Sickle cell mice exhibit mechanical allodynia and enhanced responsiveness in light touch cutaneous mechanoreceptors

Article (PDF Available)inMolecular Pain 8(1):62 · September 2012with17 Reads
DOI: 10.1186/1744-8069-8-62 · Source: PubMed
Background Sickle cell disease (SCD) is associated with both acute vaso-occlusive painful events as well as chronic pain syndromes, including heightened sensitivity to touch. We have previously shown that mice with severe SCD (HbSS mice; express 100% human sickle hemoglobin in red blood cells; RBCs) have sensitized nociceptors, which contribute to increased mechanical sensitivity. Yet, the hypersensitivity in these neural populations alone may not fully explain the mechanical allodynia phenotype in mouse and humans. Findings Using the Light Touch Behavioral Assay, we found HbSS mice exhibited increased responses to repeated application of both innocuous punctate and dynamic force compared to control HbAA mice (100% normal human hemoglobin). HbSS mice exhibited a 2-fold increase in percent response to a 0.7mN von Frey monofilament when compared to control HbAA mice. Moreover, HbSS mice exhibited a 1.7-fold increase in percent response to the dynamic light touch “puffed” cotton swab stimulus. We further investigated the mechanisms that drive this behavioral phenotype by focusing on the cutaneous sensory neurons that primarily transduce innocuous, light touch. Low threshold cutaneous afferents from HbSS mice exhibited sensitization to mechanical stimuli that manifested as an increase in the number of evoked action potentials to suprathreshold force. Rapidly adapting (RA) Aβ and Aδ D-hair fibers showed the greatest sensitization, each with a 75% increase in suprathreshold firing compared to controls. Slowly adapting (SA) Aβ afferents had a 25% increase in suprathreshold firing compared to HbAA controls. Conclusions These novel findings demonstrate mice with severe SCD exhibit mechanical allodynia to both punctate and dynamic light touch and suggest that this behavioral phenotype may be mediated in part by the sensitization of light touch cutaneous afferent fibers to suprathreshold force. These findings indicate that Aβ fibers can be sensitized to mechanical force and should potentially be examined for sensitization in other tissue injury and disease models.

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Available from: Audra Kramer
    • "Sickle mice appear to be sensitized to multiple modalities of somatosensory input. This study and others [9,17,20,28] demonstrate that sickle mice are hypersensitive to a range of intensities of mechanical stimuli, ranging from light to noxious, and to cold. It is possible that oxidative stress, induced by hypoxia from vasoocclusion , may lead to dysregulation of proteins that interact with the cold receptors on sensory neurons. "
    [Show abstract] [Hide abstract] ABSTRACT: Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. Additionally, both humans and mice with SCD experience heighted cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization, nor 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. Further, 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 TRP Ankyrin 1 (Trpa1) channels, as well as the two-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk4), and TRAAK (Kcnk10). 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.
    Full-text · Article · Jun 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Meningeal and other trigeminal nociceptors are thought to play important roles in the initiation of migraine headache. Currently, the only approved peripherally administered chronic migraine prophylactic drug is onabotulinumtoxinA. The purpose of this study was to determine how botulinum neurotoxin type A (BoNT-A) affects naïve and sensitized meningeal nociceptors. Using electrophysiological techniques, we identified 43 C- and 36 Aδ-meningeal nociceptors, and measured their spontaneous and evoked firing before and after BoNT-A administration to intracranial dura and extracranial suture-receptive fields. As a rule, BoNT-A inhibited C- but not Aδ-meningeal nociceptors. When applied to nonsensitized C-units, BoNT-A inhibited responses to mechanical stimulation of the dura with suprathreshold forces. When applied to sensitized units, BoNT-A reversed mechanical hypersensitivity. When applied before sensitization, BoNT-A prevented development of mechanical hypersensitivity. When applied extracranially to suture branches of intracranial meningeal nociceptors, BoNT-A inhibited the mechanical responsiveness of the suture branch but not dural axon. In contrast, BoNT-A did not inhibit C-unit responses to mechanical stimulation of the dura with threshold forces, or their spontaneous activity. The study provides evidence for the ability of BoNT-A to inhibit mechanical nociception in peripheral trigeminovascular neurons. These findings suggest that BoNT-A interferes with neuronal surface expression of high-threshold mechanosensitive ion channels linked preferentially to mechanical pain by preventing their fusion into the nerve terminal membrane.
    Full-text · Article · Apr 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Very little is known about pain processing in sickle cell disease (SCD). We examined the mechanical and thermal sensory patterns in children with SCD. Children aged 10 to 17 years (n=48; mean 13.7±2.0 y; 22 females) participated in quantitative sensory testing (QST) procedures and completed a quality of life (PedsQL) and anxiety and depression scale (RCADS). Thirteen children showed evidence of abnormal pain processing, indicated by decreased sensitivity to heat or cold sensations (hypoesthesia), and pain experienced with nonpainful stimuli (allodynia). Pain ratings associated with cold and warm sensations were significantly higher in the subgroup with abnormal QST compared with the 35 SCD children with normal QST (P=0.01 and P<0.0001, respectively). The presence of hypoesthesia and allodynia in children with SCD may represent abnormal changes in the peripheral and central nervous system. Clinicians need to be aware that sickle cell pain may not only be inflammatory or ischemic secondary to vasoocclusion and hypoxia, but may also be neuropathic secondary to nerve injury or nerve dysfunction. Neuropathic pain in SCD may be the result of tissue damage after vaso-occlusion in neural tissues, whether peripherally or centrally. Future studies are needed to determine the presence of neuropathic pain in children with SCD.
    Article · Jul 2014
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