for neuropathic pain relief. This review explores the therapeutic potential of MSCs in alleviating oxidative stress-mediated neuropathic pain.

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.

As a hypothesis on the origins of mind and language, the evolutionary theory of the sensorimotor paradox suggests that capacities for imagination, self-representation and abstraction would operate from a dissociation in what is known as the forward model. In some studies, sensory perception is understood as a system of prediction and confirmation (feedforward and feedback processes) that would share common yet distinct and overlapping neural networks with mental imagery. The latter would then mostly operate through internal feedback processes. The hypothesis of our theory is that dissociation and parallelism between those processes would make it less likely for imaginary prediction to match and simultaneously coincide with any sensory feedback, contradicting the stimulus/response pattern. The gap between the two and the effort required to maintain this gap, born from the development of bipedal stance and a radical change to our relation to our own hands, would be the very structural foundation to our capacity to elaborate abstract thoughts, by partially blocking and inhibiting motor action. Mental imagery would structurally be dissociated from perception, though maintaining an intricated relation of interdependence. Moreover, the content of the images would be subordinate to their function as emotional regulators, prioritising consistency with some global, conditional and socially learnt body-image. As a higher-level and proto-aesthetic function, we can speculate that the action and instrumentalisation of dissociating imagination from perception would become the actual prediction and their coordination, the expected feedback.

Following cesarean section, a significant number of women encounter moderate to severe pain. Inadequate management of acute pain post-cesarean section can have far-reaching implications, adversely impacting maternal emotional well-being, daily activities, breastfeeding, and neonatal care. It may also impede maternal organ function recovery, leading to escalated opioid usage, heightened risk of postpartum depression, and the development of chronic postoperative pain. Both the Chinese Enhanced Recovery After Surgery (ERAS) guidelines and the American ERAS Society guidelines consistently advocate for the adoption of multimodal analgesia protocols in post-cesarean section pain management. Esketamine, functioning as an antagonist of the N-Methyl-D-Aspartate receptor, has been validated for pain management in surgical patients and has exhibited effectiveness in depression treatment. Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes. This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section.

To investigate the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.

A total of 315 women undergoing elective cesarean section under combined spinal-epidural anesthesia were randomized into three groups: low-dose esketamine (0.15 mg/kg), high-dose esketamine (0.25 mg/kg), and control (saline). Postoperative Visual Analog Scale (VAS) scores were recorded at 6 hours, 12 hours, 24 hours, and 48 hours. Edinburgh Postnatal Depression Scale (EPDS) scores were noted on 2 days, 7 days and 42 days. Ramsay sedation scores were assessed at specified intervals post-injection. Postoperative adverse reactions were also recorded.

Low-dose group and high-dose group compared to control group, had significantly lower postoperative VAS pain scores at 6 hours 12 hours, and 24 hours (P < 0.05), with reduced analgesic usage (P < 0.05). EPDS scores and postpartum depression rates were significantly lower on 2 days and 7 days (P < 0.05). No significant differences in first exhaust and defecation times were observed (P > 0.05), but ambulation times were shorter (P < 0.05). Ramsay scores were higher at 5 minutes, 15 minutes, and upon room exit (P < 0.05). Low-dose group and high-dose group had higher incidences of hallucination, lethargy, and diplopia within 2 hours (P < 0.05), and with low-dose group had lower incidences of hallucination, lethargy, and diplopia than high-dose group (P < 0.05).

Esketamine enhances analgesia and postpartum recovery; a 0.15 mg/kg dose is optimal for cesarean sections, balancing efficacy with minimized adverse effects.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.

Hyperalgesic priming, a form of pain plasticity initiated by initial injury, leads to heightened sensitivity to subsequent noxious stimuli, contributing to chronic pain development in animals. While astrocytes play active roles in modulating synaptic transmission in various pain models, their specific involvement in hyperalgesic priming remains elusive. Here, we show that spinal astrocytes are essential for hyperalgesic priming formation in a mouse model of acid-induced muscle pain. We observed spinal astrocyte activation 4 h after initial acid injection, and inhibition of this activation prevented chronic pain development upon subsequent acid injection. Chemogenetic activation of spinal astrocytes mimicked the first acid-induced hyperalgesic priming. We also demonstrated that spinal phosphorylated extracellular regulated kinase (pERK)-positive neurons were mainly vesicular glutamate transporter-2 positive (Vglut2+) neurons after the first acid injection, and inhibition of spinal pERK prevented astrocyte activation. Furthermore, pharmacological inhibition of astrocytic glutamate transporters glutamate transporter-1 and glutamate-aspartate transporter abolished the hyperalgesic priming. Collectively, our results suggest that pERK activation in Vglut2+ neurons activate astrocytes through astrocytic glutamate transporters. This process eventually establishes hyperalgesic priming through spinal D-serine. We conclude that spinal astrocytes play a crucial role in the transition from acute to chronic pain.

The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the "fight-or-flight response". Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis.

Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission. As such, it represents a druggable target to treat neuropathic pain. This study aims at investigating the therapeutic potential of the novel compound (+)-2R/S-LP2, a σ1R antagonist, in reducing painful behaviour and modulating the neuroinflammatory environment. We showed that repeated administration of the compound significantly inhibited mechanical allodynia in neuropathic rats, increasing the withdrawal threshold as compared to CCI-vehicle rats. Moreover, we found that (+)-2R/S-LP2-mediated effects resolve the neuroinflammatory microenvironment by reducing central gliosis and pro-inflammatory cytokines expression levels. This effect was coupled with a significant reduction of connexin 43 (Cx43) expression levels and gap junctions/hemichannels mediated microglia-to-astrocyte communication. These results suggest that inhibition of σ1R significantly attenuates neuropathic pain chronicization, thus representing a viable effective strategy.

Satellite glial cells (SGCs) are the main type of glial cells in sensory ganglia. Animal studies have shown that these cells play essential roles in both normal and disease states. In a large number of pain models, SGCs were activated and contributed to the pain behavior. Much less is known about SGCs in humans, but there is emerging recognition that SGCs in humans are altered in a variety of clinical states. The available data show that human SGCs share some essential features with SGCs in rodents, but many differences do exist. SGCs in DRG from patients suffering from common painful diseases, such as rheumatoid arthritis and fibromyalgia, may contribute to the pain phenotype. It was found that immunoglobulins G (IgG) from fibromyalgia patients can induce pain-like behavior in mice. Moreover, these IgGs bind preferentially to SGCs and activate them, which can sensitize the sensory neurons, causing nociception. In other human diseases, the evidence is not as direct as in fibromyalgia, but it has been found that an antibody from a patient with rheumatoid arthritis binds to mouse SGCs, which leads to the release of pronociceptive factors from them. Herpes zoster is another painful disease, and it appears that the zoster virus resides in SGCs, which acquire an abnormal morphology and may participate in the infection and pain generation. More work needs to be undertaken on SGCs in humans, and this review points to several promising avenues for better understanding disease mechanisms and developing effective pain therapies.

Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a mechanism we believe to be novel in which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observed in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrated that Fabry rat sensory neurons exhibited pronounced hyperexcitability. Schwann cells probably contributed to this finding because application of mediators released from cultured Fabry Schwann cells induced spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells released elevated levels of the protein p11 (S100A10), which induced sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media caused hyperpolarization of neuronal resting membrane potentials, indicating that p11 may contribute to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that sensory neurons from rats with Fabry disease exhibit hyperactivity caused in part by Schwann cell release of the protein p11.

Since its description in 2016, the erector spinae plane block (ESPB) has become a widely employed regional anesthetic technique and kindled interest in a range of related techniques, collectively termed intertransverse process blocks. There has been ongoing controversy over mechanism of action of the ESPB, mainly due to incongruities between results of cutaneous sensory testing, clinical efficacy studies, and investigations into the neural structures that are reached by injected local anesthetic (LA). This paper reviews the spread of LA to the paravertebral and epidural space and the cutaneous anesthesia in ESPB, with specific emphasis on the dorsal root ganglion (DRG). We hypothesize that the DRG, due to its unique and complex microarchitecture, represents a key therapeutic target for modulation of nociceptive signaling in regional anesthesia. This paper discusses how the anatomical and physiological characteristics of the DRG may be one of the factors underpinning the clinical analgesia observed in ESPB and other intertransverse process blocks.

Individuals recovering from acute COVID-19 episodes may continue to suffer from various ongoing symptoms, collectively referred to as Long-COVID. Long-term pain symptoms are amongst the most common and clinically significant symptoms to be reported for this post-COVID-19 syndrome.

This systematic review and meta-analysis aimed to evaluate the proportions of persisting pain symptoms experienced by individuals past the acute phase of COVID-19 and to identify their associated functional consequences and inflammatory correlates.

Two online databases were systematically searched from their inception until 31 March 2022. We searched primary research articles in English, which evaluated individuals after laboratory-confirmed COVID-19 acute phase resolution and specifically reported on pain symptoms and their inflammatory and/or functional outcomes.

Of the 611 identified articles, 26 were included, used for data extraction, and assessed for their methodological quality and risk of bias by two independent reviewers. Pain symptoms were grouped under one of six major pain domains, serving as our primary co-outcomes. Proportional meta-analyses of pooled logit-transformed values of single proportions were performed using the random-effects-restricted maximum-likelihood model. An estimated 8%, 6%, 18%, 18%, 17%, and 12% of individuals continued to report the persistence of chest, gastrointestinal, musculoskeletal joint, musculoskeletal muscle, general body, and nervous system-related pain symptoms, respectively, for up to one year after acute phase resolution of COVID-19. Considerable levels of heterogeneity were demonstrated across all results. Functional and quality-of-life impairments and some inflammatory biomarker elevations were associated with the persistence of long-COVID pain symptoms.

This study's findings suggest that although not well characterized, long-COVID pain symptoms are being experienced by non-negligible proportions of those recovering from acute COVID-19 episodes, thus highlighting the importance of future research efforts to focus on this aspect.

Phoenixin-14 (PNX), initially discovered in the rat hypothalamus, was also detected in dorsal root ganglion (DRG) cells, where its involvement in the regulation of pain and/or itch sensation was suggested. However, there is a lack of data not only on its distribution in DRGs along individual segments of the spinal cord, but also on the pattern(s) of its co-occurrence with other sensory neurotransmitters. To fill the above-mentioned gap and expand our knowledge about the occurrence of PNX in mammalian species other than rodents, this study examined (i) the pattern(s) of PNX occurrence in DRG neurons of subsequent neuromeres along the porcine spinal cord, (ii) their intraganglionic distribution and (iii) the pattern(s) of PNX co-occurrence with other biologically active agents. PNX was found in approximately 20% of all nerve cells of each DRG examined; the largest subpopulation of PNX-positive (PNX+) cells were small-diameter neurons, accounting for 74% of all PNX-positive neurons found. PNX+ neurons also co-contained calcitonin gene-related peptide (CGRP; 96.1%), substance P (SP; 88.5%), nitric oxide synthase (nNOS; 52.1%), galanin (GAL; 20.7%), calretinin (CRT; 10%), pituitary adenylate cyclase-activating polypeptide (PACAP; 7.4%), cocaine and amphetamine related transcript (CART; 5.1%) or somatostatin (SOM; 4.7%). Although the exact function of PNX in DRGs is not yet known, the high degree of co-localization of this peptide with the main nociceptive transmitters SP and CGRP may suggests its function in modulation of pain transmission.

Pain is a main symptom in inflammation, and inflammation induces pain via inflammatory mediators acting on nociceptive neurons. Macrophages and microglia are distinct cell types, representing immune cells and glial cells, respectively, but they share similar roles in pain regulation. Macrophages are key regulators of inflammation and pain. Macrophage polarization plays different roles in inducing and resolving pain. Notably, macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators (SPMs). SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation. In this review, we discuss macrophage signaling involved in pain induction and resolution, as well as in maintaining physiological pain. Microglia are macrophage-like cells in the central nervous system (CNS) and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders. Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators. We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain. Thus, targeting macrophage and microglial signaling in distinct locations via pharmacological approaches, including immunotherapies, and non-pharmacological approaches will help to control chronic inflammation and chronic pain.

Current treatments for chronic pain are inadequate. Here, we provide an update on the new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain.

Despite the complex nature of chronic pain and its underlying mechanisms, we do know that changes in the plasticity and modality of neurons in DRGs play a pivotal role. DRG neurons are heterogenous and offer potential pain targets for different therapeutic interventions. We discuss the last advancements of these interventions, which include the use of systemic and local administrations, selective nerve drug delivery, and gene therapy. In particular, we provide updates and further details on the molecular characterization of primary sensory neurons, new analgesics entering the market, and future gene therapy approaches.

DRGs and primary sensory neurons are promising targets for chronic pain treatment due to their key role in pain signaling, unique anatomical location, and the potential for different targeted therapeutic interventions.

The normal ligamentum flavum (LF) is a well-defined elastic structure with specific innervation. Several studies investigated LF in patients with lumbar spinal stenosis (LSS) and used lumbar discus hernia (LDH) patients as control group, only on the presumed thesis that LF in this patients have normal morphology. In patients with LSS thickening of the LF is the main cause of stenosis, which is most often presented with neurogenic claudication, whose pathophysiological mechanism is not completely understood. We conducted observational cohort study of 60 operated patients divided into two groups. The first group of 30 patients underwent micro-discectomy (LSH group), and second group with 30 patients underwent decompression, after which analysis of harvested LF was performed. Patients from the LDH group and LSS group differed significantly in the frequencies of chief complaints, duration of symptoms, physical examination, and specific morphological/radiological parameters. The LF analysis showed that the groups differed significantly in the amount of collagen and elastic fibers, as well as in the histological appearance/architectonics of elastic fibers. Also, groups differ in the presence of LF nerve fibers. Our findings speak in favor of the recently postulated inflammatory theory in the origin of spinal neurogenic claudication's.

Chronic pain is one of the most common clinical syndromes affecting patients' quality of life. Regulating the transition from acute to chronic pain is a novel therapeutic strategy for chronic pain that presents a major clinical challenge. However, the mechanism underlying pain transitions remains poorly understood. A rat hyperalgesic priming (HP) model, which mimics pain transition, was established decades ago. Here, this HP model and RNA sequencing (RNA-seq) were used to study the potential role of neuroinflammation in pain transition. In this study, HP model rats developed prolonged hyperalgesia in the hind paw after carrageenan (Car) and PGE2 injection, accompanied by obvious satellite glial cell (SGC) activation in the dorsal root ganglion (DRG), as indicated by upregulation of GFAP. RNA-Seq identified a total of differentially expressed genes in the ipsilateral DRG in HP model rats. The expression of several representative genes was confirmed by real-time quantitative PCR (qPCR). Functional analysis of the differentially expressed genes indicated that genes related to the inflammatory and neuroinflammatory response showed the most significant changes in expression. We further found that the expression of the chemokine CXCL1 was significantly upregulated in the rat DRG. Pharmacological blockade of CXCL1 reduced protein kinase C epsilon overproduction as well as hyperalgesia in HP rats but did not prevent the upregulation of GFAP in the DRG. These results reveal that neuroinflammatory responses are involved in pain transition and may be the source of chronic pain. The chemokine CXCL1 in the DRG is a pivotal contributor to chronic pain and pain transition in HP model rats. Thus, our study provides a putative novel target for the development of effective therapeutics to prevent pain transition.