Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature.

BACKGROUND AND PURPOSE: We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin-induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT). EXPERIMENTAL APPROACH: Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin-induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry. KEY RESULTS: VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose-dependently attenuated cold hypersensitivity in oxaliplatin-treated mice at 3, 10 and 30 mg·kg-1 (n = 7, P < 0.05). VBJ103 (30 mg·kg-1) antinociception was influenced by neither the TRPA1 antagonist HC-030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg-1, but not 100 or 300 mg·kg-1, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg-1) dose-dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 µL; n = 5) did not alter CBT. CONCLUSIONS AND IMPLICATIONS: We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target.

In-Vivo Calcium Imaging of Sensory Neurons in the Rat Trigeminal Ganglion.

Genetically encoded calcium indicators (GECIs) enable imaging techniques to monitor changes in intracellular calcium in targeted cell populations. Their large signal-to-noise ratio makes GECIs a powerful tool for detecting stimulus-evoked activity in sensory neurons. GECIs facilitate population-level analysis of stimulus encoding with the number of neurons that can be studied simultaneously. This population encoding is most appropriately done in vivo. Dorsal root ganglia (DRG), which house the soma of sensory neurons innervating somatic and visceral structures below the neck, are used most extensively for in vivo imaging because these structures are accessed relatively easily. More recently, this technique was used in mice to study sensory neurons in the trigeminal ganglion (TG) that innervate oral and craniofacial structures. There are many reasons to study TG in addition to DRG, including the long list of pain syndromes specific to oral and craniofacial structures that appear to reflect changes in sensory neuron activity, such as trigeminal neuralgia. Mice are used most extensively in the study of DRG and TG neurons because of the availability of genetic tools. However, with differences in size, ease of handling, and potentially important species differences, there are reasons to study rat rather than mouse TG neurons. Thus, we developed an approach for imaging rat TG neurons in vivo. We injected neonatal pups (p2) intraperitoneally with an AAV encoding GCaMP6s, resulting in >90% infection of both TG and DRG neurons. TG was visualized in the adult following craniotomy and decortication, and changes in GCaMP6s fluorescence were monitored in TG neurons following stimulation of mandibular and maxillary regions of the face. We confirmed that increases in fluorescence were stimulus-evoked with peripheral nerve block. While this approach has many potential uses, we are using it to characterize the subpopulation(s) of TG neurons changed following peripheral nerve injury.

Experimental colitis-induced visceral hypersensitivity is attenuated by GABA treatment in mice.

Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis.NEW & NOTEWORTHY GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.

Efficacy and feasibility of SMS m-Health for the detection of adverse events following immunisation (AEFIs) in resource-limited setting-The Zimbabwe stimulated telephone assisted rapid safety surveillance (Zm-STARSS) randomised control trial.

INTRODUCTION: The mHealth active participant centred (MAPC) adverse events following immunisation (AEFI) surveillance is a promising area for early AEFI detection resulting in risk minimisation. Passive (spontaneous) AEFI surveillance is the backbone for vaccine pharmacovigilance, but has inherent drawbacks of under reporting, and requires strengthening with active surveillance methods. AIM: The Zimbabwe stimulated telephone assisted rapid safety surveillance (Zm-STARSS) randomised controlled trial (RCT) sought to evaluate the efficacy and feasibility of AEFI detection using a short message service (SMS) and computer assisted telephone interview (CATI) approach. METHOD: A multicentre Zm-STARSS RCT enrolled consented adult vaccinees or parents or guardians of children receiving vaccines, including COVID-19 vaccines, at study vaccination clinics. At enrolment study participants were randomised to either SMS-CATI group or control group. SMS prompts were sent on days 0-2 and 14 post-vaccination to SMS-CATI group to ascertain if a medically attendance or attention due to an Adverse event following immunisation (AEFI) had occurred. However, no SMSs were sent to the control group. SMS-CATI group who responded "Yes" to SMS prompts were interviewed by research healthcare workers (RHCWs) who completed a CATI to determine if an AEFI had occurred whilst an AEFI in control group was determined from passive AEFI reporting channels. The primary study outcome was the AEFI detection rate in the SMS-CATI group compared to the control group. RESULTS: A total of 4560 participants were enrolled after signed informed consent, all were encouraged to report AEFIs and randomised automatically on 1:1 basis into two arms SMS CATI intervention group (n = 2280) and a control passive AEFI surveillance group (n = 2280) on day 0. A total of 704 (31 %) participants responded to the SMS prompts, with 75 % (528/704) indicating "No" and 25 % (176/704) reporting "Yes" to seeking medical attention or attendance post-immunisation. 69 % (121/176) completed a CATI survey but in only 36 % (44/121) was the AEFI confirmed. There were no AEFIs reported in control group participants. The detection rate of a AEFI associated with medically attendance or attention using the SMS-CATI methodology was 2 % (44/2280) on an intention to treat cohort. CONCLUSION: Despite the low SMS response and CATI completion rate, we demonstrated that Zm-STARSS SMS system improves AEFI detection compared to passive AEFI surveillance. We recommend that this and similar approaches are explored further using cost-effective multi-channel digital approaches for holistic pharmacovigilance to improve AEFI detection in Low Middle-Income Countries (LMICs) for all vaccines.

Photothermal Excitation of Neurons Using MXene: Cellular Stress and Phototoxicity Evaluation.

Understanding the communication of individual neurons necessitates precise control of neural activity. Photothermal modulation is a remote and non-genetic technique to control neural activity with high spatiotemporal resolution. The local heat release by photothermally active nanomaterial will change the membrane properties of the interfaced neurons during light illumination. Recently, it is demonstrated that the two-dimensional Ti3 C2 Tx MXene is an outstanding candidate to photothermally excite neurons with low incident energy. However, the safety of using Ti3 C2 Tx for neural modulation is unknown. Here, the biosafety of Ti3 C2 Tx -based photothermal modulation is thoroughly investigated, including assessments of plasma membrane integrity, mitochondrial stress, and oxidative stress. It is demonstrated that culturing neurons on 25 µg cm-2 Ti3 C2 Tx films and illuminating them with laser pulses (635 nm) with different incident energies (2-10 µJ per pulse) and different pulse frequencies (1 pulse, 1 Hz, and 10 Hz) neither damage the cell membrane, induce cellular stress, nor generate oxidative stress. The threshold energy to cause damage (i.e., 14 µJ per pulse) exceeded the incident energy for neural excitation (<10 µJ per pulse). This multi-assay safety evaluation provides crucial insights for guiding the establishment of light conditions and protocols in the clinical translation of photothermal modulation.

Anaphylaxis: Revision of the Brighton collaboration case definition.

The Brighton Collaboration (BC) has formulated a number of case definitions which have primarily been applied to adverse events of special interest in the context of vaccine safety surveillance. This is a revision of the 2007 BC case definition for anaphylaxis. Recently, the BC definition has been widely used for evaluating reports of suspected anaphylaxis following COVID-19 vaccination. This has led to debate about the performance of the BC definition in comparison with those from the US National Institute of Allergy and Infectious Disease/Food Allergy Anaphylaxis Network (NIAID/FAAN) and the World Allergy Organization (WAO). BC convened an expert working group to revise the case definition based on their usual process of literature review and expert consensus. This manuscript presents the outcome of this process and proposes a revised case definition for anaphylaxis. Major and minor criteria have been re-evaluated with an emphasis on the reporting of observable clinical signs, rather than subjective symptoms, and a clearer approach to the ascertainment of levels of certainty is provided. The BC case definition has also been aligned with other contemporary and international case definitions for anaphylaxis.

Synovial joint-on-a-chip for modeling arthritis: progress, pitfalls, and potential.

Disorders of the synovial joint, such as osteoarthritis (OA) and rheumatoid arthritis (RA), afflict a substantial proportion of the global population. However, current clinical management has not been focused on fully restoring the native function of joints. Organ-on-chip (OoC), also called a microphysiological system, which typically accommodates multiple human cell-derived tissues/organs under physiological culture conditions, is an emerging platform that potentially overcomes the limitations of current models in developing therapeutics. Herein, we review major steps in the generation of OoCs for studying arthritis, discuss the challenges faced when these novel platforms enter the next phase of development and application, and present the potential for OoC technology to investigate the pathogenesis of joint diseases and the development of efficacious therapies.

Experimental models to study osteoarthritis pain and develop therapeutics.

Pain is the predominant symptom of osteoarthritis (OA) that drives patients to seek medical care. Currently, there are no pharmacological treatments that can reverse or halt the progression of OA. Safe and efficacious medications for long-term management of OA pain are also unavailable. Understanding the mechanisms behind OA pain generation at onset and over time is critical for developing effective treatments. In this narrative review, we first summarize our current knowledge on the innervation of the knee joint, and then discuss the molecular mechanism(s) currently thought to underlie OA pain. In particular, we focus on the contribution of each joint component to the generation of pain. Next, the current experimental models for studying OA pain are summarized, and the methods to assess pain in rodents are presented. The potential application of emerging microphysiological systems in OA pain research is especially highlighted. Lastly, we discuss the current challenge in standardizing models and the selection of appropriate systems to address specific questions.

Neuronally expressed PDL1, not PD1, suppresses acute nociception.

PDL1 is a protein that induces immunosuppression by binding to PD1 expressed on immune cells. In line with historical studies, we found that membrane-bound PD1 expression was largely restricted to immune cells; PD1 was not detectable at either the mRNA or protein level in peripheral neurons using single neuron qPCR, immunolabeling and flow cytometry. However, we observed widespread expression of PDL1 in both sensory and sympathetic neurons that could have important implications for patients receiving immunotherapies targeting this pathway that include unexpected autonomic and sensory related effects. While signaling pathways downstream of PD1 are well established, little to no information is available regarding the intracellular signaling downstream of membrane-bound PDL1 (also known as reverse signaling). Here, we administered soluble PD1 to engage neuronally expressed PDL1 and found that PD1 significantly reduced nocifensive behaviors evoked by algogenic capsaicin. We used calcium imaging to examine the underlying neural mechanism of this reduction and found that exogenous PD1 diminished TRPV1-dependent calcium transients in dissociated sensory neurons. Furthermore, we observed a reduction in membrane expression of TRPV1 following administration of PD1. Exogenous PD1 had no effect on pain-related behaviors in sensory neuron specific PDL1 knockout mice. These data indicate that neuronal PDL1 activation is sufficient to modulate sensitivity to noxious stimuli and as such, may be an important homeostatic mechanism for regulating acute nociception.

PrEggNut Study: protocol for a randomised controlled trial investigating the effect of a maternal diet rich in eggs and peanuts from <23 weeks' gestation during pregnancy to 4 months' lactation on infant IgE-mediated egg and peanut allergy outcomes.

INTRODUCTION: Clinical studies supported by immunological data indicate early life intervention strategies to be promising in reducing the growing global burden of food allergies. The events that predispose to food allergy, including the induction of allergen-specific immune responses, appear to be initiated early in development. Early exposure to food allergens in utero and via breast milk is likely to be important in initiating oral tolerance. We aim to determine the effectiveness of higher maternal food allergen consumption during pregnancy and lactation on infant food allergy outcomes. METHODS AND ANALYSIS: This is a multisite, parallel, two-arm (1:1 allocation), single-blinded (outcome assessors, statistical analyst and investigators), randomised controlled trial. Pregnant women (<23 weeks' gestation) whose (unborn) infants have at least two biological family members (mother, father or siblings) with medically diagnosed allergic disease are eligible to participate. After obtaining written informed consent, pregnant women are randomised to either a high egg and peanut diet (at least 6 eggs and 60 peanuts per week) or standard (low) egg and peanut diet (no more than 3 eggs and 30 peanuts per week). The women are asked to follow their allocated diet from <23 weeks' gestation to 4 months' lactation. The primary outcome is food challenge proven IgE-mediated egg and/or peanut allergy in the infants at 12 months of age. Key secondary outcomes include infant sensitisation to egg and/or peanut and infant eczema. Our target sample size is 2136 women. Analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Human Research Ethics Committee (approval number HREC/18/WCHN/42). Trial results will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12618000937213.

Effects of an Amino Acid-Based Formula Supplemented with Two Human Milk Oligosaccharides on Growth, Tolerability, Safety, and Gut Microbiome in Infants with Cow's Milk Protein Allergy.

This open-label, non-randomized, multicenter trial (Registration: NCT03661736) aimed to assess if an amino acid-based formula (AAF) supplemented with two human milk oligosaccharides (HMO) supports normal growth and is well tolerated in infants with a cow's milk protein allergy (CMPA). Term infants aged 1-8 months with moderate-to-severe CMPA were enrolled. The study formula was an AAF supplemented with 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT). Infants were fed the study formula for 4 months and were offered to remain on the formula until 12 months of age. Tolerance and safety were assessed throughout the trial. Out of 32 infants (mean age 18.6 weeks; 20 (62.5%) male), 29 completed the trial. During the 4-month principal study period, the mean weight-for-age Z score (WAZ) increased from -0.31 at the baseline to +0.28 at the 4-months' follow-up. Linear and head growth also progressed along the WHO child growth reference, with a similar small upward trend. The formula was well tolerated and had an excellent safety profile. When comparing the microbiome at the baseline to the subsequent visits, there was a significant on-treatment enrichment in HMO-utilizing bifidobacteria, which was associated with a significant increase in fecal short-chain fatty acids. In addition, we observed a significant reduction in the abundance of fecal Proteobacteria, suggesting that the HMO-supplemented study formula partially corrected the gut microbial dysbiosis in infants with CMPA.

Local translation in primary afferents and its contribution to pain.

ABSTRACT: Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. Although the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in most of those who suffer. Most notable among the changes in primary afferents is an increase in excitability or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pronociceptive signaling molecules, such as voltage-gated sodium channels, and decreases in antinociceptive signaling molecules, such as voltage-dependent or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules seem to reflect changes in gene expression as well as posttranslational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process not only is dynamically regulated but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology.

Subcutaneous nodules following vaccination.

Five patients presented to surgical clinics at our institution with subcutaneous nodules of the upper arm or thigh present for 6-18 months. Excisional or fine-needle biopsy was performed due to diagnostic uncertainty and parental concern. Histopathological examination revealed these to be cutaneous lymphoid hyperplasia in reaction to vaccine components. Nodular reactions with this histopathological pattern are well recognised within vaccine-related literature, but less commonly recognised in patients presenting to general paediatric or surgical clinics. This article reviews literature on delayed-onset nodule formation after vaccination and recommends observation and reassurance as mainstays of management of this largely benign entity.

Voltage-gated calcium currents in human dorsal root ganglion neurons.

ABSTRACT: Voltage-gated calcium channels in sensory neurons underlie processes ranging from neurotransmitter release to gene expression and remain a therapeutic target for the treatment of pain. Yet virtually all we know about voltage-gated calcium channels has been obtained through the study of rodent sensory neurons and heterologously expressed channels. To address this, high voltage-activated (HVA) Ca2+ currents in dissociated human and rat dorsal root ganglion neurons were characterized with whole-cell patch clamp techniques. The HVA currents from both species shared basic biophysical and pharmacological properties. However, HVA currents in human neurons differed from those in the rat in at least 3 potentially important ways: (1) Ca2+ current density was significantly smaller, (2) the proportion of nifedipine-sensitive currents was far greater, and (3) a subpopulation of human neurons displayed relatively large constitutive current inhibition. These results highlight the need to for the study of native proteins in their native environment before initiating costly clinical trials.

Peripheral GABAA receptor signaling contributes to visceral hypersensitivity in a mouse model of colitis.

ABSTRACT: Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due to, at least in part, a decrease in peripheral GAR-mediated inhibition. Acute colitis was induced with 5 days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. By contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low-affinity and high-affinity GAR, the VMR was increased in control mice and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice but decreased it in DSS-treated mice. These data suggest that activating of low-affinity GAR or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.

Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles.

Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mφs). On the other hand, the response of Mφs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mφs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mφs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mφs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mφs may be a critical target for the clinical treatment of cPE induced fibrosis.

Mechanisms Underlying the Selective Therapeutic Efficacy of Carbamazepine for Attenuation of Trigeminal Nerve Injury Pain.

Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the NaV1.1 channel blocker ICA-121431 and NaV1.1 protein in the ION, but no change in NaV1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain.SIGNIFICANCE STATEMENT This study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of NaV1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of NaV1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury.

Ti3C2Tx MXene Flakes for Optical Control of Neuronal Electrical Activity.

Understanding cellular electrical communications in both health and disease necessitates precise subcellular electrophysiological modulation. Nanomaterial-assisted photothermal stimulation was demonstrated to modulate cellular activity with high spatiotemporal resolution. Ideal candidates for such an application are expected to have high absorbance at the near-infrared window, high photothermal conversion efficiency, and straightforward scale-up of production to allow future translation. Here, we demonstrate two-dimensional Ti3C2Tx (MXene) as an outstanding candidate for remote, nongenetic, optical modulation of neuronal electrical activity with high spatiotemporal resolution. Ti3C2Tx's photothermal response measured at the single-flake level resulted in local temperature rises of 2.31 ± 0.03 and 3.30 ± 0.02 K for 635 and 808 nm laser pulses (1 ms, 10 mW), respectively. Dorsal root ganglion (DRG) neurons incubated with Ti3C2Tx film (25 µg/cm2) or Ti3C2Tx flake dispersion (100 µg/mL) for 6 days did not show a detectable influence on cellular viability, indicating that Ti3C2Tx is noncytotoxic. DRG neurons were photothermally stimulated using Ti3C2Tx films and flakes with as low as tens of microjoules per pulse incident energy (635 nm, 2 µJ for film, 18 µJ for flake) with subcellular targeting resolution. Ti3C2Tx's straightforward and large-scale synthesis allows translation of the reported photothermal stimulation approach in multiple scales, thus presenting a powerful tool for modulating electrophysiology from single-cell to additive manufacturing of engineered tissues.