| 1. |
- Jongsma, Helen, et al.
(författare)
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Alteration of PACAP distribution and PACAP receptor binding in the rat sensory nervous system following sciatic nerve transection
- 2000
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Ingår i: Brain Research. - 0006-8993. ; 853, s. 96-186
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Tidskriftsartikel (refereegranskat)abstract
- Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely expressed neuropeptide that has been involved in nerve regeneration, neurone survival and nociception. In this study, the distribution of PACAP and PACAP-receptors were investigated in rat dorsal root ganglia (DRG), spinal cord and medulla oblongata at 3, 7 or 14 days following unilateral sciatic nerve transection using immunohistochemistry, 125I-PACAP-binding and in situ hybridisation. In control (contralateral side) DRG, about 30% of the nerve cell bodies (92% being small) were PACAP-immunoreactive (PACAP-IR). In the spinal cord, PACAP-IR fibres were seen in laminae I-II but not in the gracile nuclei. Following sciatic nerve transection, PACAP-IR fibres appeared in the gracile nuclei and occasionally in the deeper laminae of the dorsal horn consistent with the relative increase in larger PACAP-IR DRG neurones. However, the relative number of small PACAR-IR neurones was significantly lower on the transected side as compared to the control side suggesting a dual reaction for PACAP in the DRG following nerve injury. 125I-PACAP-binding was found in laminae I-II, around the central canal and in the gracile nuclei but not in the DRG. At 14 days after transection, 125I-PACAP-binding density was significantly reduced in the ipsilateral dorsal horn. PACAP-receptor (PAC(1)) mRNA was detected in neurones of the dorsal and ventral horn and in the gracile nuclei with no overt changes observed after transection. Very few DRG nerve cell bodies contained PAC(1) mRNA. The findings are consistent with a role for PACAP both in nociception and regeneration.
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| 2. |
- Jongsma, Helen, et al.
(författare)
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Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor
- 2001
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Ingår i: NeuroReport. - 1473-558X. ; 12:10, s. 2215-2219
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been proposed to have a role in nociception. Here we have used the formalin test, thermal laser stimulation and mechanical von Frey stimulation to investigate possible alteration of PAC1-/- mice nociceptive behaviour. Our finding, that PAC1-/- mice have a substantial, 75% decrease in nociceptive response during the late phase, provides clear evidence that the specific PACAP-receptor PAC1 is involved in the mediation of nociceptive responses during chronic conditions such as inflammation. PAC1-/- mice had small or no changes in the response to mechanical and thermal laser stimulation. This suggests a limited, if any, involvement of PAC1 in nociception after short-lasting stimuli. Injury-induced changes in DRG neuropeptide expression were more pronounced in PAC1-/- mice, implying neuroregulatory functions of PAC1.
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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Mulder, Hindrik, et al.
(författare)
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Pituitary adenylate cyclase-activating polypeptide and islet amyloid polypeptide in primary sensory neurons : Functional implications from plasticity in expression on nerve injury and inflammation
- 1999
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Ingår i: Molecular Neurobiology. - 0893-7648. ; 19:3, s. 229-253
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Forskningsöversikt (refereegranskat)abstract
- Primary sensory neurons serve a dual role as afferent neurons, conveying sensory information from the periphery to the central nervous system, and as efferent effectors mediating, e.g., neurogenic inflammation. Neuropeptides are crucial for both these mechanisms in primary sensory neurons. In afferent functions, they act as messengers and modulators in addition to a principal transmitter; by release from peripheral terminals, they induce an efferent response, 'neurogenic inflammation,' which comprises vasodilatation, plasma extravasation, and recruitment of immune cells. In this article, we introduce two novel members of the sensory neuropeptide family: pituitary adenylate cyclase-activating polypeptide (PACAP) and islet amyloid polypeptide (IAPP). Whereas PACAP, a vasoactive intestinal polypeptide-resembling peptide, predominantly occurs in neuronal elements, IAPP, which is structurally related to calcitonin gene-related peptide, is most widely known as a pancreatic β-cell peptide; as such, it has been recognized as a constituent of amyloid deposits in type 2 diabetes. In primary sensory neurons, under normal conditions, both peptides are predominantly expressed in small-sized nerve cell bodies, suggesting a role in nociception. On axotomy, the expression of PACAP is rapidly induced, whereas that of IAPP is reduced. Such a regulation of PACAP suggests that it serves a protective role during nerve injury, but that of IAPP may indicate that it is an excitatory messenger under normal conditions. In contrast, in localized adjuvant-induced inflammation, expression of both peptides is rapidly induced. For IAPP, studies in IAPP-deficient mice support the notion that IAPP is a pronociceptive peptide, because these mutant mice display a reduced nociceptive response when challenged with formalin.
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