Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0184567 (acute pain)
 3,962 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3(-/-) mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3(-/-) mice but not Tlr7(-/-) mice. Consequently, central sensitization-driven pain hypersensitivity, but not acute pain, was impaired in Tlr3(-/-) mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3(-/-) mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.
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PMID:TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. 2256 12

Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas-related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions.
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PMID:New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? 2363 73

Itch is an unpleasant sensation that initiates scratching behavior. The itch-scratch reaction is a complex phenomenon that implicates supraspinal structures required for regulation of sensory, emotional, cognitive, and motivational aspects. However, the central mechanisms underlying the processing of itch and the interplay of the supraspinal regions and spinal cord in regulating itch-scratch processes are poorly understood. Here, we have shown that the neural projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a critical circuit element for regulating itch-related behaviors in the brains of male C57BL/6J mice. Moreover, we demonstrate that ACC-DMS projections selectively modulate histaminergic, but not nonhistaminergic, itch-related behavior. Furthermore, photoactivation of ACC-DMS projections has also no significant effects on pain behavior induced by thermal, mechanical, and chemical stimuli except for a relief on inflammatory pain evoked by formalin and complete Freund's adjuvant. We further demonstrate that the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons, which represent a population of spinal inhibitory interneurons that mediate the inhibition of itch. Therefore, this study presents the first evidence that the ACC-DMS projections modulate histaminergic itch-related behavior and reveals an interplay between the supraspinal and spinal levels in histaminergic itch regulation.SIGNIFICANCE STATEMENT This study reveals that the projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a supraspinal circuit for modulation of histaminergic, but not nonhistaminergic, itch. Manipulation of ACC-DMS projections has no effect on acute pain sensation. Furthermore, the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons. Understanding the supraspinal itch circuits is of great significance in the development of new therapies for chronic itch-related intractable diseases.
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PMID:ACC to Dorsal Medial Striatum Inputs Modulate Histaminergic Itch Sensation. 2954 May 48

Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here, we find that S1P triggers itch and pain in male mice in a concentration-dependent manner, with low levels triggering acute itch alone and high levels triggering both pain and itch. Ca2+ imaging and electrophysiological experiments revealed that S1P signals via S1P receptor 3 (S1PR3) and TRPA1 in a subset of pruriceptors and via S1PR3 and TRPV1 in a subset of heat nociceptors. Consistent with these findings, S1P-evoked itch behaviors are selectively lost in mice lacking TRPA1, whereas S1P-evoked acute pain and heat hypersensitivity are selectively lost in mice lacking TRPV1. We conclude that S1P acts via different cellular and molecular mechanisms to trigger itch and pain. Our discovery elucidates the diverse roles that S1P signaling plays in somatosensation and provides insight into how itch and pain are discriminated in the periphery.SIGNIFICANCE STATEMENT Itch and pain are major health problems with few effective treatments. Here, we show that the proinflammatory lipid sphingosine 1-phosphate (S1P) and its receptor, S1P receptor 3 (S1PR3), trigger itch and pain behaviors via distinct molecular and cellular mechanisms. Our results provide a detailed understanding of the roles that S1P and S1PR3 play in somatosensation, highlighting their potential as targets for analgesics and antipruritics, and provide new insight into the mechanistic underpinnings of itch versus pain discrimination in the periphery.
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PMID:S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways. 3008 22