Development and Evaluation of a Hybrid Measurement System to Determine the Kinematics of the Wrist.

Optical Motion Capture Systems (OMCSs) are considered the gold standard for kinematic measurement of human movements. However, in situations such as measuring wrist kinematics during a hairdressing activity, markers can be obscured, resulting in a loss of data. Other measurement methods based on non-optical data can be considered, such as magneto-inertial measurement units (MIMUs). Their accuracy is generally lower than that of an OMCS. In this context, it may be worth considering a hybrid system [MIMU + OMCS] to take advantage of OMCS accuracy while limiting occultation problems. The aim of this work was (1) to propose a methodology for coupling a low-cost MIMU (BNO055) to an OMCS in order to evaluate wrist kinematics, and then (2) to evaluate the accuracy of this hybrid system [MIMU + OMCS] during a simple hairdressing gesture. During hair cutting gestures, the root mean square error compared with the OMCS was 4.53° (1.45°) for flexion/extension, 5.07° (1.30°) for adduction/abduction, and 3.65° (1.19°) for pronation/supination. During combing gestures, they were significantly higher, but remained below 10°. In conclusion, this system allows for maintaining wrist kinematics in case of the loss of hand markers while preserving an acceptable level of precision (<10°) for ergonomic measurement or entertainment purposes.

Identification of bacterial lipopeptides as key players in IBS.

OBJECTIVES: Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA). DESIGN: We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity. RESULTS: Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus, in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs. CONCLUSION: PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.

Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life.

BACKGROUND: Perinatal exposure to titanium dioxide (TiO2), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel disease (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2'-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis. RESULTS: In pregnant and lactating mice, foodborne TiO2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO2-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring. CONCLUSIONS: Our findings indicate that foodborne TiO2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.

Influence of Normal Aging and Multisensory Data Fusion on Cybersickness and Postural Adaptation in Immersive Virtual Reality.

Immersive Virtual Reality (VR) systems are expanding as sensorimotor readaptation tools for older adults. However, this purpose may be challenged by cybersickness occurrences possibly caused by sensory conflicts. This study aims to analyze the effects of aging and multisensory data fusion processes in the brain on cybersickness and the adaptation of postural responses when exposed to immersive VR. METHODS: We repeatedly exposed 75 participants, aged 21 to 86, to immersive VR while recording the trajectory of their Center of Pressure (CoP). Participants rated their cybersickness after the first and fifth exposure. RESULTS: The repeated exposures increased cybersickness and allowed for a decrease in postural responses from the second repetition, i.e., increased stability. We did not find any significant correlation between biological age and cybersickness scores. On the contrary, even if some postural responses are age-dependent, a significant postural adaptation occurred independently of age. The CoP trajectory length in the anteroposterior axis and mean velocity were the postural parameters the most affected by age and repetition. CONCLUSIONS: This study suggests that cybersickness and postural adaptation to immersive VR are not age-dependent and that cybersickness is unrelated to a deficit in postural adaptation or age. Age does not seem to influence the properties of multisensory data fusion.

Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis.

BACKGROUND: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. METHODS: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. CONCLUSION: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.

Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis.

OBJECTIVE: Data from clinical research suggest that certain probiotic bacterial strains have the potential to modulate colonic inflammation. Nonetheless, these data differ between studies due to the probiotic bacterial strains used and the poor knowledge of their mechanisms of action. DESIGN: By mass-spectrometry, we identified and quantified free long chain fatty acids (LCFAs) in probiotics and assessed the effect of one of them in mouse colitis. RESULTS: Among all the LCFAs quantified by mass spectrometry in Escherichia coli Nissle 1917 (EcN), a probiotic used for the treatment of multiple intestinal disorders, the concentration of 3-hydroxyoctadecaenoic acid (C18-3OH) was increased in EcN compared with other E. coli strains tested. Oral administration of C18-3OH decreased colitis induced by dextran sulfate sodium in mice. To determine whether other bacteria composing the microbiota are able to produce C18-3OH, we targeted the gut microbiota of mice with prebiotic fructooligosaccharides (FOS). The anti-inflammatory properties of FOS were associated with an increase in colonic C18-3OH concentration. Microbiota analyses revealed that the concentration of C18-3OH was correlated with an increase in the abundance in Allobaculum, Holdemanella and Parabacteroides. In culture, Holdemanella biformis produced high concentration of C18-3OH. Finally, using TR-FRET binding assay and gene expression analysis, we demonstrated that the C18-3OH is an agonist of peroxisome proliferator activated receptor gamma. CONCLUSION: The production of C18-3OH by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. The production of LCFA-3OH by bacteria could be implicated in the microbiota/host interactions.

Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice.

OBJECTIVE: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes. DESIGN: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human. RESULTS: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic. CONCLUSIONS: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

Peripheral Opioid Receptor Blockade Enhances Epithelial Damage in Piroxicam-Accelerated Colitis in IL-10-Deficient Mice.

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.

Polyunsaturated fatty acid metabolites: biosynthesis in Leishmania and role in parasite/host interaction.

Inside the human host, Leishmania infection starts with phagocytosis of infective promastigotes by macrophages. In order to survive, Leishmania has developed several strategies to manipulate macrophage functions. Among these strategies, Leishmania as a source of bioactive lipids has been poorly explored. Herein, we assessed the biosynthesis of polyunsaturated fatty acid metabolites by infective and noninfective stages of Leishmania and further explored the role of these metabolites in macrophage polarization. The concentration of docosahexaenoic acid metabolites, precursors of proresolving lipid mediators, was increased in the infective stage of the parasite compared with the noninfective stage, and cytochrome P450-like proteins were shown to be implicated in the biosynthesis of these metabolites. The treatment of macrophages with lipids extracted from the infective forms of the parasite led to M2 macrophage polarization and blocked the differentiation into the M1 phenotype induced by IFN-γ. In conclusion, Leishmania polyunsaturated fatty acid metabolites, produced by cytochrome P450-like protein activity, are implicated in parasite/host interactions by promoting the polarization of macrophages into a proresolving M2 phenotype.

Nod2: The intestinal gate keeper.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host-pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses' and parasites' infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.

Endogenous analgesia mediated by CD4(+) T lymphocytes is dependent on enkephalins in mice.

BACKGROUND: T cell-derived opioids play a key role in the control of inflammatory pain. However, the nature of opioids produced by T cells is still matter of debate in mice. Whereas ß-endorphin has been found in T lymphocytes by using antibody-based methods, messenger RNA (mRNA) quantification shows mainly mRNA encoding for enkephalins. The objective of the study is to elucidate the nature of T cell-derived opioids responsible for analgesia and clarify discrepancy of the results at the protein and genetic levels. METHODS: CD4(+) T lymphocytes were isolated from wild-type and enkephalin-deficient mice. mRNA encoding for ß-endorphin and enkephalin was quantified by RT-qPCR. The binding of commercially available polyclonal anti-endorphin antibodies to lymphocytes from wild-type or enkephalin knockout mice was assessed by cytofluorometry. Opioid-mediated analgesic properties of T lymphocytes from wild-type and enkephalin-deficient mice were compared in a model of inflammation-induced somatic pain by measuring sensitivity to mechanical stimuli using calibrated von Frey filaments. RESULTS: CD4(+) T lymphocytes expressed high level of mRNA encoding for enkephalins but not for ß-endorphin in mice. Anti-ß-endorphin polyclonal IgG antibodies are specific for ß-endorphin but cross-react with enkephalins. Anti-ß-endorphin polyclonal antibodies bound to wild-type but not enkephalin-deficient CD4(+) T lymphocytes. Endogenous regulation of inflammatory pain by wild-type T lymphocytes was completely abolished when T lymphocytes were deficient in enkephalins. Pain behavior of immune-deficient (i.e., without B and T lymphocytes) mice was superimposable to that of mice transferred with enkephalin-deficient lymphocytes. CONCLUSIONS: Rabbit polyclonal anti-ß-endorphin serum IgG bind to CD4(+) T lymphocytes because of their cross-reactivity towards enkephalins. Thus, staining of T lymphocytes by anti-ß-endorphin polyclonal IgG reported in most of studies in mice is because of their binding to enkephalins. In mice, CD4(+) T lymphocytes completely lose their analgesic opioid-mediated activity when lacking enkephalins.

TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis.

Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild-type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1-deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation.

Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice.

BACKGROUND & AIMS: A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice. METHODS: Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention. RESULTS: In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T-helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation-associated visceral hypersensitivity. CONCLUSIONS: In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain.

Learning to tune the antero-posterior propulsive forces during walking: a necessary skill for mastering upright locomotion in toddlers.

This study examines the process of learning to walk from a functional perspective. To move forward, one must generate and control propulsive forces. To achieve this, it is necessary to create and tune a distance between the centre of mass (CoM) and the centre of pressure (CoP) along the antero-posterior axis. We hypothesize that learning to walk consists of learning how to calibrate these self-generated propulsive forces to control such distance. We investigated this question with six infants (three girls and three boys) who we followed up weekly for the first 8 weeks after the onset of walking and then biweekly until they reached 14-16 weeks of walking experience. The infants' walking patterns (kinematics and propelling forces) were captured via synched motion analysis and force plate. The results show that the distance between the CoM and the CoP along the antero-posterior axis increased rapidly during the first months of learning to walk and that this increase was correlated with an increase in velocity. The initial small values of (CoM-CoP) observed at walking onset, coupled with small velocity are interpreted as the solution infants adopted to satisfy a compromise between the need to generate propulsive forces to move forward while simultaneously controlling the disequilibrium resulting from creating a with distance between the CoM and CoP.

Thoracic spinous process nonunion as an unusual cause of back pain: a case report and review of the literature.

BACKGROUND: Purely isolated spinous processes fractures are rare and are usually treated conservatively, although a few authors have reported cases of nonunion that ultimately required surgical resection. CASE PRESENTATION: We present a case of an isolated T6 spinous process pseudoarthrosis that was treated by surgical resection of the tip of the spinous process. A 34-year-old Caucasian male patient was complaining of mid-thoracic back pain without neurologic impairment more than 2 years after an isolated spinous process fracture. Magnetic Resonance Imaging (MRI) and Single Photon Emission Computed Tomography (SPECT) revealed a nonunion. We performed a resection without further complication. CONCLUSION: Although spinous process nonunions may in some cases be well tolerated, surgical resection appears to be a reliable option in case of persistent symptoms. This illustrated case shows the description of an isolated thoracic spinous process nonunion and its surgical treatment.

Alternative activation of mast cells by CD4+ T helper cells.

Effector CD4+ T lymphocytes (Teff) infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells strategically located near blood vessels and T cell rich areas. MC/Teff cells interactions shape Teff cell responses but in turn, Teff cell action on MC is still poorly understood. Here, we analyzed the human MC/Teff cells interplay through both the application of RNAseq and functional assays. We showed that activated Teff cells induce a specific transcriptomic program in MCs including production of both inflammatory cytokines and chemokines, prostaglandin, and a FcεRI-dependent degranulation facilitation thereby driving them toward an inflammatory phenotype. Moreover, Teff cells induce in MCs the capacity to interact with CD4+ T cell through a wide-range of dedicated soluble and membrane ligands and to play the role of antigen presenting cells (APCs).

Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice.

CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor.

BACKGROUND & AIMS: Nutrients influence non-alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes, including hepatic steatosis, through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified. METHODS: We used wild type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors. RESULTS: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency. CONCLUSIONS: This work identifies, for the first time, the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.

Endogenous opioid-mediated analgesia is dependent on adaptive T cell response in mice.

Pain is an inherent component of inflammation often accompanying immune response. A large spectrum of molecules released within the inflamed tissue induces pain by stimulating primary afferent neurons in situ. Activity of primary sensitive fibers can be counteracted by local opioid release by leukocytes. In this study, we investigated the endogenous regulation of CFA-induced inflammatory pain in the context of adaptive T cell immune response. The nociceptive response to mechanical stimuli was studied using von Frey filaments in mice immunized with OVA in CFA. The nociceptive response of nude versus wild-type mice was dramatically increased, demonstrating T cell deficiency associated with increased pain sensitivity. Based on adoptive transfer experiments of OVA-specific CD4(+) T lymphocytes into nude mice, we show that Ag-specific activated, but not resting T lymphocytes are responsible for the spontaneous relief of inflammation-induced pain following Ag challenge. The analgesia was dependent on opioid release by Ag-primed CD4(+) T lymphocytes at the inflammatory site. Indeed, T cell-mediated analgesia was inhibited by local injection of an opioid receptor antagonist, unable to cross the blood-brain barrier. Notably, we found opioid precursor mRNA to be >7-fold increased in Ag-specific activated CD4(+) T lymphocytes, as compared with resting T lymphocytes in vivo. Taken together, our results show that CD4(+) T lymphocytes acquire antinociceptive effector properties when specifically primed by Ag and point out analgesia as a property linked to the effector phase of adaptive T cell response.