Nociceptive Research Articles

Electrophoretic Delivery of Clinically Approved Anesthetic Drug for Chronic Pain Therapy

AbstractDespite a range of available pain therapies, most patients report so‐called “breakthrough pain.” Coupled with global issues like opioid abuse, there is a clear need for advanced therapies and technologies for safe and effective pain management. Here the authors demonstrate a candidate for such an advanced therapy: precise and fluid‐flow‐free electrophoretic delivery via organic electronic ion pumps (OEIPs) of the commonly used anesthetic drug bupivacaine. Bupivacaine is delivered to dorsal root ganglion (DRG) neurons in vitro. DRG neurons are a good proxy for pain studies as they are responsible for relaying ascending sensory signals from nociceptors (pain receptors) in the peripheral nervous system to the central nervous system. Capillary based OEIPs are used due to their probe‐like and free‐standing form factor, ideal for interfacing with cells. By delivering bupivacaine with the OEIP and recording dose versus response (Ca2+ imaging), it is observed that only cells close to the OEIP outlet (≤75 µm) are affected (“anaesthetized”) and at concentrations up to 10s of thousands of times lower than with bulk/bolus delivery. These results demonstrate the first effective OEIP deliveryof a clinically approved and widely used analgesic pharmaceutical, and thus are a major translational milestone for this technology.

Targeting Nociceptive Neurons and Transient Receptor Potential Channels for the Treatment of Migraine.

Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptive neurons in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptive neurons innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting nociceptive neurons is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptive neurons in migraine, the challenges of current anti-migraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

Piezo2 regulates colonic mechanical sensitivity in a sex specific manner in mice

The mechanosensitive ion channel Piezo2 in mucosa and primary afferents transduces colonic mechanical sensation. Here we show that chemogenetic activation or nociceptor-targeted deletion of Piezo2 is sufficient to regulate colonic mechanical sensitivity in a sex dependent manner. Clozapine N-oxide-induced activation of Piezo2;hM3Dq-expressing sensory neurons evokes colonic hypersensitivity in male mice, and causes dyspnea in female mice likely due to effects on lung sensory neurons. Activation of Piezo2-expressing colonic afferent neurons also induces colonic hypersensitivity in male but not female mice. Piezo2 levels in nociceptive neurons are higher in female than in male mice. We also show that Piezo2 conditional deletion from nociceptive neurons increases body weight growth, slows colonic transits, and reduces colonic mechanosensing in female but not male mice. Piezo2 deletion blocks colonic hypersensitivity in male but not female mice. These results suggest that Piezo2 in nociceptive neurons mediates innocuous colonic mechanosensing in female mice and painful sensation in male mice, suggesting a sexual dimorphism of Piezo2 function in the colonic sensory system.

Self-assembled innervated vasculature-on-a-chip to study nociception

Nociceptor sensory neurons play a key role in eliciting pain. An active crosstalk between nociceptor neurons and the vascular system at the molecular and cellular level is required to sense and respond to noxious stimuli. Besides nociception, interaction between nociceptor neurons and vasculature also contributes to neurogenesis and angiogenesis. In vitro models of innervated vasculature can greatly help delineate these roles while facilitating disease modeling and drug screening. Herein, we report the development of a microfluidic-assisted tissue model of nociception in the presence of microvasculature. The self-assembled innervated microvasculature was engineered using endothelial cells and primary dorsal root ganglion (DRG) neurons. The sensory neurons and the endothelial cells displayed distinct morphologies in presence of each other. The neurons exhibited an elevated response to capsaicin in the presence of vasculature. Concomitantly, increased transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor expression was observed in the DRG neurons in presence of vascularization. Finally, we demonstrated the applicability of this platform for modeling nociception associated with tissue acidosis. While not demonstrated here, this platform could also serve as a tool to study pain resulting from vascular disorders while also paving the way towards the development of innervated microphysiological models.

Multi-target modulation of ion channels underlying the analgesic effects of α-mangostin in dorsal root ganglion neurons

Backgroundα-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of α-mangostin with ion channels in the nociceptive neurons, electrophysiological investigation of the underlying mechanism has not been performed. HypothesisWe hypothesized that α-Mangostin exerts its analgesic effects by modulating the activity of various ion channels in dorsal root ganglion (DRG) neurons. MethodsWe performed a whole-cell patch clamp study using mouse DRG neurons, HEK293T cells overexpressing targeted ion channels, and ND7/23 cells. Molecular docking (MD) and in silico absorption, distribution, metabolism, and excretion (ADME) analyses were conducted to obtain further insights into the binding sites and pharmacokinetics, respectively. ResultsApplication of α-mangostin (1–3 µM) hyperpolarized the resting membrane potential (RMP) of small-sized DRG neurons by increasing background K+ conductance and thereby inhibited action potential generation. At micromolar levels, α-mangostin activates TREK-1, TREK-2, or TRAAK, members of the two-pore domain K+ channel (K2P) family known to be involved in RMP formation in DRG neurons. Furthermore, capsaicin-induced TRPV1 currents were potently inhibited by α-mangostin (0.43 ± 0.27 µM), and partly suppressed tetrodotoxin-sensitive voltage-gated Na+ channel (NaV) currents. MD simulation revealed that multiple oxygen atoms in α-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and NaV channels. In silico ADME tests suggested that α-mangostin may satisfy the drug-likeness properties without penetrating the blood–brain barrier. ConclusionThe analgesic properties of α-mangostin might be mediated by the multi-target modulation of ion channels, including TREK/TRAAK activation, TRPV1 inhibition, and reduction of the tetrodotoxin-sensitive NaV current. The findings suggest that the phytochemical can be a multi-ion channel-targeting drug and an alternative drug for effective pain management.

Phosphodiesterase (PDE) 4 inhibition boosts Schwann cell myelination in a 3D regeneration model

Phosphodiesterase 4 (PDE4) inhibitors have been extensively researched for their anti-inflammatory and neuroregenerative properties. Despite the known neuroplastic and myelin regenerative properties of nonselective PDE4 inhibitors on the central nervous system, the direct impact on peripheral remyelination and subsequent neuroregeneration has not yet been investigated. Therefore, to examine the possible therapeutic effect of PDE4 inhibition on peripheral glia, we assessed the differentiation of primary rat Schwann cells exposed in vitro to the PDE4 inhibitor roflumilast. To further investigate the differentiation promoting effects of roflumilast, we developed a 3D model of rat Schwann cell myelination that closely resembles the in vivo situation. Using these in vitro models, we demonstrated that pan-PDE4 inhibition using roflumilast significantly promoted differentiation of Schwann cells towards a myelinating phenotype, as indicated by the upregulation of myelin proteins, including MBP and MAG. Additionally, we created a unique regenerative model comprised of a 3D co-culture of rat Schwann cells and human iPSC-derived neurons. Schwann cells treated with roflumilast enhanced axonal outgrowth of iPSC-derived nociceptive neurons, which was accompanied by an accelerated myelination speed, thereby showing not only phenotypic but also functional changes of roflumilast-treated Schwann cells. Taken together, the PDE4 inhibitor roflumilast possesses a therapeutic benefit to stimulate Schwann cell differentiation and, subsequently myelination, as demonstrated in the biologically relevant in vitro platform used in this study. These results can aid in the development of novel PDE4 inhibition-based therapies in the advancement of peripheral regenerative medicine.

Spinal dopaminergic D1-and D2-like receptors have a sex-dependent effect in an experimental model of fibromyalgia

There is evidence about the importance of sex in pain. The purpose of this study was to investigate the effect of sex in the antiallodynic activity of spinal dopamine D1-and D2-like receptors in a model of fibromyalgia-type pain in rats. Reserpine induced the same extent of tactile allodynia in female and male rats. Intrathecal injection of SCH-23390 (3–30 nmol, D1-like receptor antagonist), pramipexole (0.15–15 nmol) or quinpirole (1–10 nmol D2-like receptor agonists) increased withdrawal threshold in reserpine-treated female rats. Those drugs induced a greater antiallodynic effect in female rats. Sex-difference was also observed in a nerve injury model. Ovariectomy abated the antiallodynic effect of SCH-23390 (30 nmol) in reserpine-treated rats, while systemic reconstitution of 17β-estradiol levels or intrathecal injection of estrogen receptor-α agonist protopanaxatriol in ovariectomized reserpine-treated females restored the antiallodynic effect of SCH-23390. Intrathecal administration of ICI-182,780 (estrogen receptor-α/β antagonist) or methyl-piperidino-pyrazole hydrate (estrogen receptor-α antagonist) abated 17β-estradiol-restored antiallodynic effect of SCH-23390 in rats. In contrast, ovariectomy slightly reduced the effect of pramipexole (15 nmol) or quinpirole (10 nmol) in reserpine-treated rats, whereas systemic reconstitution of 17β-estradiol levels did not modify the antiallodynic effect of both drugs. Combination 17β-estradiol/progesterone, but not 17β-estradiol nor progesterone alone, restored the antiallodynic effect of pramipexole and quinpirole in the rats. Mifepristone (progesterone receptor antagonist) abated 17β-estradiol + progesterone restoration of the antiallodynic effect of pramipexole and quinpirole. These data suggest that the antiallodynic effect of dopamine D1-and D2-like receptors in fibromyalgia-type pain depends on spinal 17β-estradiol/estrogen receptor-α and progesterone receptors, respectively.

NURSING CARE POST OPERATIONAL APPENDICITIS PATIENTS WITH NURSING PROBLEMS ACUTE PAIN IN BIMA ROOM RSUD JOMBANG

Background : Appendicitis is an inflammation of the appendix caused by a bacterial infection as the main cause. Method : This research design is a case study using 2 clients who experience postoperative appendicitis with acute pain nursing problems, nursing care is carried out for 3 consecutive days using non-pharmacological therapeutic interventions. Result: The results showed that acute pain with Benson relaxation and aromatherapy therapy, the problem was resolved by reducing the severe pain scale to a mild pain scale for both clients. Analysis : To carry out nursing care for clients who experience Post operational appendicitis with priority problems of Acute pain. Conclusion : Giving Benson relaxation therapy for 30 minutes will decrease pain receptors and stimulate the release of endophins so as to create a relaxed or calming state that can overcome complaints of postoperative pain after appendicitis this therapy is given for 3 days in a row.

Contralateral Afferent Input to Lumbar Lamina I Neurons as a Neural Substrate for Mirror-Image Pain.

Mirror-image pain arises from pathologic alterations in the nociceptive processing network that controls functional lateralization of the primary afferent input. Although a number of clinical syndromes related to dysfunction of the lumbar afferent system are associated with the mirror-image pain, its morphophysiological substrate and mechanism of induction remain poorly understood. Therefore, we used ex vivo spinal cord preparation of young rats of both sexes to study organization and processing of the contralateral afferent input to the neurons in the major spinal nociceptive projection area Lamina I. We show that decussating primary afferent branches reach contralateral Lamina I, where 27% of neurons, including projection neurons, receive monosynaptic and/or polysynaptic excitatory drive from the contralateral Aδ-fibers and C-fibers. All these neurons also received ipsilateral input, implying their involvement in the bilateral information processing. Our data further show that the contralateral Aδ-fiber and C-fiber input is under diverse forms of inhibitory control. Attenuation of the afferent-driven presynaptic inhibition and/or disinhibition of the dorsal horn network increased the contralateral excitatory drive to Lamina I neurons and its ability to evoke action potentials. Furthermore, the contralateral Aβδ-fibers presynaptically control ipsilateral C-fiber input to Lamina I neurons. Thus, these results show that some lumbar Lamina I neurons are wired to the contralateral afferent system whose input, under normal conditions, is subject to inhibitory control. A pathologic disinhibition of the decussating pathways can open a gate controlling contralateral information flow to the nociceptive projection neurons and, thus, contribute to induction of hypersensitivity and mirror-image pain.SIGNIFICANCE STATEMENT We show that contralateral Aδ-afferents and C-afferents supply lumbar Lamina I neurons. The contralateral input is under diverse forms of inhibitory control and itself controls the ipsilateral input. Disinhibition of decussating pathways increases nociceptive drive to Lamina I neurons and may cause induction of contralateral hypersensitivity and mirror-image pain.

Multiplex epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD-conditioned media-induced mechanical sensitivity.

Low back pain is a major contributor to disability worldwide and generates a tremendous socioeconomic impact. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to discogenic pain by sensitizing nociceptive neurons innervating the disc to stimuli that is nonpainful in healthy patients. Previously, we demonstrated the ability of degenerative IVDs to sensitize neurons to mechanical stimuli; however, elucidation of degenerative IVDs discogenic pain mechanisms is required to develop therapeutic strategies that directly target these mechanisms. In this study, we utilized CRISPR epigenome editing of nociceptive neurons to identify mechanisms of degenerative IVD-induced changes to mechanical nociception and demonstrated the ability of multiplex CRISPR epigenome editing of nociceptive neurons to modulate inflammation-induced mechanical nociception. Utilizing an in vitro model, we demonstrated degenerative IVD-produced IL-6-induced increases in nociceptive neuron activity in response to mechanical stimuli, mediated by TRPA1, ASIC3, and Piezo2 ion channel activity. Once these ion channels were identified as mediators of degenerative IVD-induced mechanical nociception, we developed singleplex and multiplex CRISPR epigenome editing vectors that modulate endogenous expression of TRPA1, ASIC3, and Piezo2 via targeted gene promoter histone methylation. When delivered to nociceptive neurons, the multiplex CRISPR epigenome editing vectors abolished degenerative IVD-induced mechanical nociception while preserving nonpathologic neuron activity. This work demonstrates the potential of multiplex CRISPR epigenome editing as a highly targeted gene-based neuromodulation strategy for the treatment of discogenic pain, specifically; and, for the treatment of inflammatory chronic pain conditions, more broadly.

Disexcitation in the ASH/RIM/ADL negative feedback circuit fine-tunes hyperosmotic sensation and avoidance in Caenorhabditis elegans.

Sensations, especially nociception, are tightly controlled and regulated by the central and peripheral nervous systems. Osmotic sensation and related physiological and behavioral reactions are essential for animal well-being and survival. In this study, we find that interaction between secondary nociceptive ADL and primary nociceptive ASH neurons upregulates Caenorhabditis elegans avoidance of the mild and medium hyperosmolality of 0.41 and 0.88 Osm but does not affect avoidance of high osmolality of 1.37 and 2.29 Osm. The interaction between ASH and ADL is actualized through a negative feedback circuit consisting of ASH, ADL, and RIM interneurons. In this circuit, hyperosmolality-sensitive ADL augments the ASH hyperosmotic response and animal hyperosmotic avoidance; RIM inhibits ADL and is excited by ASH; thus, ASH exciting RIM reduces ADL augmenting ASH. The neuronal signal integration modality in the circuit is disexcitation. In addition, ASH promotes hyperosmotic avoidance through ASH/RIC/AIY feedforward circuit. Finally, we find that in addition to ASH and ADL, multiple sensory neurons are involved in hyperosmotic sensation and avoidance behavior.

The Cytidine N-Acetyltransferase NAT10 Participates in Peripheral Nerve Injury-Induced Neuropathic Pain by Stabilizing SYT9 Expression in Primary Sensory Neurons.

RNA N4-acetylcytidine (ac4C) modification is increasingly recognized as an important layer of gene regulation; however, the involvement of ac4C in pain regulation has not been studied. Here, we report that N-acetyltransferase 10 protein (NAT10; the only known ac4C "writer") contributes to the induction and development of neuropathic pain in an ac4C-dependent manner. Peripheral nerve injury increases the levels of NAT10 expression and overall ac4C in injured dorsal root ganglia (DRGs). This upregulation is triggered by the activation of upstream transcription factor 1 (USF1), a transcription factor that binds to the Nat10 promoter. Knock-down or genetic deletion of NAT10 in the DRG abolishes the gain of ac4C sites in Syt9 mRNA and the augmentation of SYT9 protein, resulting in a marked antinociceptive effect in nerve-injured male mice. Conversely, mimicking NAT10 upregulation in the absence of injury evokes the elevation of Syt9 ac4C and SYT9 protein and induces the genesis of neuropathic-pain-like behaviors. These findings demonstrate that USF1-governed NAT10 regulates neuropathic pain by targeting Syt9 ac4C in peripheral nociceptive sensory neurons. Our findings establish NAT10 as a critical endogenous initiator of nociceptive behavior and a promising new target for treating neuropathic pain.SIGNIFICANCE STATEMENT The cytidine N4-acetylcytidine (ac4C), a new epigenetic RNA modification, is crucial for the translation and stability of mRNA, but its role for chronic pain remains unclear. Here, we demonstrate that N-acetyltransferase 10 (NAT10) acts as ac4C N-acetyltransferase and plays an important role in the development and maintenance of neuropathic pain. NAT10 was upregulated via the activation of the transcription factor upstream transcription factor 1 (USF1) in the injured dorsal root ganglion (DRG) after peripheral nerve injury. Since pharmacological or genetic deleting NAT10 in the DRG attenuated the nerve injury-induced nociceptive hypersensitivities partially through suppressing Syt9 mRNA ac4C and stabilizing SYT9 protein level, NAT10 may serve as an effective and novel therapeutic target for neuropathic pain.

A206 SYNERGISTIC EFFECTS OF HISTAMINE AND PROTEASES IN VISCERAL HYPERSENSITIVITY

Abstract Background Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain. Previous work has shown IBS fecal supernatants (FS) increase the excitability of nociceptive neurons compared to healthy volunteer FS. Altered production of intestinal mediators, including elevated histamine content and proteolytic activity, have been implicated in these effects. We hypothesized that the effects of histamine and proteases on neuronal excitability may be synergistic. Purpose 1) Determine whether the excitatory effect of IBS patient FS can be abolished by histamine receptor antagonists and protease inhibitors. 2) Investigate whether the excitatory effects of histamine and proteases potentiate each other’s effects on visceral nociception Method Extracellular recordings were performed, measuring action potentials from mechanosensitive extrinsic afferent nerves innervating the mouse colon during colonic distensions to 60 mmHg. Colons were perfused (20 minutes) with histamine receptor antagonists (1 µM pyrilamine, 10 µM ranitidine, 30 nM clobenpropit, 1 µM JNJ7777120) or protease inhibitors (10 µM EDTA, 0.2 µM bestatin, 0.03 µM Pepstatin A, 0.03 µM E-64) prior to treatment with the IBS patient FS. Perforated patch clamp experiments were used to measure neuronal excitability from mouse dorsal root ganglion neurons by recording rheobase (minimum current required to elicit an action potential fire). This technique was used to examine the effect of subthreshold concentrations of histamine (1µM) and trypsin (5nM), as well as their simultaneous administration on the neurons. Result(s) Luminal administration of histamine antagonists or protease inhibitors blocked the excitatory effect of the IBS patient FS (two-way ANOVA P=0.44 for protease antagonists, two-way ANOVA P=0.37 for histamine antagonists). Patch clamp experiments revealed that a subthreshold concentration of either histamine (1µM) or trypsin (5nM) had no effect on neuronal rheobase, whereas the combination significantly decreased neuronal rheobase (one-way ANOVA with Tukey’s test, P=0.006). Image Conclusion(s) These findings demonstrate that either histamine receptor antagonists or protease inhibitors inhibit the excitatory effect of IBS patient FS and suggest that a potentiating effect exists between the actions of histamine and proteases on nociceptive neurons. Disclosure of Interest None Declared

A272 EVIDENCE OF SEX DIFFERENCES IMPACTING PAIN SIGNALING BY LUMINAL MEDIATORS IN IRRITABLE BOWEL SYNDROME

Abstract Background Irritable bowel syndrome (IBS) is more than twice as common in women and female patients report more severe abdominal pain. This suggests that sex-specific mechanisms may contribute to the pathophysiology of IBS. Many IBS patients have altered gut microbiota and luminal meditators, implicating the gut microbiota in abdominal pain. These luminal mediators can alter excitability of visceral nociceptors, thus potentially contributing to abdominal pain in IBS. Furthermore, in a subset of IBS patients a low FODMAP diet (LFD) reduces the effect of luminal mediators on pain sensing neurons. The LFD may improve abdominal pain at greater rates in women, and numerous putative mechanisms contributing to abdominal pain in IBS are susceptible to sex-specific mediators. However, it is unknown whether luminal mediators have similar effects on visceral pain signaling in both males and females. We hypothesize that luminal mediators will cause greater differences in neuronal excitability and pain signaling in female mice due to sex-specific factors. Purpose To determine whether FS from IBS patients (IBS FS) affects nociceptors from female mice more than nociceptors from male mice. Method Neurons from dorsal root ganglia from male and female mice were incubated overnight in media containing fecal supernatant (FS) from IBS patients (N=2 females) before and after the LFD, or healthy controls (HC, N=1 female and 1 male). Ratiometric Ca2+ imaging with FURA-2-AM was employed to quantify TRPV1 channel sensitization following application of capsaicin (100nM for 1 minute) as a measure of neuronal excitability. Data was analyzed using chi-squared test as well as two-way and mixed-effects model ANOVA as appropriate, followed by Sidak’s multiple comparisons test. Result(s) IBS FS caused a 177% larger Ca2+ influx in response to capsaicin compared to HC FS in female mice (p=0.0148, N=6-7 mice, neurons=43-49). In male mice, IBS FS increased Ca2+ influx by only 13% compared to HC FS (p=0.79, N=5 mice, neurons=28-35). In female mice, 117% more neurons responded to capsaicin after incubation with IBS FS versus HC FS (p=0.0004), while in male mice, only 17% more neurons responded following incubation with IBS FS (p=0.46). Finally, FS from the same IBS patients following a LFD reduced neuronal Ca2+ influx by 39% compared to IBS FS in female mice (p=0.0434, N=4-6 mice, neurons=18-49). In male mice, LFD FS reduced Ca2+ influx by 11% versus IBS FS (p=0.98, N=5 mice, neurons=28-35). Conclusion(s) Nociceptive neurons from female mice are more sensitive to the pro-nociceptive effects of FS from IBS patients, as well as a reduction of these excitatory effects following the LFD. This suggests a potential role of sex hormones in pain signaling in IBS. Disclosure of Interest None Declared

The HDM allergen orchestra and its cysteine protease maestro: Stimulators of kaleidoscopic innate immune responses

House dust mite (HDM) encloses an explosive cocktail of allergenic proteins sensitizing hundreds of millions of people worldwide. To date, the innate cellular and molecular mechanism(s) orchestrating the HDM-induced allergic inflammation remains partially deciphered. Understanding the kaleidoscope of HDM-induced innate immune responses is hampered by (1) the large complexity of the HDM allergome with very diverse functional bioreactivities, (2) the perpetual presence of microbial compounds (at least LPS, β-glucan, chitin) promoting as well pro-Th2 innate signaling pathways and (3) multiple cross-talks involving structural, neuronal and immune cells. The present review provides an update on the innate immune properties, identified so far, of multiple HDM allergen groups. Experimental evidence highlights the importance of HDM allergens displaying protease or lipid-binding activities on the initiation of the allergic responses. Specifically, group 1 HDM cysteine proteases are considered as the key initiators of the allergic response through their capacities to impair the epithelial barrier integrity, to stimulate the release of pro-Th2 danger-associated molecular patterns (DAMPs) in epithelial cells, to produce super-active forms of IL-33 alarmin and to mature thrombin leading to Toll-like receptor 4 (TLR4) activation. Remarkably, the recently evidenced primary sensing of cysteine protease allergens by nociceptive neurons confirms the critical role of this HDM allergen group in the early events leading to Th2 differentiation.

Molecular mechanisms of the development of the phenomena of peripheral and central sensitization in rheumatoid arthritis

Modern tactics for the treatment of rheumatoid arthritis is aimed at achieving remission or low activity of the disease, the maximum elimination of the manifestations of the disease and the restoration of physical and social activity of patients. At the same time, despite the wide range of the most modern pathogenetic agents, a good therapeutic response can’t be obtained in all cases. A difficult problem is the so-called rheumatoid arthritis RA (difficult to treat), in which two or more sequentially prescribed genetically engineered biological drugs or JAK inhibitors are ineffective. One of the important factors negatively affecting the outcome of RA treatment are functional disorders of the nociceptive system, such as peripheral and central sensitization. These phenomena, associated with persistent activation of nociceptive neurons and the development of nociplastic changes, are caused by systemic autoimmune inflammation and the influence of various cytokines and chemokines on the neuronal membrane. This review considers the molecular biological aspects of the formation of peripheral and central sensitization in RA, with a separate analysis of the pathogenetic role of individual interleukins.

Acute Pain Have Strong Intensity

Acute pain is a normal and predictable physiological response to a stimulus caused by a surgical procedure, injury, or acute illness. Chronic pain is pathological pain that lasts longer than the usual time to heal an injury or treat a disease. The causes are chronic and irreversible pathological processes in body cells and organs or damage to the peripheral or central nervous system. Acute pain occurs within 0.1 seconds after irritation. Acute pain is of strong intensity and is caused by stimulation of pain receptors.

Axon-axon interactions determine modality-specific wiring and subcellular synaptic specificity in a somatosensory circuit.

Synaptic connections between neurons are often formed in precise subcellular regions of dendritic arbors with implications for information processing within neurons. Cell-cell interactions are widely important for circuit wiring; however, their role in subcellular specificity is not well understood. We studied the role of axon-axon interactions in precise targeting and subcellular wiring of Drosophila somatosensory circuitry. Axons of nociceptive and gentle touch neurons terminate in adjacent, non-overlapping layers in the central nervous system (CNS). Nociceptor and touch receptor axons synapse onto distinct dendritic regions of a second-order interneuron, the dendrites of which span these layers, forming touch-specific and nociceptive-specific connectivity. We found that nociceptor ablation elicited extension of touch receptor axons and presynapses into the nociceptor recipient region, supporting a role for axon-axon interactions in somatosensory wiring. Conversely, touch receptor ablation did not lead to expansion of nociceptor axons, consistent with unidirectional axon-axon interactions. Live imaging provided evidence for sequential arborization of nociceptive and touch neuron axons in the CNS. We propose that axon-axon interactions and modality-specific timing of axon targeting play key roles in subcellular connection specificity of somatosensory circuitry.

Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Endocannabinoids, anandamide and 2-AG, regulate mechanosensitivity of mucosal afferents in the Guinea pig bladder

Bladder afferents play a crucial role in urine storage and voiding, and conscious sensations from the bladder. Endocannabinoids, anandamide (AEA) and 2-arachidonolylglycerol (2-AG), are endogenous ligands of G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2) found in the CNS and peripheral organs. They also have off-target effects on some ligand- and voltage-gated channels. The aim of this study is to determine the role of AEA and 2-AG in regulation of mechanosensitivity of probable nociceptive neurons innervating the bladder - capsaicin-sensitive mucosal afferents. The activity of these afferents was determined by ex vivo single unit extracellular recordings in the guinea pig bladder. A stable analogue of anandamide, methanandamide (mAEA) evoked initial excitatory response of mucosal afferents followed by potentiation of their responses to mechanical stimulation. In the presence of TRPV1 antagonist (AMG9810), mAEA's effect on mechanosensitivity switched from excitatory to inhibitory. The inhibitory effect of mAEA is due to activation of both CB1 and CB2 cannabinoid receptors since it was abolished by combined application of selective CB1 (NESS0327) and CB2 (SR144528) antagonists. 2-AG application evoked a brief excitation of mucosal afferents, without potentiation of their mechanosensitivity, followed by the inhibition of their responses to mechanical stimulation. CB2 receptor antagonist, SR144528 abolished the inhibitory effect of 2-AG. Our data indicated that anandamide and 2-AG have opposite effects on mechanosensitivity of mucosal capsaicin-sensitive afferents in the guinea pig bladder; mAEA potentiated while 2-AG inhibited responses of mucosal afferents to mechanical stimulation. These findings are important for understanding of the role of endocannabinoids in regulating bladder sensation and function.