| 1. |
- Blind, Per-Jonas, et al.
(författare)
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Unique antitumour effects of L-2,4 diaminobutyric acid on cultured hepatoma cells
- 2003
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Ingår i: Anticancer research. - 1791-7530. ; 23:2B, s. 1245-1248
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Tidskriftsartikel (refereegranskat)abstract
- A single hepatoma cell line was grown in vitro and incubated with L-2,4 diaminobutyric acid (DAB), a non-metabolizable amino acid, under various conditions. The tumour cells were irreversibly damaged by incubation for 8 hours with 8 mmol/L of DAB. The tumour cell-destroying effect of DAB was dose- and time-dependent with no effect at a DAB concentration of 1.6 mmol/L. The presence of N-methyl a-aminoisobutyric acid (a specific substrate of amino acid transport system A) in the incubation medium abrogated the tumour cell destructive effect of DAB in a dose- dependent fashion. The presence of it on-physiological amino acids in the incubation medium per se was not the cause of tumour cell destruction, since inclusion of a-amino-isobutyric acid and N-methyl a-aminoisobutyric acid in the incubation medium did not influence the viability of hepatoma cells. We conclude that the tumour cell destructive effect of DAB was the result of a huge and unlimited uptake of DAB energized by the Na+-gradient and that this uptake was not subjected to the law of saturation kinetics. This was combined with a tumour cell energy crisis in attempts to restore the Na+-gradient.
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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. |
- Petersson, Per, et al.
(författare)
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Spontaneous muscle twitches during sleep guide spinal self-organization.
- 2003
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 424:6944, s. 72-75
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Tidskriftsartikel (refereegranskat)abstract
- During development, information about the three-dimensional shape and mechanical properties of the body is laid down in the synaptic connectivity of sensorimotor systems through unknown adaptive mechanisms. In spinal reflex systems, this enables the fast transformation of complex sensory information into adequate correction of movements. Here we use a computer simulation to show that an unsupervised correlation-based learning mechanism, using spontaneous muscle twitches, can account for the functional adaptation of the withdrawal reflex system. We also show that tactile feedback resulting from spontaneous muscle twitches during sleep(1-3) does indeed modify sensorimotor transformation in young rats in a predictable manner. The results indicate that these twitches, corresponding to human fetal movements(4), are important in spinal self-organization.
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| 4. |
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| 5. |
- Waldenström Ellervik, Alexandra, et al.
(författare)
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Developmental learning in a pain-related system: Evidence for a cross-modality mechanism
- 2003
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 23:20, s. 7719-7725
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Tidskriftsartikel (refereegranskat)abstract
- The nociceptive spinal reflex system performs highly precise sensorimotor transformations that require functionally specified synaptic strengths. The specification is gradually attained during early development and appears to be learning dependent. Here we determine the time course of this specification for heat-nociceptive tail withdrawal reflexes and analyze which types of primary afferents are important for the learning by applying various forms of noninvasive sensory deprivations. The percentage of erroneous heat-nociceptive tail withdrawal reflexes (i.e., movements directed toward the stimulation) decreased gradually from 64.1 +/- 2.5% ( mean +/- SEM) to <10% during postnatal days 10-21. This improvement was completely blocked by anesthetizing the tail during the adaptation period, confirming that an experience-dependent mechanism is involved in the specification of synaptic strengths. However, the results show that the adaptation occurs to a significant extent despite local analgesia and protection of the tail from noxious input, provided that tactile sensitivity is preserved. Therefore, it appears that a nociceptive input is not necessary for the adaptation, and that input from tactile receptors can be used to guide the nociceptive synaptic organization during development. Sensory deprivation in the adult rat failed to affect the heat-nociceptive withdrawal reflex system, indicating that the adaptation has a "critical period" during early development. These findings provide a key to the puzzle of how pain-related systems can be functionally adapted through experience despite the rare occurrence of noxious input during early life.
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| 6. |
- Waldenström Ellervik, Alexandra
(författare)
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NO PAIN, STILL GAIN- cross-modality development learning guided by spinal spontaneous activity
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies indicate that experience dependent mechanisms shape the pain system during the development. In view of that painful stimuli are rare during development it is not clear how this is accomplished. In this thesis it is confirmed, using a battery of sensory deprivations in the rat, that the development of an essential component of the pain system, the nociceptive withdrawal reflexes (NWR), is subject to experience dependent learning. Moreover, the learning in the NWR occurs despite absence of nociceptive stimuli. Instead it requires tactile experience. This novel ‘cross-modality learning’ occurs within a particular time window during development, normally lasting 5-7 days, after which the central connections are stabilized. A correlation between the cross modality learning and spontaneous movements was established. The spontaneous tail movements, studied during the postnatal days 1-25, were found to be generated in the spinal cord. They peak postnatally, preced and overlap in time the functional adaptation of NWR. The NWR adaptation occurs simultaneously with a qualitative change in spontaneous movements (towards simple uni-directional movements), presumably reflecting a maturation of spinal reflex circuits connections. It is proposed that an unsupervised correlation-based learning mechanism, using spontaneous muscle twitches, account for the functional adaptation of the NWR system. In this learning mechanism, spontaneously active reflex interneurones cause movements that in turn lead to altered sensory feedback informing about the consequencies of the movements, which is used to set the gain in the nociceptive connections. A simulation of this new learning mechanism, termed Motor Directed Somatosensory Imprinting (MDSI), showed that it is plausible. In behavioural experiments, it was demonstrated that tactile feedback resulting from spontaneous muscle twitches during sleep(Blumberg and Lucas, 1996b;Blumberg and Lucas, 1994a) indeed modifies the sensorimotor transformation in young rats in the predicted manner. These findings thus indicate that spontaneous movements, corresponding to human foetal movements, play a key role for establishing functional nociceptive networks. This learning occurs during a sleep state called active sleep, which is similar to REM sleep in adults, indicating a novel role for sleep in learning and memory.
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| 7. |
- Waldenström Ellervik, Alexandra, et al.
(författare)
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Spontaneous movements: Effect of denervation and relation to the adaptation of nociceptive withdrawal reflexes in the rat.
- 2009
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Ingår i: Physiology & Behavior. - : Elsevier BV. - 1873-507X .- 0031-9384. ; 98, s. 532-536
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Tidskriftsartikel (refereegranskat)abstract
- Spontaneous movements are a ubiquitous phenomenon during development. Recently, we demonstrated that these movements play a key role in the functional adaptation of spinal reflex circuits. Here, we analyse the role of afferent input in the generation of spontaneous movements and characterize the occurrence of different types of spontaneous movements and their relation to the functional adaptation of the nociceptive withdrawal reflexes (NWR) up to postnatal day 22 (P22). Noxious thermal stimulation was used to evoke reflex responses in awake rats. Spontaneous tail movements occurring during active sleep were counted during the first three postnatal weeks and classified into two major classes: simple movements (unidirectional) and complex twitches (bi-directional and oscillating). All spinal nerves caudal to L2 were cut at P12 to study the effect of deafferentation on spontaneous movements. The number of simple movements and complex twitches in the deafferented animals did not differ as compared to control animals. The adaptation of tail NWR occurred during the period P7-P22. Spontaneous tail movements occurred relatively frequently and overlapped in time the adaptation of NWR. Notably, the relative number of simple movements increased in parallel with the functional adaptation of the NWR, suggesting a role of simple twitches in NWR adaptation. The present findings indicate that the spontaneous movements studied are driven by intrinsic mechanisms in the CNS and suggest that sensory feedback does not influence the spontaneous movement patterns. Moreover, the NWR adaptation appears to be related to a qualitative change in spontaneous movements caused by maturation in spinal reflex circuit connections.
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