ArticlePain2014
Cold hypersensitivity increases with age in mice with sickle cell disease.
Article in Pain, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature.Pediatric blood & cancer · 2015Pooled it
- Endothelin receptor antagonism in sickle cell disease: Is the time now?Canadian journal of physiology and pharmacology · 2026Review
- Article
- Behavioral and transcriptional effects of age in HbSS-BERK humanized SCD mice.Journal of sickle cell disease · 2025Article
- Mast cell extracellular trap formation underlies vascular and neural injury and hyperalgesia in sickle cell disease.Life science alliance · 2024Article
- Genetic contributions to pain modulation in sickle cell: A focus on single nucleotide polymorphisms.Gene reports · 2024Article
- Article
- Mouse models of sickle cell disease: Imperfect and yet very informative.Blood cells, molecules & diseases · 2024Review
- Descending Facilitation of Nociceptive Transmission From the Rostral Ventromedial Medulla Contributes to Hyperalgesia in Mice with Sickle Cell Disease.Neuroscience · 2023Article
- The Complex Association of Daily Opioid Dose with Visits for Pain in Sickle Cell Disease: Tolerance or Treatment-Refractory Pain?Pain medicine (Malden, Mass.) · 2023Observational
- Article
- Topical Vapocoolant-Associated Vaso-occlusive Event in a 10-year-old with Sickle Cell Disease.Pain management nursing : official journal of the American Society of Pain Management Nurses · 2021Article
- Article
- Mechanisms of pain in sickle cell disease.British journal of pain · 2021Article
- Neuropathic Pain and Sickle Cell Disease: a Review of Pharmacologic Management.Current pain and headache reports · 2020Review
- End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain.Blood advances · 2019Article
- Gabapentin alleviates chronic spontaneous pain and acute hypoxia-related pain in a mouse model of sickle cell disease.British journal of haematology · 2019Article
- Spinal and afferent PKC signaling mechanisms that mediate chronic pain in sickle cell disease.Neuroscience letters · 2019Review
- Sensitization of nociceptors and dorsal horn neurons contributes to pain in sickle cell disease.Neuroscience letters · 2019Review
- Sensitization of nociceptors by prostaglandin EBlood · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. In addition, both humans and mice with SCD experience heightened cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization or its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Furthermore, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the transient receptor potential melastatin 8 (Trpm8) and transient receptor potential ankyrin 1 (Trpa1) channels, as well as the 2-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk10), and TRAAK (Kcnk4). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes, and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.