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- Jongsma Wallin, Helen, et al.
(författare)
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Exogenous NT-3 and NGF differentially modulate PACAP expression in adult sensory neurons, suggesting distinct roles in injury and inflammation
- 2001
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 14:2, s. 267-282
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Tidskriftsartikel (refereegranskat)abstract
- Expression of pituitary adenylate cyclase-activating polypeptide in sensory neurons varies with injury or inflammation. The neurotrophins NGF and NT-3 are profound regulators of neuronal peptidergic phenotype in intact and injured sensory neurons. This study examined their potential for modulation of PACAP expression in adult rat with intact and injured L4-L6 spinal nerves with or without immediate or delayed intrathecal infusion of NT-3 or NGF. Results indicate that in L5 DRG, few trkC neurons express high levels of PACAP mRNA in the intact state, but many do following injury. The elevated expression in injured neurons is mitigated by NT-3 infusion, suggesting a role for NT-3 in returning the 'injured phenotype' back towards an 'Intact phenotype'. NGF dramatically up-regulated PACAP expression in trkA-positive neurons in both intact and injured DRGs, implicating NGF as a positive regulator of PACAP expression in nociceptive neurons. Surprisingly, NT-3 modulates PACAP expression in an antagonistic fashion to NGF in intact neurons, an effect most evident in the trkA neurons not expressing trkC. Both NT-3 and NGF infusion results in decreased detection of PACAP protein in the region of the gracile nuclei, where central axons of the peripherally axotomized large sensory fibers terminate. NGF infusion also greatly increased the amount of PACAP protein detected in the portion of the dorsal horn innervated by small-medium size DRG neurons, while both neurotrophins appear able to prevent the decrease in PACAP expression observed in these afferents with injury. These results provide the first insights into the potential molecules implicated in the complex regulation of PACAP expression in sensory neurons.
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- Jongsma Wallin, Helen
(författare)
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PACAP in adult sensory neurons - implications in injury and pain
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The data presented in this thesis deal with the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in adult sensory neurons. We have used different injury and pain models to determine the involvement of PACAP during such conditions. The role of neurotrophins for PACAP expression was also investigated. PACAP is one of the excitatory neuropeptides expressed in small sized DRG neurons. The level of PACAP expression in such neurons is increased following peripheral inflammation but is decreased following sciatic nerve injury and instead induced in medium to large sized neurons. Data showed that under normal conditions and upon peripheral inflammation PACAP mRNA was expressed in trkA positive DRG L5 neurons. Intrathecally applied NGF dramatically increased both the number and the level of PACAP mRNA expression in small to medium sized neurons. The increased expression of PACAP after peripheral inflammation was inhibited by anti-NGF treatment. Hence, NGF seems to be a strong positive regulator of PACAP expression and appears to be responsible for the increased levels of PACAP expression during inflammation. In the formalin test, mice lacking the PACAP preferring receptor, PAC1 had a profoundly decreased nociceptive response in the late, inflammatory phase suggesting that the PAC1 receptor is important in the mediation of inflammatory pain. Intrathecally applied NT-3 reduced PACAP expression in intact neurons. Thus, while NGF appears to promote PACAP expression NT-3 appears to antagonise it. The dramatic increase of PACAP expression following nerve injury occurs in trkC positive, medium to large sized neurons and can be effectively mitigated by NT-3 and to a lesser degree by NGF. PAC1-/- mice had greater injury-induced changes in the expression of other neuropeptides, especially galanin, implying neuroregulatory functions of the PAC1 receptor after injury.
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