| 1. |
- Kalezic, Ivana, et al.
(författare)
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Changes in Tetrodotoxin-Resistant C-Fibre Activity during Fatiguing Isometric Contractions in the Rat
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science, PLoS. - 1932-6203. ; 8:9, s. e73980-
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Tidskriftsartikel (refereegranskat)abstract
- It is by now well established that tetrodotoxin-resistant (TTX-R) afferent fibres from muscle in the rat exhibit a multisensitive profile, including nociception. TTX-R afferent fibres play an important role in motor control, via spinal and supraspinal loops, but their activation and function during muscle exercise and fatigue are still unknown. Therefore, the specific effect of isometric fatiguing muscle contraction on the responsiveness of TTX-R C-fibres has been investigated in this study. To quantify the TTX-R afferent input we recorded the cord dorsum potential (CDP), which is the result of the electrical fields set up within the spinal cord by the depolarisation of the interneurons located in the dorsal horn, activated by an incoming volley of TTX-R muscle afferents. The changes in TTX-R CDP size before, during and after fatiguing electrical stimulation of the gastrocnemius-soleus (GS) muscle have been taken as a measure of TTX-R C-unit activation. At the end of the fatiguing protocol, following an exponential drop in force, TTX-R CDP area decreased in the majority of trials (9/14) to 0.75 +/- 0.03% (mean +/- SEM) of the pre-fatigue value. Recovery to the control size of the TTX-R CDP was incomplete after 10 min. Furthermore, fatiguing trials could sensitise a fraction of the TTX-R C-fibres responding to muscle pinch. The results suggest a long-lasting activation of the TTX-R muscle afferents after fatiguing stimulation. The role of this behaviour in chronic muscle fatigue in connection with pain development is discussed. Accumulation of metabolites released into the interstitium during fatiguing stimulation might be one of the reasons underlying the C-fibres' long-lasting activation.
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| 2. |
- Kalezic, Ivana, et al.
(författare)
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Distinctive pattern of c-fos expression in the feline cervico-lumbar spinal cord after stimulation of vanilloid receptors in dorsal neck muscles
- 2004
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Ingår i: Neuroscience Letters. - Amsterdam : Elsevier Science. - 0304-3940 .- 1872-7972. ; 364:2, s. 94-97
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, c-fos expression in the spinal cord has been used as a marker of neuronal activation induced by capsaicin-sensitive sensory afferents from the dorsal neck muscles in cats (n = 6). The number of Fos-immunoreactive neurons, which were revealed using the avidin-biotin-peroxidase method, was significantly increased in the cervical and lumbar spinal cord. In contrast to the control group (n = 3), 2 h after intramuscular capsaicin injection, c-fos expression was more extensive ipsilaterally to the injected side in the C3-C6 segments, and bilaterally in the L4-L6 segments. Most labeled neurons in the cervical spinal cord were small and giant cells, predominantly located in the middle and lateral parts of lamina I and, additionally, at the neck of the dorsal horn (lamina V), i.e., within the zones of termination of high-threshold muscle afferents. The widespread distribution of labeled cells throughout the cervical cord within the intermediate zone (lamina VII) coincided with the sites of last-order premotor interneurons and cells of origin of long crossed and uncrossed descending propriospinal pathways to the lumbar spinal cord. These findings suggest possible mechanisms for spreading of nociceptive signals between cervical and lumbar regions.
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| 3. |
- Kalezic, Ivana
(författare)
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Experimental studies of spinal mechanisms associated with muscle fatigue
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle fatigue is ubiquitous in every day life.Muscle fatigue might be considered as an altered state of motor behaviour, which impairs motor performance. By contrast, muscle fatigue could also be considered a positive phenomenon, which protects muscle tissue from damage that might be incurred to it by overuse. The principal aim of the thesis was to explore some of the mechanisms of muscle fatigue at the spinal level in animal models.The activation of multiple motor units of a single calf muscle may influence contractile properties of its neighbouring, otherwise inactive units, providing evidence for spatial spreading of fatigue between different muscle parts. The release of metabolites, their action on inactive muscle units and the effects of local hypoxia are the most likely causes. Fatigue-induced metabolite shift in the interstitium provokes excitation and/or sensitisation of high-threshold afferent fibers, with complex effects on the spinal premotoneuronal network involved in the modulation of motoneuronal output. This was examined by studing the intrasegmental lamellar distribution of the lumbar spinal interneurons following fatiguing contractions of the triceps surae muscle. Furthermore, fatigue of calf muscles enhanced the activity of fusimotor neurons to these muscles irrespective of the regime of muscle activity (isometric vs. lengthening) in conditions that simulate locomotion. Altered fusimotor activity, through increased or maintained muscle spindle afferent responsiveness may be advantageous, providing support to the skeletomotor activity and enhanced information about muscle periphery to higher nervous centres. The particular effects of interneuronal network at motor input (presynaptic inhibition system) and output (recurrent inhibition system) stages were then addressed. Fatigue of triceps surae muscle induced a suppression of the monosynaptic reflex. The intensity of presynaptic inhibition increased, while the intensity of recurrent inhibition decreased. Post fatigue-evoked changes in monosynaptic reflexes and presynaptic inhibition indicate the possibility that high-threshold afferents inhibit group Ia terminals pre-synaptically, which would allow fatigue-induced signals from the muscle to reduce the relevance of proprioceptive feedback. Besides intrasegmental, intersegmental spreading of nociceptive signals was explored. Activation of sensory afferents from dorsal neck muscles by capsaicin induces powerful activation of interneurons located in the cervical spinal cord, as well as a widespread activation of cells in lumbar spinal cord segments. The results confirm the pivotal role of small diameter muscle afferents in the orchestration of segmental responses to fatigue and show complex interactions that may lead to limited accuracy of motor output. They also depict processes that may be related to, and even become precursors of chronic muscle pain.
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| 4. |
- Kalezic, Ivana, et al.
(författare)
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Fatigue-related depression of the feline monosynaptic gastrocnemius-soleus reflex
- 2004
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Ingår i: Journal of Physiology. - London : Cambridge U. P.. - 0022-3751 .- 1469-7793. ; 556:1, s. 293-296
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Tidskriftsartikel (refereegranskat)abstract
- In decerebrate cats, changes in the monosynaptic reflex (MSR) of gastrocnemius-soleus (G-S) motoneurones were studied after fatiguing stimulation (FST) of the G-S muscles. Monosynaptic reflexes were evoked by stimulation of Ia fibres in the G-S nerve and recorded from a filament of ventral root (VR) L7. FST (intermittent 40 s(-1) stimulation for 10-12 min) was applied to the distal part of the cut VR S1. FST reduced MSR amplitudes to 0.64 +/- 0.04 (mean +/-s.e.m.) of the prefatigue values. The suppression remained stable for approximately 25 min and then MSR amplitudes gradually returned towards the normal. To test for the involvement of presynaptic and recurrent inhibition, MSRs were conditioned by stimulation of the nerve to the posterior biceps and semitendinosus (PBSt) muscles or a filament of VR L7, respectively. The intensity of presynaptic inhibition (reduction of the normalized value of MSR amplitude during conditioning) increased from 0.19 +/- 0.02 in prefatigue to 0.44 +/- 0.04 within a 5.3-18.2 min interval after FST, followed by a recovery. In contrast, the intensity of recurrent inhibition first diminished from 0.23 +/- 0.02 in prefatigue to 0.15 +/- 0.01 within 15.6-30.1 min after FST and then gradually recovered. Both primary afferent depolarization and the intensity of antidromic discharges in primary afferents increased with the presynaptic inhibition intensity. These results demonstrate a fatigue-related suppression of Ia excitation of synergistic motoneurones, probably arising from the activation of group III and IV afferents. The effects could in part be due to increased presynaptic inhibition, while recurrent inhibition plays a minor role.
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| 5. |
- Kostyukov, Alexander I, et al.
(författare)
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Effects in feline gastrocnemius-soleus motoneurones induced by muscle fatigue.
- 2005
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 163:3, s. 284-94
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Tidskriftsartikel (refereegranskat)abstract
- Responses of gastrocnemius-soleus (G-S) motoneurones to stretches of the homonymous muscles were recorded intracellularly in decerebrate cats before, during and after fatiguing stimulation (FST) of G-S muscles. Ventral roots (VR) L7 and S1 were cut, and FST was applied to VR S1, a single FST session including 4 to 5 repetitions of 12-s periods of regular 40 s(-1) stimulation. Muscle stretches consisted of several phases of slow sinusoidal shortening-lengthening cycles and intermediate constant lengths. The maximal stretch of the muscles was 8.8 mm above the rest length. Effects of FST on excitatory postsynaptic potentials (EPSPs) and spikes evoked by the muscle stretches were studied in 12 motoneurones from ten experiments. Stretch-evoked EPSPs and firing were predominantly suppressed after FST, with the exception of a post-contraction increase of the first EPSP after FST, which was most likely due to after-effects in the activity of muscle spindle afferents. The post-fatigue suppression of EPSPs and spike activity was followed by restoration within 60-100 s. Additional bouts of FST augmented the intensity of post-fatigue suppression of EPSPs, with the spike activity sometimes disappearing completely. FST itself elicited EPSPs at latencies suggesting activation of muscle spindle group Ia afferents via stimulation of beta-fibres. The suppression of the stretch-evoked responses most likely resulted from fatigue-evoked activity of group III and IV muscle afferents. Presynaptic inhibition could be one of the mechanisms involved, but homosynaptic depression in the FST-activated group Ia afferents may also have contributed.
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| 6. |
- Kostyukov, AI, et al.
(författare)
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Spreading of fatigue-related effects from active to inactive parts in the medial gastrocnemius muscle of the cat
- 2002
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 86:4, s. 295-307
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Tidskriftsartikel (refereegranskat)abstract
- In the medial gastrocnemius muscle of the decerebrate cat, the spatial spread of fatigue between active and inactive muscle parts was studied. Conditioning fatiguing stimulation (CFS) was applied to a part of the muscle to test whether it had an effect on the contraction efficiency in an unstimulated part. To exclude somato-sympathetic reflexes during CFS, a full rhizotomy of the lumbo-sacral spinal cord was performed. The same ipsilateral ventral root, either L7 or S1, was divided into seven filaments, one of which was used for the test stimulation, and four or five for CFS. The CFS consisted of 12 s sessions of distributed stimulation of five (or four) filaments at a rate of 40 s(-1), the sessions were repeated, every 40 s, 15 or more times. The test consisted of 12 s of regular stimulation at a rate of 10 s(-1), preceded and followed by a single stimulus. The tests applied just after CFS showed a strong decline of both tension and electromyogram (EMG), amounting to only [mean (SD)] 0.45 (0.18) and 0.51 (0.19) (n = 15), respectively, of the corresponding values in the tests before CFS. It thus turned out that depressive fatigue-related effects could spread within the muscle. At the same time, control reactions recorded in the lateral gastrocnemius during stimulation of its cut nerve did not change. Subsequent repetitions of the tests usually revealed a tendency towards restoration. The EMG reactions recovered more quickly than tension. The depression of EMG after CFS was accompanied by a slowing of the constituent M-waves; their latencies decreased during restoration. Distinct changes in the systemic blood pressure were observed during CFS. These changes were usually correlated well with muscle tension changes. The factors possibly underlying the observed effects may include diffusion of metabolites from active to inactive muscle fibres, lowering of the efficiency of neuro-muscular transmission due to squeezing of efferent motor terminals and changes in outer metabolite content, as well as local hypoxia due to increases in intramuscular pressure.
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| 7. |
- Lee, Edward W, et al.
(författare)
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Neuropeptide Y (NPY) : A neurogenic mediator of angiogenesis
- 2004
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Ingår i: 7th International NPY Meeting Coimbra. ; , s. 36-36
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- NPY, previously known as a sympathetic vasoconstricting co-transmitter, recently has also emerged as an important vascular growth factor, stimulating proliferation of vascular smooth muscle and endothelial cells (ECs). Both in vitro and in vivo, NPY stimulates angiogenesis starting at sub-picomolar, non-vasoconstrictive concentrations, and with maximal effects similar to those of other known angiogenic factors e.g. vascular endothelial growth factor (VEGF). To determine if NPY is a physiological mediator in vivo, we studied 1 ) ischemic angiogenesis in a rodent model of femoral artery occlusion 2) vascular development in rats over-expressing NPY gene; 3) changes in angiogenesis with aging. Hindlimb ischemia increased local NPY release and shifted NPY receptor (R) expression from predominantly Yl to the Y2R type, and up-regulated dipeptidyl peptidase IV (DPPIV, peptidase forming Y2/YS agonist). Increasing local NPY levels 2-fold with a slow-release pellet (Il.g/14 days, below arterial occlusion), additionally induced YSR mRNA, and stimulated capillary angiogenesis and collateral vessel growth - leading to restoration of blood flow and contractile function of ischemic muscles. These effects were markedly reduced in Y2R-/- mice, as was NPY-induced aortic sprouting ex vivo; the latter was also reduced by anti-VEGF antibody and completely abolished in endothelial nitric oxide synthase (eNOS)-/- mice. The role of NPY in vascular development was further revealed by the severe impairment of spontaneous aortic sprouting in NPY-/- mice and changes in vascular density of non-ischemic muscles: reduction in Y2-/- mice and marked increase in NPY-Tg rats. With aging, in mice, NPY-induced angiogenesis decreased together with Y2 and DPPIV expression, and in human ECs, the proliferative effects of NPY declined too, similarly to those of VEGF or basic fibroblast growth factor (bFGF). Since NPY-induced EC proliferation was similarly blocked by anti-VEGF and anti-FGF antibodies in young and old patients, this suggests that age-induced impaired activity of the NPY-Y2R system could lead to lower secretion of these growth factors, in addition to decreased responsiveness of old vessels to VEGF and bFGF. Taken together, our studies indicate that NPY is a physiological neurogenic factor playing an important role ip revascularization of ischemic tissues and in age-related changes in vascular development. NPY's angiogenic activity requires Y2Rs and eNOS, and involves release of VEGF and bFGF. Thus, sympathetic nerve activity, via NPY, may be an important upstream mechanism triggering a cascade of molecular events leading to vascular remodeling during tissue ischemia and growth.
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| 8. |
- Ljubisavljevic, M, et al.
(författare)
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Changes in fusimotor activity during repetitive lengthening muscle contractions in decerebrate cats
- 1998
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Ingår i: Neuroscience. - 0306-4522 .- 1873-7544. ; 86:4, s. 1337-1342
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Tidskriftsartikel (refereegranskat)abstract
- Responses of fusimotor neurons to lengthening vs isometric contractions have been studied in decerebrate cats. Spike discharges of fusimotor neurons to the medial gastrocnemius muscle were recorded from this muscle nerve filament during sequences of contractions and/or stretches of the lateral gastrocnemius and soleus muscles. The sequences lasted for 250-450s (duty cycle 4:2 s). Isometric contractions were elicited by electrical stimulation (40 Hz, 1.3 times motor threshold) of the muscle nerves. Lengthening contractions were elicited in the same way while the muscles were stretched by 4 mm at a velocity of 1 mm/s. Of 25 fusimotor neurons studied, 23 responded to muscle contractions with an increase in firing rate, subsiding towards the end of the sequence. The increase was either modulated with each subsequent contraction or smooth throughout the sequence. Approximately 64% of fusimotor neurons, responding to muscle contractions, responded in a similar way to the sequences of muscle stretches, applied alone. Responses to sequences of the lengthening contractions were significantly larger, on average, than those to the isometric ones, but smaller than the sum of the responses to the contractions and stretches applied separately. On the other hand, they were also larger in fusimotor units, showing no overt responses to muscle stretches alone.
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| 9. |
- Pilyavskii, Alexander I, et al.
(författare)
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c-fos expression and NADPH-d reactivity in spinal neurons after fatiguing stimulation of hindlimb muscles in the rat
- 2001
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Ingår i: Brain Research. - 0006-8993 .- 1872-6240. ; 923:1-2, s. 91-102
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of Fos-immunoreactive (Fos-ir) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons in the rat lumbar spinal cord was examined following muscle fatigue caused by intermittent high-rate (100 s(-1)) electrical stimulation of the triceps surae muscle or the ventral root L5 (VRL5) for 30 min. Following both types of stimulation, the fatigue-related c-fos gene expression was more extensive in the L2-L5 segments on the stimulated side, and the majority of Fos-ir neurons were concentrated in the dorsal horn. After direct muscle stimulation, the highest number of Fos-ir neurons were detected in two regions: layer 5, and superficial layers (1 and 2(o)), although many labeled cells were also found in layers 3, 4, 6, and 7. In response to VRL5 stimulation, the maximal density of Fos-ir neurons was detected in the middle and lateral parts of layers 1 and 2(o), the zone of termination of high-threshold muscle afferents(.) Statistically significant prevalence of Fos-ir cell number was also found in layers 5 and 7 on the stimulated side. A few Fos-ir neurons were detected in the ventral horn (layer 8 and area 10) on both sides. The lamellar distribution of NADPH-d-reactive neurons was similar over all experimental groups of animals. In the L3-L6 segments, such reactive cells were arranged in two distinct regions: dorsal horn (layers 2(i), 3, and 5) and area 10; in the L1 and L2 segments, an additional cluster of NADPH-d positive cells was found in the intermediolateral cell column (IML). Double-labeled cells were not detected. We suggest that c-fos expression in response to muscle fatigue reveals activity of functionally different types of spinal neurons which could operate together with NOS-containing cells in pre-motoneuronal networks to modulate the motoneuron output.
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