Pain-related sodium channels in sensory neurons : gene expression during development and after injury
Author: Thun, Jonas
Date: 2008-06-12
Location: Föreläsningssalen Månen, 9Q, Alfred Nobels Allé 8, Huddinge
Time: 10.00
Department: Institutionen för odontologi / Department of Odontology
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thesis.pdf (974.9Kb)
Abstract
Pain that goes on over years as a result of nerve damage is an affliction
which disables millions of people worldwide. Chronic injury-induced pain
can become severely debilitating and extremely difficult to treat. The
process of pain transmission in primary sensory neurons is extremely
complex, and involves several sodium channels, which in many cases appear
to be specific for pain processing. These channels could, if their roles
were fully understood, become targets for new analgesics. Most work on
pain mechanisms has been carried out in spinal nerve systems, and has
provided great insight into the mechanisms of neuropathic pain. It is
obvious that much of these data is relevant to studies of craniofacial
pain. However, it is now clear that the pathophysiology of the
craniofacial trigeminal nerve is in many ways different to that found in
spinal nerves. Studies of trigeminal pain mechanisms require a thorough
understanding of the regional neurobiological characteristics in
combination with knowledge of the diverse and complex clinical problems
which can arise. The aim of this thesis was to elucidate the regulation
of pain-related sodium channels in developing and injured primary sensory
neurons in spinal dorsal root ganglia as well as in trigeminal ganglia.
Investigation of the developing trigeminal ganglion using in situ hybridization showed that specific voltage gated sodium channels, some of which are specifically associated with paintransmitting neurons, mature in waves that are particular for each channel. The results suggest that some craniofacial primary sensory neuron voltage gated sodium channels mature earlier than their counterparts at segmental levels during development. They also clearly indicate that different facial regions may differ in the ability to transmit sensory signals during early life.
The results also conclude that the down-regulation of the voltage gated sodium channel transcripts Nav1.8 and Nav1.9 mRNA that occurs in injured dorsal root ganglion cells is not influenced by interferon-gamma. Thus, the reduced pain-related behavior seen in nerve-injured interferon-gamma receptor knockout mice is not due to changes in the regulation of Nav1.8 and Nav1.9.
The evaluation of a photochemically-induced injury to the infraorbital nerve, a branch of the trigeminal nerve, revealed behavioral changes indicative of evoked and possible ongoing painlike responses in the facial region, and a spread of mechanical hypersensitivity to the body. In the trigeminal ganglion, robust changes in the mRNA expression of voltage gated sodium channel transcripts were seen after the ischemic infraorbital nerve injury. It seems reasonable to assume that these changes are related to the development of pain-related behavior in the affected animals.
Using real-time PCR and in situ hybridization techniques, it was shown that the expression of specific voltage gated sodium channel isoforms in the dorsal root ganglion and the dorsal horn of the spinal cord correlate across mouse strains with pain behavior (autotomy) in the neuroma model of neuropathic pain. Nerve injury induced significantly altered levels of Nav1.3, Nav1.5 and Nav1.7 in one strain only. However, Contactin, a voltage gated sodium channel-associated protein, and Nav1.6 were down-regulated in a majority of the strains to expression levels that tightly correlated to autotomy behavior. In the spinal cord, Nav1.7 expression was strongly upregulated following nerve injury to levels well correlated with pain-like behavior.
Investigation of the developing trigeminal ganglion using in situ hybridization showed that specific voltage gated sodium channels, some of which are specifically associated with paintransmitting neurons, mature in waves that are particular for each channel. The results suggest that some craniofacial primary sensory neuron voltage gated sodium channels mature earlier than their counterparts at segmental levels during development. They also clearly indicate that different facial regions may differ in the ability to transmit sensory signals during early life.
The results also conclude that the down-regulation of the voltage gated sodium channel transcripts Nav1.8 and Nav1.9 mRNA that occurs in injured dorsal root ganglion cells is not influenced by interferon-gamma. Thus, the reduced pain-related behavior seen in nerve-injured interferon-gamma receptor knockout mice is not due to changes in the regulation of Nav1.8 and Nav1.9.
The evaluation of a photochemically-induced injury to the infraorbital nerve, a branch of the trigeminal nerve, revealed behavioral changes indicative of evoked and possible ongoing painlike responses in the facial region, and a spread of mechanical hypersensitivity to the body. In the trigeminal ganglion, robust changes in the mRNA expression of voltage gated sodium channel transcripts were seen after the ischemic infraorbital nerve injury. It seems reasonable to assume that these changes are related to the development of pain-related behavior in the affected animals.
Using real-time PCR and in situ hybridization techniques, it was shown that the expression of specific voltage gated sodium channel isoforms in the dorsal root ganglion and the dorsal horn of the spinal cord correlate across mouse strains with pain behavior (autotomy) in the neuroma model of neuropathic pain. Nerve injury induced significantly altered levels of Nav1.3, Nav1.5 and Nav1.7 in one strain only. However, Contactin, a voltage gated sodium channel-associated protein, and Nav1.6 were down-regulated in a majority of the strains to expression levels that tightly correlated to autotomy behavior. In the spinal cord, Nav1.7 expression was strongly upregulated following nerve injury to levels well correlated with pain-like behavior.
List of papers:
I. Thun J, Fried K (2008). "Differential expression of neuronal voltage-gated sodium channel mRNAs during the development of the rat trigeminal ganglion." (Submitted)
II. Eriksson J, Fried K (2003). "Expression of the sodium channel transcripts Na(v)1.8 and Na(v)1.9 in injured dorsal root ganglion neurons of interferon-gamma or interferon-gamma receptor deficient mice." Neurosci Lett 338(3): 242-6
Pubmed
III. Eriksson J, Jablonski A, Persson AK, Hao JX, Kouya PF, Wiesenfeld-Hallin Z, Xu XJ, Fried K (2005). "Behavioral changes and trigeminal ganglion sodium channel regulation in an orofacial neuropathic pain model." Pain 119(1-3): 82-94. Epub 2005 Nov 16
Pubmed
IV. Persson AK, Thun J, Xu XJ, Wiesenfeld-Hallin Z, Devor M, Lidman O, Fried K (2008). "Pain behavior induced by nerve injury correlates with the expression of specific sodium channels in mouse strains." (Submitted)
I. Thun J, Fried K (2008). "Differential expression of neuronal voltage-gated sodium channel mRNAs during the development of the rat trigeminal ganglion." (Submitted)
II. Eriksson J, Fried K (2003). "Expression of the sodium channel transcripts Na(v)1.8 and Na(v)1.9 in injured dorsal root ganglion neurons of interferon-gamma or interferon-gamma receptor deficient mice." Neurosci Lett 338(3): 242-6
Pubmed
III. Eriksson J, Jablonski A, Persson AK, Hao JX, Kouya PF, Wiesenfeld-Hallin Z, Xu XJ, Fried K (2005). "Behavioral changes and trigeminal ganglion sodium channel regulation in an orofacial neuropathic pain model." Pain 119(1-3): 82-94. Epub 2005 Nov 16
Pubmed
IV. Persson AK, Thun J, Xu XJ, Wiesenfeld-Hallin Z, Devor M, Lidman O, Fried K (2008). "Pain behavior induced by nerve injury correlates with the expression of specific sodium channels in mouse strains." (Submitted)
Issue date: 2008-05-22
Rights:
Publication year: 2008
ISBN: 978-91-7409-060-4
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