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Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow—often referred to as ‘niches’—that represent complex regulatory milieux influenced by multiple cellular constituents, including nerves 1 , 2 . Although sympathetic nerves are known to regulate the HSC niche 3 – 6 , the contribution of nociceptive neurons in the bone marrow remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and that they collaborate with sympathetic nerves to maintain HSCs in the bone marrow. Nociceptor neurons drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of calcitonin gene-related peptide (CGRP). Unlike sympathetic nerves, which regulate HSCs indirectly via the niche 3 , 4 , 6 , CGRP acts directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CALCRL) to promote egress by activating the Gα s /adenylyl cyclase/cAMP pathway. The ingestion of food containing capsaicin—a natural component of chili peppers that can trigger the activation of nociceptive neurons—significantly enhanced HSC mobilization in mice. Targeting the nociceptive nervous system could therefore represent a strategy to improve the yield of HSCs for stem cell-based therapeutic agents. Stimulation of pain-sensing neurons, which can be achieved in mice by the ingestion of capsaicin, promotes the migration of haematopoietic stem cells from the bone marrow into the blood.

Chambers et al . use a combination of small-molecule pathway inhibitors to rapidly differentiate human pluripotent stem cells into nociceptors, a type of sensory neuron. The conversion occurs about three-fold faster than during development, suggesting that pathway inhibition may offer a general approach for speeding up the generation of specific cell types in vitro . Considerable progress has been made in identifying signaling pathways that direct the differentiation of human pluripotent stem cells (hPSCs) into specialized cell types, including neurons. However, differentiation of hPSCs with extrinsic factors is a slow, step-wise process, mimicking the protracted timing of human development. Using a small-molecule screen, we identified a combination of five small-molecule pathway inhibitors that yield hPSC-derived neurons at >75% efficiency within 10 d of differentiation. The resulting neurons express canonical markers and functional properties of human nociceptors, including tetrodotoxin (TTX)-resistant, SCN10A-dependent sodium currents and response to nociceptive stimuli such as ATP and capsaicin. Neuronal fate acquisition occurs about threefold faster than during in vivo development 1 , suggesting that use of small-molecule pathway inhibitors could become a general strategy for accelerating developmental timing in vitro . The quick and high-efficiency derivation of nociceptors offers unprecedented access to this medically relevant cell type for studies of human pain.

Voltage-gated sodium (Na v ) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na v channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider ( Heteroscodra maculata ) toxins that selectively activate the Na v 1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na v 1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na v 1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na v 1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain. Two spider toxins are shown to target the Na v 1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling. Na v 1.1 channels mediate mechanical pain Mutations affecting several Na v 1 subtype voltage-gated sodium channels have been shown to be associated with insensitivity to pain or persistent pain syndromes. Na v 1.1 is expressed by somatosensory neurons, but no direct link has been established between this subtype and nociception. Further studies have been hampered by a paucity of pharmacological agents that discriminate between the closely related members of the Na v 1 family. Now David Julius and colleagues have identified two spider toxins specifically targeting Na v 1.1, and use them to show that this channel is key to the specific transduction of mechanical but not thermal pain by myelinated Aδ sensory fibres. Previous genetic studies of Na v 1.1 indicate that such selective agents may open therapeutic avenues in disorders associated with the central nervous system, such as epilepsy, autism and Alzheimer disease. The involvement of Na v 1.1 channels in mediating mechanical pain reported here was unexpected.

In mice, it is possible to induce a psoriasis-like condition by applying imiquimod; here, the production of interleukin-23 that is stimulated by such skin inflammation is shown to depend on the interaction of nociceptors expressing the Na v 1.8 and TRPV1 channels with skin-resident dendritic cells. Peripheral neurons involved in inflammation Repeated topical application of the antiviral immune modifier imiquimod (IMQ) to murine skin provokes interleukin-23-mediated inflammatory lesions that resemble human psoriasis. Ulrich von Andrian and colleagues show that the production of skin inflammation in this disease model depends on the interaction of a subset of sensory neurons expressing the ion channels TRPV1 and Na v 1.8 with skin-resident dendritic cells. Taken together with other recent work, this finding suggests a scenario in which noxious pain fibres integrate environmental signals to modulate local immune responses to a variety of infectious and pro-inflammatory stimuli. The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation 1 , 2 , 3 , 4 . The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear 5 , 6 . We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation 7 , 8 . Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Na v 1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors 9 , 10 , 11 , DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response 12 . These findings indicate that TRPV1 + Na v 1.8 + nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

Transient receptor potential vanilloid type 1 (TRPV1) agonist-induced analgesia is a current hot topic of pain research and a promising possibility to alleviate chronic/neuropathic pain. Local applications in humans and animals and systemic administration in experimental animals of TRPV1 agonists have been demonstrated to produce a long-lasting blockade of nociceptors leaving the function of other types of sensory nerves, as well as autonomic and motor nerve fibers, intact. Morphological studies revealed that TRPV1 agonist-mediated drug action is linked to distinct structural alterations involving reversible and/or irreversible neuronal degenerative processes. This review is intended to summarize the available information on morphological changes associated with TRPV1 agonist-induced activation and defunctionalization of nociceptors expressing the TRPV1/capsaicin receptor. In addition, morphological alterations associated with some pathologies involving TRPV1-expressing nociceptors will also be dealt with. Activation and defunctionalization can be elicited from any domain of TRPV1 receptor-expressing neurons. Considering the similar membrane properties of perikarya, axons and peripheral receptive nerve endings, the term chemosensitive nociceptor neuron is proposed to denote this particular class of primary sensory neurons.

Chronic pain remains a significant medical challenge with complex underlying mechanisms, and an urgent need for new treatments. Our research built and utilized the iPain single-cell atlas to study chronic pain progression in dorsal root and trigeminal ganglia. We discovered that senescence of a small subset of pain-sensing neurons may be a driver of chronic pain. This mechanism was observed in animal models after nerve injury and in human patients diagnosed with chronic pain or diabetic painful neuropathy. Notably, treatment with senolytics, drugs that remove senescent cells, reversed pain symptoms in mice post-injury. These findings highlight the role of cellular senescence in chronic pain development, demonstrate the therapeutic potential of senolytic treatments, and underscore the value of the iPain atlas for future pain research. Chronic pain remains a major clinical challenge with unclear causes and a need for new treatment. Using the single-cell transcriptomics atlas iPain, here the authors show that nociceptor senescence may drive chronic pain and present senolytics as a potential therapeutic approach.

Nociceptors respond to noxious stimuli and transmit pain signals to the central nervous system. In the cornea, the nociceptors located in the most external layer provide a myriad of sensation modalities. Damage to these corneal nerve fibers can induce neuropathic pain. In response, corneal nerves become sensitized to previously non-noxious stimuli. Assessing corneal pain origin is a complex ophthalmic challenge due to variations in its causes and manifestations. Current FDA-approved therapies for corneal nociceptive pain, such as acetaminophen and NSAIDs, provide only broad-acting relief with unwanted side effects, highlighting the need for precision medicine for corneal nociceptive pain. A few targeted treatments, including perfluorohexyloctane (F6H8) eye drops and Optive Plus (TRPV1 antagonist), are FDA-approved, while others are in preclinical development. Treatments that target signaling pathways related to neurotrophic factors, such as nerve growth factors and ion channels, such as the transient receptor potential (TRP) family or tropomyosin receptor kinase A, may provide a potential combinatory therapeutic approach. This review describes the roles of nociceptors in corneal pain. In addition, it evaluates molecules within nociceptor signaling pathways for their potential to serve as targets for efficient therapeutic strategies for corneal nociceptive pain aimed at modulating neurotrophic factors and nociceptive channel sensitivity.

In humans, intradermal administration of β-alanine (ALA) and bovine adrenal medulla peptide 8–22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates ( Macaca nemestrina ), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22, and histamine, which activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain.

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects.We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors.These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant.Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.

Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between δ-opioid receptors (DORs) and μ-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca²⁺ currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.