Neuroinflammation influences the development of chronic pain, an increasingly prevalent condition impacting the lives of many worldwide. Given the challenges of managing chronic pain, it is essential to explore new neuroimmune targets for the development of safe and effective analgesics. α7 nicotinic acetylcholine receptors (α7 nAChR) have been explored for their role in pain and inflammation. It was hypothesized that α7 nAChR expression within myeloid cells mediates an anti-inflammatory response that mitigates pain states. Two mouse strains were engineered, with deletion of the α7 gene (Chrna7) globally and from myeloid lineage cells conditionally. These mice were characterized in chemotherapy-induced peripheral neuropathy (CIPN) using paclitaxel and acute and chronic inflammatory pain models. Spontaneous and evoked pain-related behaviors, gene expression of pro-inflammatory cytokines in peripheral nervous tissue, and other physiological parameters were measured. Additionally, RNA-sequencing and pathway enrichment analysis of spinal cord tissues from mice treated with paclitaxel were performed. Mice deficient for α7 nAChR in myeloid cells showed a marked increase in evoked pain behaviors in CIPN and chronic inflammatory models with a corresponding increase in gene expression of key pro-inflammatory cytokines in the peripheral sensory nervous system. Enrichment analysis identified changes in pathways pertaining to vascular function and enriched pathways associated with extracellular matrix function and angiogenesis in conditional knock-out mice treated with paclitaxel. This study suggests α7 nAChR expression in myeloid cells mediates an endogenous cholinergic anti-inflammatory pathway, which plays a critical role in chronic neuropathic and inflammatory pain and is an important target for developing novel analgesic agents. PERSPECTIVE: This article presents evidence that α7 nicotinic receptors located on myeloid cells are critical for attenuating neuropathic and chronic inflammatory pain. This provides new insight into a cellular target for the treatment of these conditions.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment. Paclitaxel activates peripheral macrophages, generating a neuroinflammatory response that contributes to CIPN development and maintenance. Astrocyte Elevated Gene-1 (AEG-1), also known as Metadherin or LYRIC, is a multifunctional protein that modulates macrophage activity and regulates inflammation through direct interaction with NF-κB, a transcriptional regulator of proinflammatory cytokine/chemokine (PIC) expression. We aimed to determine whether AEG-1 contributes to the development and maintenance of CIPN pathologies by using both global (AEG-1 KO) and myelocyte-specific knockout (AEG-1ΔMAC) transgenic mouse strains in an animal model of CIPN that replicates specific human clinical phenotypes. We hypothesized that inhibition of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the development and maintenance of CIPN. Our results showed that global AEG-1 deletion prevented the development of CIPN pathologies induced by PAC, as well as oxaliplatin (OHP). PAC treatment was found to increase AEG-1 and PIC expression in the DRGs of WT mice and in peritoneal macrophages isolated from C57BL/6J mice. However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice. This preventative phenotype and PIC expression profile was mirrored in AEG-1ΔMAC mice, which also displayed reduced NF-κB protein levels and F4/80+ macrophages trafficked to the lumbar DRGs following PAC treatment. In summary, our results are the first to demonstrate the biological role AEG-1, particularly in myeloid cells, in development of CIPN.

A 47-year-old man with a history of transposition of the great arteries after a Mustard atrial switch procedure and prior inferior vena cava filter placement for venous thromboembolism presented for removal before being listed for orthotopic heart transplantation in anticipation of cardiopulmonary bypass cannulation. The filter was retrieved using a right transjugular approach without disruption of his existing atrial baffle. Contingency planning in the event of unsuccessful baffle navigation included a transfemoral everted filter approach. A thorough understanding of unique patient anatomy and multidisciplinary team approach is critical to safe procedural intervention in patients with congenital cardiovascular anomalies.

IntroductionLarge population-based studies have suggested a link between increased alcohol use and reduced pain. In addition, these studies suggest that higher levels of pain intensity are associated with an increase in alcohol consumption and rates of hazardous drinking which potentiates the risk of developing alcohol use disorders (AUD). The mechanisms and determinants of the alcohol-pain interaction can be studied in preclinical studies.MethodsThe overall goal of this study is to use animal models to explore the impact of acute postoperative pain on alcohol intake. To achieve this, we characterized the timeline and levels of alcohol intake and preference in mice after laparotomy in the 2-bottle choice paradigm.ResultsOur results show that laparotomy surgery increased alcohol intake and preference in male mice but not females in the 2-bottle choice and 3-bottle choice assays. In addition, ketoprofen administration blocked the increase in alcohol consumption in male mice after laparotomy. We also found that changes in alcohol initial sensitivity and acute functional tolerance, using loss of righting reflex (LORR) response, occur after surgery in mice.ConclusionTaken together, these findings suggests that sex, pain and alcohol sensitivity-related factors may modulate the relationship between alcohol consumption and pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment for cancer patients. Taxanes, such as Paclitaxel, are a class of chemotherapeutics associated with high prevalence of CIPN development in patients. Taxanes are known to activate peripheral macrophages, generating a neurotoxic inflammatory response that contributes to the development and maintenance of neuropathy. Astrocyte Elevated Gene-1 (AEG-1) is a multifunctional protein that operates in a variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with NFκB, a transcriptional regulator of proinflammatory cytokine (PIC) expression. Our goal is to investigate if AEG-1 contributes to the development and maintenance of Paclitaxel-Induced Peripheral Neuropathy (PIPN) and associated neuroinflammation in dorsal root ganglia (DRG). Twelve- to 24-week old AEG-1 global knockout (KO) and wildtype (WT) male and female mice on C57BL/6J background were used in a model of CIPN produced by administration of four 8 mg/kg, i.p. injections of paclitaxel. Mechanical hypersensitivity and cold sensitivity were assessed via Von Frey filaments and acetone test, respectively. mRNA expression was quantified via qRT-PCR. Plasma level concentrations of paclitaxel were assessed via mass spectrometry. AEG-1 KO mice displayed protection from paclitaxel-induced mechanical hypersensitivity and cold sensitivity, unlike their WT counterparts. Paclitaxel increased the expression of AEG-1 and multiple PIC (TNFα, IL1-β, IL-6) in the DRGs of male WT mice. However, these cytokine levels were unchanged in paclitaxel treated AEG-1 KO male mice. Plasma concentration levels of paclitaxel did not differ between AEG-1 KO or WT mice at any time following drug administration. Our data suggest that AEG-1 plays a significant role in the development and maintenance of paclitaxel-induced mechanical and cold hypersensitivity. And that the expression of AEG-1 mediates paclitaxel-induced neuroinflammation in the DRGs. Grant support from 1R01CA221260-01. Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment for cancer patients. Taxanes, such as Paclitaxel, are a class of chemotherapeutics associated with high prevalence of CIPN development in patients. Taxanes are known to activate peripheral macrophages, generating a neurotoxic inflammatory response that contributes to the development and maintenance of neuropathy. Astrocyte Elevated Gene-1 (AEG-1) is a multifunctional protein that operates in a variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with NFκB, a transcriptional regulator of proinflammatory cytokine (PIC) expression. Our goal is to investigate if AEG-1 contributes to the development and maintenance of Paclitaxel-Induced Peripheral Neuropathy (PIPN) and associated neuroinflammation in dorsal root ganglia (DRG). Twelve- to 24-week old AEG-1 global knockout (KO) and wildtype (WT) male and female mice on C57BL/6J background were used in a model of CIPN produced by administration of four 8 mg/kg, i.p. injections of paclitaxel. Mechanical hypersensitivity and cold sensitivity were assessed via Von Frey filaments and acetone test, respectively. mRNA expression was quantified via qRT-PCR. Plasma level concentrations of paclitaxel were assessed via mass spectrometry. AEG-1 KO mice displayed protection from paclitaxel-induced mechanical hypersensitivity and cold sensitivity, unlike their WT counterparts. Paclitaxel increased the expression of AEG-1 and multiple PIC (TNFα, IL1-β, IL-6) in the DRGs of male WT mice. However, these cytokine levels were unchanged in paclitaxel treated AEG-1 KO male mice. Plasma concentration levels of paclitaxel did not differ between AEG-1 KO or WT mice at any time following drug administration. Our data suggest that AEG-1 plays a significant role in the development and maintenance of paclitaxel-induced mechanical and cold hypersensitivity. And that the expression of AEG-1 mediates paclitaxel-induced neuroinflammation in the DRGs. Grant support from 1R01CA221260-01.

Paclitaxel is widely used in the treatment of various types of solid malignancies. Paclitaxel-induced peripheral neuropathy (PIPN) is often characterized by burning pain, cold, and mechanical allodynia in patients. Currently, specific pharmacological treatments against PIPN are lacking. Curcumin, a polyphenol of Curcuma longa, shows antioxidant, anti-inflammatory, and neuroprotective effects and has recently shown efficacy in the mitigation of various peripheral neuropathies. Here, we tested, for the first time, the therapeutic effect of 1.5% dietary curcumin and Meriva (a lecithin formulation of curcumin) in preventing the development of PIPN in C57BL/6J mice. Curcumin or Meriva treatment was initiated one week before injection of paclitaxel and continued throughout the study (21 days). Mechanical and cold sensitivity as well as locomotion/motivation were tested by the von Frey, acetone, and wheel-running tests, respectively. Additionally, sensory-nerve-action-potential (SNAP) amplitude by caudal-nerve electrical stimulation, electronic microscopy of the sciatic nerve, and inflammatory-protein quantification in DRG and the spinal cord were measured. Interestingly, a higher concentration of curcumin was observed in the spinal cord with the Meriva diet than the curcumin diet. Our results showed that paclitaxel-induced mechanical hypersensitivity was partially prevented by the curcumin diet but completely prevented by Meriva. Both the urcumin diet and the Meriva diet completely prevented cold hypersensitivity, the reduction in SNAP amplitude and reduced mitochondrial pathology in sciatic nerves observed in paclitaxel-treated mice. Paclitaxel-induced inflammation in the spinal cord was also prevented by the Meriva diet. In addition, an increase in α7 nAChRs mRNA, known for its anti-inflammatory effects, was also observed in the spinal cord with the Meriva diet in paclitaxel-treated mice. The use of the α7 nAChR antagonist and α7 nAChR KO mice showed, for the first time in vivo, that the anti-inflammatory effects of curcumin in peripheral neuropathy were mediated by these receptors. The results presented in this study represent an important advance in the understanding of the mechanism of action of curcumin in vivo. Taken together, our results show the therapeutic potential of curcumin in preventing the development of PIPN and further confirms the role of α7 nAChRs in the anti-inflammatory effects of curcumin.

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is a major adverse effect of this chemotherapeutic agent that is used in the treatment of a number of solid malignancies. PIPN leads notably to burning pain, cold and mechanical allodynia. PIPN is thought to be a consequence of alterations of mitochondrial function, hyperexcitability of neurons, nerve fiber loss, oxidative stress and neuroinflammation in dorsal root ganglia (DRG) and spinal cord (SC). Therefore, reducing neuroinflammation could potentially attenuate neuropathy symptoms. Peroxisome proliferator-activated receptor-α (PPAR-α) nuclear receptors that modulate inflammatory responses can be targeted by non-selective agonists, such as fenofibrate, which is used in the treatment of dyslipidemia. Methods: Our studies tested the efficacy of a fenofibrate diet (0.2% and 0.4%) in preventing the development of PIPN. Paclitaxel (8 mg/kg) was administered via 4 intraperitoneal (i.p.) injections in C57BL/6J mice (both male and female). Mechanical and cold hypersensitivity, wheel running activity, sensory nerve action potential (SNAP), sciatic nerve histology, intra-epidermal fibers, as well as the expression of PPAR-α and neuroinflammation were evaluated in DRG and SC. Results: Fenofibrate in the diet partially prevented the development of mechanical hypersensitivity but completely prevented cold hypersensitivity and the decrease in wheel running activity induced by paclitaxel. The reduction in SNAP amplitude induced by paclitaxel was also prevented by fenofibrate. Our results indicate that suppression of paclitaxel-induced pain by fenofibrate involves the regulation of PPAR-α expression through reduction in neuroinflammation. Finally, co-administration of paclitaxel and the active metabolite of fenofibrate (fenofibric acid) did not interfere with the suppression of tumor cell growth or clonogenicity by paclitaxel in ovarian and breast cancer cell lines. Conclusions: Taken together, our results show the therapeutic potential of fenofibrate in the prevention of PIPN development.

Patients treated with cancer chemotherapeutics frequently report chemotherapy-induced peripheral neuropathy (CIPN), changes in mood (depression and anxiety) and functional impairments. Rodent models of CIPN elicit limited alterations in functional behaviors, which pose challenges in developing preclinical models of chemotherapy-induced behavioral depression. The study examined the consequences of chemotherapy-induced mechanical hypersensitivity (paclitaxel: 32 or 64 mg/kg, cumulative; oxaliplatin: 30 mg/kg, cumulative) on behavioral depression, as measured with operant responding for palatable food during periods of food restriction and ad libitum chow, consumption of noncontingently available palatable food in the presence of ad libitum chow, and voluntary wheel running. The study employed two inbred mouse strains (C57BL/6J and Balb/cJ) and examined potential sex differences. All chemotherapeutic regimens caused profound mechanical hypersensitivity for the duration of the observation periods (up to 7 months), but no treatments changed voluntary wheel running or consumption of noncontingent palatable food. The high dose of paclitaxel temporarily reduced operant responding for palatable food in male C57BL/6J mice undergoing food restriction or maintained on ad libitum chow. However, paclitaxel failed to decrease operant responding for palatable food in free-feeding female C57BL/6J mice or Balb/cJ mice of either sex. Moreover, oxaliplatin did not significantly alter operant responding for palatable food in male or female C57BL/6J mice maintained on ad libitum chow. These findings demonstrate a dissociation between chemotherapy-induced mechanical hypersensitivity and behavioral depression. The transient effects of paclitaxel on operant responding in male C57BL/6J mice may represent a fleeting behavioral correlate of chemotherapy-associated pain-like behaviors.

Peripheral neuropathies (PN) can be triggered after metabolic diseases, traumatic peripheral nerve injury, genetic mutations, toxic substances, and/or inflammation. PN is a major clinical problem, affecting many patients and with few effective therapeutics. Recently, interest in natural dietary compounds, such as polyphenols, in human health has led to a great deal of research, especially in PN. Curcumin is a polyphenol extracted from the root of Curcuma longa. This molecule has long been used in Asian medicine for its anti-inflammatory, antibacterial, and antioxidant properties. However, like numerous polyphenols, curcumin has a very low bioavailability and a very fast metabolism. This review addresses multiple aspects of curcumin in PN, including bioavailability issues, new formulations, observations in animal behavioral tests, electrophysiological, histological, and molecular aspects, and clinical trials published to date. The, review covers in vitro and in vivo studies, with a special focus on the molecular mechanisms of curcumin (anti-inflammatory, antioxidant, anti-endoplasmic reticulum stress (anti-ER-stress), neuroprotection, and glial protection). This review provides for the first time an overview of curcumin in the treatment of PN. Finally, because PN are associated with numerous pathologies (e.g., cancers, diabetes, addiction, inflammatory disease...), this review is likely to interest a large audience.

Patients with chronic pain report decreased general activity and emotional distress. Therefore, the development of various animal models that encompass different aspects of pain are crucial for the discovery of genetic differences and the assessment of novel analgesics to improve quality of life. C57BL/6J and DBA/2J mice received unilateral intraplantar injections of 100 % CFA, paclitaxel, or CCI surgery to compare their distance traveled in a voluntary wheel running assay, paw edema diameter, and mechanical sensitivity. Mechanical withdrawal thresholds were lower in both strains of mice that received CFA when compared to their vehicle. However, a decrease in distance traveled was observed in CFA-treated C57BL/6J but not DBA/2J mice. In a separate group, chemotherapy agent paclitaxel 8 mg/kg, i.p. was administered to both strains of mice to induce CIPN which was confirmed by lower mechanical thresholds in paclitaxel-treated mice compared to vehicle-treated mice. Only female C57BL/6J mice showed attenuation of distance traveled following treatment, whereas male C57BL/6J and DBA/2J mice did not. Lastly, C57BL/6J mice underwent chronic constriction injury (CCI) or sham surgery to observe the impact of another chronic neuropathic pain model in wheel running assay. CCI mice showed a gradual decrease in mechanical withdrawal threshold and a decrease in distance traveled compared to sham 5 days following the procedure. Comparing these chronic inflammatory and neuropathic pain models in different mouse strains may help us better understand genetic differences underlying pain perception and its impact on reflexive and nonreflexive outcome measures.