Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions.

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-ß are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-ß can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.

The active fragments of ghrelin cross the blood-brain barrier and enter the brain to produce antinociceptive effects after systemic administration.

G (1-5)-NH2, G (1-7)-NH2, and G (1-9) are the active fragments of ghrelin. The aim of this study was to investigate the antinociceptive effects, their ability to cross the blood-brain barrier, and the receptor mechanism(s) of these fragments using the tail withdrawal test in male Kunming mice. The antinociceptive effects of these fragments (2, 6, 20, and 60 nmol/mouse) were tested at 5, 10, 20, 30, 40, 50, and 60 min after intravenous (i.v.) injection. These fragments induced dose- and time-related antinociceptive effects relative to saline. Using the near infrared fluorescence imaging experiments, our results showed that these fragments could cross the brain-blood barrier and enter the brain. The antinociceptive effects of these fragments were completely antagonized by naloxone (intracerebroventricular, i.c.v.); however, naloxone methiodide (intraperitoneal, i.p.), which is the peripheral restricted opioid receptor antagonist, did not antagonize these antinociceptive effects. Furthermore, the GHS-R1α antagonist [D-Lys3]-GHRP-6 (i.c.v.) completely antagonized these antinociceptive effects, too. These results suggested that these fragments induced antinociceptive effects through central opioid receptors and GHS-R1α. In conclusion, our studies indicated that these active fragments of ghrelin could cross the brain-blood barrier and enter the brain and induce antinociceptive effects through central opioid receptors and GHS-R1α after intravenous injection.

Ultra-purified alginate gel implantation decreases inflammatory cytokine levels, prevents intervertebral disc degeneration, and reduces acute pain after discectomy.

Lumbar intervertebral disc (IVD) herniation causes severe low back pain (LBP), which results in substantial financial and emotional strains. Despite the effectiveness of discectomy, there is no existing treatment for post-operative LBP induced by progressive IVD degeneration. Two key factors of LBP are intradiscal inflammation, indicated by tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and sensory nerve ingrowth into the inner layer of the annulus fibrosus, triggered by nerve growth factor/high-affinity tyrosine kinase A (TrkA) signalling. In an animal models of discectomy, the bioresorbable ultra-purified alginate (UPAL) gel with an extremely low-toxicity has been effective in acellular tissue repair. We aimed to investigate whether UPAL gel can alleviate LBP using a rat nucleus pulposus (NP) punch model and a rabbit NP aspirate model. In both models, we assessed TNF-α and IL-6 production and TrkA expression within the IVD by immunohistochemistry. Further, histological analysis and behavioural nociception assay were conducted in the rat model. UPAL gel implantation suppressed TNF-α and IL-6 production, downregulated TrkA expression, inhibited IVD degeneration, and reduced nociceptive behaviour. Our results suggest the potential of UPAL gel implantation as an innovative treatment for IVD herniation by reducing LBP and preventing IVD degeneration after discectomy.

Virtual reality for acute and chronic pain management in adult patients: a narrative review.

Virtual reality is a computer-generated environment that immerses the user in an interactive artificial world. This ability to distract from reality has been utilised for the purposes of providing pain relief from noxious stimuli. As technology rapidly matures, there is potential for anaesthetists and pain physicians to incorporate virtual reality devices as non-pharmacological therapy in a multimodal pain management strategy. This systematic narrative review evaluates clinical studies that used virtual reality in adult patients for management of acute and chronic pain. A literature search found 690 citations, out of which 18 studies satisfied the inclusion criteria. Studies were assessed for quality using the Jadad and Nottingham-Ottawa Scales. Agreement on scores between independent assessors was 0.87 (95%CI 0.73-0.94). Studies investigated virtual reality use: intra-operatively; for labour analgesia; for wound dressing changes; and in multiple chronic pain conditions. Twelve studies showed reduced pain scores in acute or chronic pain with virtual reality therapy, five studies showed no superiority to control treatment arms and in one study, the virtual reality exposure group had a worsening of acute pain scores. Studies were heterogeneous in: methods; patient population; and type of virtual reality used. These limitations suggest the evidence-base in adult patients is currently immature and more rigorous studies are required to validate the use of virtual reality as a non-pharmacological adjunct in multimodal pain management.

Role of orexin receptors within the dentate gyrus in antinociception induced by chemical stimulation of the lateral hypothalamus in an animal model of inflammatory pain.

Pain is a complex experience consisting of sensory, affective-motivational, and cognitive dimensions. Hence, identifying the multiple neural pathways subserving these functional aspects is a valuable task. The role of dentate gyrus (DG) as a relay station of neocortical afferents in the hippocampal formation (HF) in persistent pain is still controversial. The lateral hypothalamus (LH)-HF neural circuits are involved in numerous situations such as anxiety-like behavior, reward processing, feeding, orofacial as well as acute pain. Nonetheless, to our knowledge, the involvement of the LH-DG neural circuit in persistent pain has already remained unexplored. Adult male Wistar rats weighing 220-250 g were undergone stereotaxic surgery for unilateral implantation of two separate cannulae into the LH and DG. Intra-DG administration of the orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists, SB334867 and TCS OX2 29, respectively, was performed 5 min before intra-LH microinjection of carbachol. Animals were then undergone the formalin test using 50 µl formalin injection (2.5%) into the plantar surface of the hind paw. Microinjection of SB334867 or TCS OX2 29 into the DG region attenuated the antinociceptive effect produced by carbachol microinjection into the LH. The preventive effect of SB334867 and TCS OX2 29 on intra-LH carbachol-induced antinociception was approximately equal in both early and late phases of formalin nociception. The results suggest a neural pathway from the LH to the DG, which contributes to the modulation of formalin-induced inflammatory pain through the recruitment of OX1 and OX2 receptors within the DG.

Outpatient pain clinic and intranasal fentanyl to improve sickle cell disease outcomes.

BACKGROUND: Acute pain events are a leading complication for sickle cell patients. In an attempt to improve pain outcomes, we developed an outpatient pain clinic, and included intranasal fentanyl in the opioid emergency department (ED) pain order set. We evaluated admission rates and opioid administration for patients that attended both the outpatient pain clinic and ED within a 3-month period. METHODS: We recorded the admission rate, IV morphine equivalents, and time from triage for each opioid order and administration from both an outpatient pain clinic and ED visit within a 3-month period for an individual pediatric patient with sickle cell disease. RESULTS: Thirty patients received acute pain management in both settings. We identified a significant reduction in hospital admission when patients received care in the pain clinic as compared to the ED (17% vs 43%, P = .02). Additionally, outpatient pain clinic patients received significantly less IV morphine equivalents than patients received in the ED (5.6 vs 10.6 IV morphine equivalents, P < .0001). In the ED, intranasal fentanyl was administered in a significantly shorter time than patients ordered intravenous opioid (43 vs 75 min, P = .02). The mean time to receiving an opioid in the outpatient pain clinic was 57 min. CONCLUSION: The use of an outpatient pain clinic can reduce admission rates as compared to the ED. The use of intranasal fentanyl reduced the time to first opioid administration in the ED. Patient-centered research or quality improvement projects should continue to focus on novel approaches to acute pain event management.

Transitioning from acute to chronic pain: a simulation study of trajectories of low back pain.

BACKGROUND: Identifying how pain transitions from acute to chronic is critical in designing effective prevention and management techniques for patients' well-being, physically, psychosocially, and financially. There is an increasingly pressing need for a quantitative and predictive method to evaluate how low back pain trajectories are classified and, subsequently, how we can more effectively intervene during these progression stages. METHODS: In order to better understand pain mechanisms, we investigated, using computational modeling, how best to describe pain trajectories by developing a platform by which we studied the transition of acute chronic pain. RESULTS: The present study uses a computational neuroscience-based method to conduct such trajectory research, motivated by the use of hypothalamic-pituitary-adrenal (HPA) axis activity-history over a time-period as a way to mimic pain trajectories. A numerical simulation study is presented as a "proof of concept" for this modeling approach. CONCLUSIONS: This model and its simulation results have highlighted the feasibility and the potential of developing such a broader model for patient evaluations.

Case report: painful exanthems caused by enterovirus D68 in an adolescent.

RATIONALE: Unlike other enteroviruses which can cause herpangina or hand-foot-and-mouth disease, enterovirus D68 (EV-D68) has usually been linked to respiratory and neurological problems in young children. Skin manifestations had rarely been described in current literatures. PATIENT CONCERNS: We report a 17-year-old girl with fever and painful skin rash over legs and soles for 9 days. Pitting edema was also noted below the knees. There was no respiratory tract or neurological symptoms in this patient. DIAGNOSES: EV-D68 was detected from a throat swab by RT-PCR and confirmed to be subclade B3 by sequencing. INTERVENTIONS: Supportive management. OUTCOMES: The patient was afebrile after 9 days and got full recovery on the 23rd day at outpatient follow-up. LESSONS: To the best of our knowledge, this is the first report of EV-D68 infection with skin manifestations, clinical images, and detailed clinical course. Our findings in this particular case extend the understanding of the disease spectrum.

Photobiomodulation therapy reduces acute pain and inflammation in mice.

Photobiomodulation (PBM) is a therapy suggested for the treatment of pain and inflammation. Different mechanisms have been proposed to explain the analgesic and inflammatory effects of photobiomodulation, but there are still gaps on the mechanisms underlying. The objective was to investigate the analgesic and anti-inflammatory effect of red LED, as well as to investigate the possible mechanism of action in acute nociception models. Radiation was applied with red LED (660 nm, 215 mW, 84.64 mW/cm2, 2.531 J/cm2 (30s); 5.07 J/cm2 (60s) 7.61 J/cm2 (90s) and 10.15 J/cm2 (120 s)). The red LED applied 60 s before the experiments, promoted reduction of the nociceptive neurogenic (1st phase) and inflammatory pain (2nd phase) induced by intraplantar (i.pl.) injection of formalin. This effect duration in the second phase was 180 min after pretreatment of the LED. Red LED also reduced nociception induced by intraperitoneal injection of acetic acid. Furthermore, red LED prevented nociception induced by i.pl. injection of cinnamaldehyde, capsaicin, menthol and acidified saline. It was demonstrate the involvement of glutamatergic system with the reduction the nociception induced by glutamate. The red LED was able to prevent nociception induced by intracellular signaling cascades activators, phorbol 12-myristate 13-acetate (PMA), bradykinin, forskolin and prostaglandin. In addition, red LED, respectively, from 30 to 90s demonstrated an antiedematogenic effect on ear edema and reduction the migration of inflammatory cells induced by single application of croton oil. Thus, the new findings in this study support some underlying mechanism by which red LED phototherapy reduces acute pain. However, need further clarification regarding analgesic and anti-inflammatory effect of the photobiomodulation in preclinical studies.

[PROTECTIVE PROPERTIES OF DRUGS OF PLANT ORIGION IN ACUTE EMOTIONAL AND PAINFUL STRESS IN RATS].

The aim of the investigation was to study the protective properties of the herbal preparation - biotrite and tranquilizer diazepam under the modeling of emotional and painful stress in rats. Materials and methods. The experiment was conducted on 24 white male rats of 5 months of age. Animals (6 rats in the group) were kept on the standard diet of the vivarium: 1st group was intact; rats of the 2nd, 3rd and 4th groups were reproduced acute painful emotional stress for 3 hours. 60 minutes before the stress, rats received per os: the 2nd group - water, the 3rd group - diazepam in a dose of 1.25 mg / kg body weight of rats; 4th group - a preparation of biotrite in a dose of 50 mg / kg. Results and conclusion. The conducted studies demonstrated significant adaptive properties of the biotrite preparation, and the degree of their manifestations was higher than the stress-protective effects of diazepam.

The role of ultrasound in the evaluation of acute pelvic pain in pregnancy and postpartum period: a review.

PURPOSE OF REVIEW: Acute pelvic pain in pregnant and postpartum patients presents diagnostic and therapeutic challenges. Ultrasound remains the primary imaging modality of choice for assessing pregnant and postpartum women. The purpose of this review is to help practitioners ensure a correct diagnosis of acute pelvic pain in pregnancy and the postpartum period. RECENT FINDINGS: This review describes the various causes and highlights the sonographic features and characteristics of acute pelvic pain in pregnancy and the postpartum period. SUMMARY: Evaluation of acute pelvic pain in pregnancy and the postpartum period is challenging. Knowledge of the clinical settings and sonographic features of acute pelvic pain in pregnancy and the postpartum period can lead to accurate diagnosis and appropriate management of the condition.

Morphine effects within the rodent anterior cingulate cortex and rostral ventromedial medulla reveal separable modulation of affective and sensory qualities of acute or chronic pain.

Modulation of pain may result from engagement of opioid receptors in multiple brain regions. Whether sensory and affective qualities of pain are differentially affected by brain opioid receptor circuits remains unclear. We previously reported that opioid actions within the rostral anterior cingulate cortex (ACC) produce selective modulation of affective qualities of neuropathic pain in rodents, but whether such effects may occur in other areas of the ACC is not known. Here, morphine was microinjected into 3 regions of the ACC or into the rostral ventromedial medulla (RVM), and pain behaviors in naive, sham, or spinal nerve ligated (SNL) rats were evaluated. In naive animals, the tail-flick response was inhibited by RVM, but not ACC, morphine. Anterior cingulate cortex morphine did not affect tactile allodynia (the von Frey test) or mechanical (Randall-Selitto) or thermal (Hargreaves) hyperalgesia in spinal nerve ligated rats. In contrary, RVM morphine reduced tactile allodynia and produced both antihyperalgesic and analgesic effects against mechanical and thermal stimuli as well as conditioned place preference selectively in nerve-injured rats. Within the RVM, opioids inhibit nociceptive transmission reflected in both withdrawal thresholds and affective pain behaviors. Activation of mu opioid receptors within specific rostral ACC circuits, however, selectively modulates affective dimensions of ongoing pain without altering withdrawal behaviors. These data suggest that RVM and ACC opioid circuits differentially modulate sensory and affective qualities of pain, allowing for optimal behaviors that promote escape and survival. Targeting specific ACC opioid circuits may allow for treatment of chronic pain while preserving the physiological function of acute pain.

Scaling Up Cortical Control Inhibits Pain.

Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC) is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain.

TRPV1 gain-of-function mutation impairs pain and itch sensations in mice.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which can detect various noxious stimuli that cause pain, inflammation, hyperalgesia, and itch. TRPV1 knock-out mice show deficiency in nociception, but the in vivo effects of persistent activation of TRPV1 are not completely understood. Here, we generated TRPV1 knock-in mice with a G564S mutation. In the heterologous expression system, an electrophysiological study showed that the G564S mutation in mouse TRPV1 caused increased basal current and a leftward shift of voltage dependence. Intriguingly, using behavioral analysis, we found that knock-in mice showed a thermosensory defect, impaired inflammatory thermal pain, and capsaicin sensitivity. We also demonstrated an attenuated behavioral response to the pruritic agent histamine in the knock-in mice. Indeed, calcium imaging together with electrophysiology showed that the overactive mutant had decreased capsaicin sensitivity. Western blot analysis revealed that the G564S mutant reduced TRPV1 phosphorylation and cell membrane trafficking. Together, we have generated a mouse model with a gain-of-function mutation in Trpv1 gene and demonstrated that the pain and histamine-dependent itch sensations in these mice are impaired due to a decreased phosphorylation level and reduced membrane localization of TRPV1.

A new tridecapeptide with an octaarginine vector has analgesic therapeutic potential and prevents morphine-induced tolerance.

A growing body of evidence suggests that peptides may possess analgesic effects without tolerance development. The synthetic tetrapeptide Tyr-d-Arg-Phe-Gly-NH2 was modified with the inclusion of a (d-Arg)8 vector to prevent the action of endopeptidase and to increase the duration of the analgesic action of the tetrapeptide when administered orally. The aim of this study was to estimate the analgesic efficacy of the tetrapeptide with (d-Arg)8 (tridecapeptide, TDP) in experimental models of acute and chronic pain. The analgesic effects of TDP were estimated using a model of acute visceral pain in mice (writhing test) and a model of chronic neuropathic pain (chronic constriction injury (CCI) of the sciatic nerve) in rats. The intravenous administration of morphine (0.32-1mg/kg) and TDP (0.32-1.8mg/kg) produced significant dose-related antinociceptive effects in the writhing test. The potency of TDP after i.g. administration was lower than that after i.v. administration but comparable with that of i.g. morphine. In the CCI model, TDP (0.1, 1 and 10mg/kg, i.g.) induced marked analgesia with repeated administration without any signs of tolerance. The single administration of TDP after morphine treatment (7days) produced a significant analgesic effect in morphine-tolerant rats, indicating the absence of cross-tolerance between these two drugs. The combined administration of TDP and morphine resulted in the reduction of analgesic tolerance to morphine. The absence of cross-tolerance to morphine and the ability to prevent morphine tolerance allows this compound to be a prospective candidate for chronic pain therapy. In order to find the target receptors for TDP, a docking study was performed. It was found that the molecule can bind to the NMDA receptor using electrostatic, hydrogen bonding and hydrophobic interactions.

Circulating miR-23b-3p, miR-145-5p and miR-200b-3p are potential biomarkers to monitor acute pain associated with laminitis in horses.

Circulating microRNAs (miRNAs) are emerging as promising biomarkers for several disorders and related pain. In equine practice, acute laminitis is a common disease characterised by intense pain that severely compromises horse welfare. Recently, the Horse Grimace Scale (HGS), a facial expression-based pain coding system, was shown to be a valid welfare indicator to identify pain linked to acute laminitis. The present study aimed to: determine whether miRNAs can be used as biomarkers for acute pain in horses (Equus caballus) affected by laminitis; integrate miRNAs to their target genes and to categorise target genes for biological processes; gather additional evidence on concurrent validity of HGS by investigating how it correlates to miRNAs. Nine horses presenting acute laminitis with no prior treatment were recruited. As control group, nine healthy horses were further included in the experimental design. Samples were collected from horses with laminitis at admission before any treatment ('pre-treatment') and 7 days after routine laminitis treatment ('post-treatment'). The expression levels of nine circulating miRNAs, namely hsa-miR-532-3p, hsa-miR-219-5p, mmu-miR-134-5p, mmu-miR-124a-3p, hsa-miR-200b-3p, hsa-miR-146a-5p, hsa-miR-23b-3p, hsa-miR-145-5p and hsa-miR-181a-5p, were detected and assessed as potential biomarkers of pain by quantitative PCR using TaqMan® probes. The area under the receiver operating curve (AUC) was then used to evaluate the diagnostic performance of miRNAs. Molecular data were integrated with HGS scores assessed by one trained treatment and time point blind veterinarian. The comparative analysis demonstrated that the levels of miR-23b-3p (P=0.029), miR-145-5p (P=0.015) and miR-200b-3p (P=0.023) were significantly higher in pre-treatment and the AUCs were 0.854, 0.859 and 0.841, respectively. MiR-200b-3p decreased after routine laminitis treatment (P=0.043). Combining two miRNAs in a panel, namely miR-145-5p and miR-200b-3p, increased efficiency in distinguishing animals with acute pain from controls. In addition, deregulated miRNAs were positively correlated to HGS scores. Computational target prediction and functional enrichment identified common biological pathways between different miRNAs. In particular, the glutamatergic pathway was affected by all three miRNAs, suggesting a crucial role in the pathogenesis of pain. In conclusion, the dynamic expression of circulating miR-23b-3p, miR-145-5p and miR-200b-3p was detected in horses with acute laminitis and miRNAs can be considered potentially promising pain biomarkers. Further studies are needed in order to assess their relevancy in other painful conditions severely compromising horse welfare. An important implication would be the possibility to use them for the concurrent validation of non-invasive indicators of pain in horses.

Anti-hypersensitivity effects of the phthalimide derivative N-(4methyl-phenyl)-4-methylphthalimide in different pain models in mice.

The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1ß, bradykinin, prostaglandin E2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target.

The Dorsolateral Prefrontal Cortex in Acute and Chronic Pain.

The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region and a key node of several brain networks, implicated in cognitive, affective, and sensory processing. As such, the DLPFC is commonly activated in experimental pain studies, and shows abnormally increased function in chronic pain populations. Furthermore, several studies have shown that some chronic pains are associated with decreased left DLPFC gray matter and that successful interventions can reverse this structural abnormality. In addition, studies have indicated that noninvasive stimulation of the left DLPFC effectively treats some chronic pains. In this article, we review the neuroimaging literature regarding the role of the DLPFC and its potential as a therapeutic target for chronic pain conditions, including studies showing the involvement of the DLPFC in encoding and modulating acute pain and studies demonstrating the reversal of DLPFC functional and structural abnormalities after successful interventions for chronic pain. We also review studies of noninvasive brain stimulation of the DLPFC showing acute pain modulation and some effectiveness as a treatment for certain chronic pain conditions. We further discuss the network architecture of the DLPFC, and postulate mechanisms by which DLPFC stimulation alleviates chronic pain. Future work testing these mechanisms will allow for more effective therapies. PERSPECTIVE: The structure and function of the DLPFC is abnormal in some chronic pain conditions. Upon successful resolution of pain, these abnormalities are reversed. Understanding the underlying mechanisms and the role of this region can lead to the development of an effective therapeutic target for some chronic pain conditions.

Thiazolidine reacts with thioreactive biomolecules.

The thiazolidine ring is a biologically active chemical structure and is associated with many pharmacological activities. However, the biological molecules that can interact with the thiazolidine ring are not known. We show that thiazolidine causes sustained activation of the TRPA1 channel and chemically reacts with glutathione, and the chemical reactivity of thiazolidine ring is required for TRPA1 activation. Reducing agents reverse thiazolidine-induced TRPA1 activation, and mutagenesis studies show that nucleophilic cysteine residues in TRPA1 are critical, suggesting an activation mechanism involving thioreactive chemical reactions. In vivo studies show that thiazolidine induces acute pain and inflammation in mouse and these responses are specifically dependent on TRPA1. These results indicate that thiazolidine compounds can chemically react with biological molecules containing nucleophilic cysteines, thereby exerting biological activities.