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Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice.

Lakomá J, Rimondini R, Donadio V, Liguori R, Caprini M - PLoS ONE (2014)

Bottom Line: Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies.At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8.Notably, these alterations are observed in young animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.

ABSTRACT
Fabry disease (FD) is one of the X-linked lysosomal storage disorders caused by deficient functioning of the alpha-galactosidase A (α-GalA) enzyme. The α-GalA deficiency leads to multi-systemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide in the endothelium and vascular smooth muscles. A hallmark symptom of FD patients is peripheral pain that appears in the early stage of the disease. Pain in FD patients is a peripheral small-fiber idiopathic neuropathy, with intra-epidermal fiber density and integrity being used for diagnosing FD in humans. However, the molecular correlates underlying pain sensation in FD remain elusive. Here, we have employed the α-GalA gene KO mouse as a model of FD in rodents to investigate molecular changes in their peripheral nervous system that may account for their algesic symptoms. The α-GalA mice display neuropathic pain as evidenced by thermal hyperalgesia and mechanical allodynia, with histological analyses showing alterations in cutaneous innervation. Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies. At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8. Notably, these alterations are observed in young animals. Taken together, our findings imply that the α-GalA KO mouse is a good model in which to study the peripheral small fiber neuropathy exhibited by FD patients, and provides molecular evidence for a hyperexcitability of small nociceptors in FD.

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Mechanical and thermal sensitivity of α-GalA KO males.Basal sensitivity towards mechanical stimulation (latency time (A); applied force (B)). Comparison of the basal sensitivity of male α-GalA KO (n = 16) and relative WT (n = 28) in response to mechanical stimulation, p<0.0001. Basal sensitivity to hot and cold temperature stimuli in male α-GalA KO (n = 34) and relative WT (n = 32), p<0.0001 as measured using the hot plate (C) and the acetone test (D) revealed the significant insensitivity of α-GalA KO (n = 19) males in comparison to their relative WT (n = 13), p = 0.0008. Basal insensitivity to noxious temperature of cold stimulus in male α-GalA KO (n = 7) and relative WT (n = 8), p = 0.0466 as measured via cold plate assay (E). The data from plantar cold sensitivity assay confirmed the observed insensitivity of KO males (n = 10) to cold stimuli when compared to WT males (n = 10), p = 0.0028 (F). Data are expressed as mean±SEM.
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pone-0108641-g002: Mechanical and thermal sensitivity of α-GalA KO males.Basal sensitivity towards mechanical stimulation (latency time (A); applied force (B)). Comparison of the basal sensitivity of male α-GalA KO (n = 16) and relative WT (n = 28) in response to mechanical stimulation, p<0.0001. Basal sensitivity to hot and cold temperature stimuli in male α-GalA KO (n = 34) and relative WT (n = 32), p<0.0001 as measured using the hot plate (C) and the acetone test (D) revealed the significant insensitivity of α-GalA KO (n = 19) males in comparison to their relative WT (n = 13), p = 0.0008. Basal insensitivity to noxious temperature of cold stimulus in male α-GalA KO (n = 7) and relative WT (n = 8), p = 0.0466 as measured via cold plate assay (E). The data from plantar cold sensitivity assay confirmed the observed insensitivity of KO males (n = 10) to cold stimuli when compared to WT males (n = 10), p = 0.0028 (F). Data are expressed as mean±SEM.

Mentions: To determine whether the loss of activity of α-galactosidase A (α-GalA) affects mechanical sensitivity, an automated von Frey test was performed on α-GalA(−/0) males and control mice. Two parameters were analysed: latency time to paw withdrawal and the force of the stimulus. There was a significant difference in withdrawal threshold (reaction time and force) to a mechanical stimulus between KO and control (WT) mice (Figure 2A and Bp<0.0001, n = 28 animals for WT, n = 16 animals for KO). This decrease in withdrawal threshold to a mechanical stimulus could be due to a hyperalgesic state induced by the loss of activity of α-GalA.


Pain related channels are differentially expressed in neuronal and non-neuronal cells of glabrous skin of fabry knockout male mice.

Lakomá J, Rimondini R, Donadio V, Liguori R, Caprini M - PLoS ONE (2014)

Mechanical and thermal sensitivity of α-GalA KO males.Basal sensitivity towards mechanical stimulation (latency time (A); applied force (B)). Comparison of the basal sensitivity of male α-GalA KO (n = 16) and relative WT (n = 28) in response to mechanical stimulation, p<0.0001. Basal sensitivity to hot and cold temperature stimuli in male α-GalA KO (n = 34) and relative WT (n = 32), p<0.0001 as measured using the hot plate (C) and the acetone test (D) revealed the significant insensitivity of α-GalA KO (n = 19) males in comparison to their relative WT (n = 13), p = 0.0008. Basal insensitivity to noxious temperature of cold stimulus in male α-GalA KO (n = 7) and relative WT (n = 8), p = 0.0466 as measured via cold plate assay (E). The data from plantar cold sensitivity assay confirmed the observed insensitivity of KO males (n = 10) to cold stimuli when compared to WT males (n = 10), p = 0.0028 (F). Data are expressed as mean±SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4206276&req=5

pone-0108641-g002: Mechanical and thermal sensitivity of α-GalA KO males.Basal sensitivity towards mechanical stimulation (latency time (A); applied force (B)). Comparison of the basal sensitivity of male α-GalA KO (n = 16) and relative WT (n = 28) in response to mechanical stimulation, p<0.0001. Basal sensitivity to hot and cold temperature stimuli in male α-GalA KO (n = 34) and relative WT (n = 32), p<0.0001 as measured using the hot plate (C) and the acetone test (D) revealed the significant insensitivity of α-GalA KO (n = 19) males in comparison to their relative WT (n = 13), p = 0.0008. Basal insensitivity to noxious temperature of cold stimulus in male α-GalA KO (n = 7) and relative WT (n = 8), p = 0.0466 as measured via cold plate assay (E). The data from plantar cold sensitivity assay confirmed the observed insensitivity of KO males (n = 10) to cold stimuli when compared to WT males (n = 10), p = 0.0028 (F). Data are expressed as mean±SEM.
Mentions: To determine whether the loss of activity of α-galactosidase A (α-GalA) affects mechanical sensitivity, an automated von Frey test was performed on α-GalA(−/0) males and control mice. Two parameters were analysed: latency time to paw withdrawal and the force of the stimulus. There was a significant difference in withdrawal threshold (reaction time and force) to a mechanical stimulus between KO and control (WT) mice (Figure 2A and Bp<0.0001, n = 28 animals for WT, n = 16 animals for KO). This decrease in withdrawal threshold to a mechanical stimulus could be due to a hyperalgesic state induced by the loss of activity of α-GalA.

Bottom Line: Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies.At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8.Notably, these alterations are observed in young animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.

ABSTRACT
Fabry disease (FD) is one of the X-linked lysosomal storage disorders caused by deficient functioning of the alpha-galactosidase A (α-GalA) enzyme. The α-GalA deficiency leads to multi-systemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide in the endothelium and vascular smooth muscles. A hallmark symptom of FD patients is peripheral pain that appears in the early stage of the disease. Pain in FD patients is a peripheral small-fiber idiopathic neuropathy, with intra-epidermal fiber density and integrity being used for diagnosing FD in humans. However, the molecular correlates underlying pain sensation in FD remain elusive. Here, we have employed the α-GalA gene KO mouse as a model of FD in rodents to investigate molecular changes in their peripheral nervous system that may account for their algesic symptoms. The α-GalA mice display neuropathic pain as evidenced by thermal hyperalgesia and mechanical allodynia, with histological analyses showing alterations in cutaneous innervation. Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies. At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8. Notably, these alterations are observed in young animals. Taken together, our findings imply that the α-GalA KO mouse is a good model in which to study the peripheral small fiber neuropathy exhibited by FD patients, and provides molecular evidence for a hyperexcitability of small nociceptors in FD.

Show MeSH
Related in: MedlinePlus