Biomedical subjects

M Marsala

Publications and source records attributed to M Marsala.

At least 19 recordsLinked to original sources

PubMed2006

Development of GABA-sensitive spasticity and rigidity in rats after transient spinal cord ischemia: a qualitative and quantitative electrophysiological and histopathological study.

Transient spinal cord ischemia may lead to a progressive degeneration of spinal interneurons and subsequently to increased hind limb motor tone. In the present work we sought to characterize the rigidity and spasticity components of this altered motor function by: i) tonic electromyographic activity measured in gastrocnemius muscle before and after ischemia, ii) measurement of muscle resistance during the period of ankle flexion and corresponding changes in electromyographic activity, iii) changes in Hoffmann reflex, and, iv) motor evoked potentials. In addition the effect of intrathecal treatment with baclofen (GABAB receptor agonist; 1 microg), nipecotic acid (GABA uptake inhibitor; 300 microg) and dorsal L2-L5 rhizotomy on spasticity and rigidity was studied. Finally, the changes in spinal choline acetyltransferase (ChAT) and vesicular glutamate transporter 2 and 1 (VGLUT2 and VGLUT1) expression were characterized using immunofluorescence and confocal microscopy. At 3-7 days after ischemia an increase in tonic electromyographic activity with a variable degree of rigidity was seen. In animals with modest rigidity a velocity-dependent increase in muscle resistance and corresponding appearance in electromyographic activity (consistent with the presence of spasticity) was measured during ankle rotation (4-612 degrees /s rotation). Measurement of the H-reflex revealed a significant increase in Hmax/Mmax ratio and a significant loss of rate-dependent inhibition. In the same animals a potent increase in motor evoked potential amplitudes was measured and this change correlated positively with the increased H-reflex responses. Spasticity and rigidity were consistently present for a minimum of 3 months after ischemia. Intrathecal treatment with baclofen (GABA B receptor agonist) and nipecotic acid (GABA uptake inhibitor) provided a significant suppression of spasticity, rigidity, H-reflex or motor evoked potentials. Dorsal L2-L5 rhizotomy significantly decreased muscle resistance but had no effect on increased amplitudes of motor evoked potentials. Confocal analysis of spinal cord sections at 8 weeks-12 months after ischemia revealed a continuing presence of ChAT positive alpha-motoneurons, Ia afferents and VGLUT2 and VGLUT1-positive terminals but a selective loss of small presumably inhibitory interneurons between laminae V-VII. These data demonstrate that brief transient spinal cord ischemia in rat leads to a consistent development of spasticity and rigidity. The lack of significant suppressive effect of dorsal L2-L5 rhizotomy on motor evoked potentials response indicates that descending motor input into alpha-motoneurons is independent on Ia afferent couplings and can independently contribute to increased alpha-motoneuronal excitability. The pharmacology of this effect emphasizes the potent role of GABAergic type B receptors in regulating both the spasticity and rigidity.

Acetyltransferases↗

PubMed2006

Spatiotemporal alterations of the NO/NOS neuronal pools following transient abdominal aorta occlusion: morphological and biochemical studies in the rabbit.

1. Brief interruption of spinal cord blood flow resulting from transient abdominal aortic occlusion may lead to degeneration of specific spinal cord neurons and to irreversible loss of neurological function. The alteration of nitric oxide/nitric oxide synthase (NO/NOS) pool occurring after ischemic insult may play a protective or destructive role in neuronal survival of affected spinal cord segments. 2. In the present study, the spatiotemporal changes of NOS following transient ischemia were evaluated by investigating neuronal NOS immunoreactivity (nNOS-IR), reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry, and calcium-dependent NOS (cNOS) conversion of [(3)H] l-arginine to [(3)H] l-citrulline. 3. The greatest levels of these enzymes and activities were detected in the dorsal horn, which appeared to be most resistant to ischemia. In that area, the first significant increase in NADPHd staining and cNOS catalytic activity was found immediately after a 15-min ischemic insult. 4. Increases in the ventral horn were observed later (i.e., after a 24-h reperfusion period). While the most intense increase in nNOS-IR was detected in surviving motoneurons of animals with a shorter ischemic insult (13 min), the greatest increase of cNOS catalytic activity and NADPHd staining of the endothelial cells was found after stronger insult (15 min). 5. Given that the highest levels of nNOS, NADPHd, and cNOS were found in the ischemia-resistant dorsal horn, and nNOS-IR in surviving motoneurons, it is possible that NO production may play a neuroprotective role in ischemic/reperfusion injury.

Animals↗

PubMed2005

Mu and delta, but not kappa, opioid agonists induce spastic paraparesis after a short period of spinal cord ischaemia in rats.

BACKGROUND: Intrathecal (IT) morphine given after a short interval of aortic occlusion in a rodent model induced transient spastic paraparesis via opioid receptor-predicted actions in spinal cord. To determine the role(s) of spinal opioid receptor subtypes we investigated whether IT administration of various selective opioid receptor agonists can induce paraparesis following a short period of spinal cord ischaemia in rats. METHODS: In Sprague-Dawley rats implanted with an IT catheter, spinal cord ischaemia was induced for 6 min using an intraaortic balloon. Mu ([D-Ala2, N-Me Phe4, Gly-ol5] enkephalin), kappa (U50488H) or delta ([D-Pen(2,5)] enkephalin) selective agonists were injected intrathecally 30 min after reperfusion. A separate group of animals was used to investigate the dose-response effect on this motor dysfunction. For this purpose, three doses of mu, kappa, or delta agonists were injected intrathecally after ischaemia. After IT injection, recovery of motor function was assessed periodically using the motor deficit index (0=complete recovery; 6=complete paraplegia). RESULTS: IT administration of mu and delta but not kappa agonists produced dose-dependent effects in the induction of spastic paraparesis. In addition, this spasticity induced by IT mu and delta agonists was reversed completely by IT naloxone and naltrindole, respectively. CONCLUSION: These results suggest that the effect of various opioids on motor function after a short period of spinal cord ischaemia depends upon individual opioid receptor subtypes.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2005

Experimental cauda equina compression induces HSP70 synthesis in dog.

The heat shock protein 70 (HSP70) is a key component of the stress response induced by various noxious conditions such as heat, oxygen stress, trauma and infection. In present study we have assessed the consequences of the compression of lower lumbar and sacral nerve roots caused by a multiple cauda equina constrictions (MCEC) on HSP70 immunoreactivity (HSP70-IR) in the dog. Our data indicate that constriction of central processes evokes HSP70 up-regulation in the spinal cord (L7, S1-Co3) as well as in the corresponding dorsal root ganglion cells (DRGs) (L7-S1) two days following injury. A limited number of bipolar or triangular HSP-IR neurons were found in the lateral collateral pathway (LCP) as well as in the pericentral region (lamina X) of the spinal cord. In contrast, a high number of HSP70 exhibiting motoneurons with fine processes appeared in the ventral horn (laminae VIII-IX) of lumbosacral segments. Concomitantly, close to them a few lightly HSP70-positive neuronal somata or cell bodies lacking the HSP70-IR occurred. In the DRGs, HSP70 expression was mildly up-regulated in small and medium-sized neurons and in satellite cells. On the contrary, DRGs from intact or sham-operated dogs did not reveal HSP70 specific neuronal staining. In conclusion, we have demonstrated that the MCEC in dogs mimicking the cauda equina syndrome in clinical settings evokes expression of HSP70 synthesis in specific neurons of the lumbo-sacro-coccygeal spinal cord segments and in small and medium sized neurons of corresponding DRGs. This suggests that HSP70 may play an active role in neuroprotective processes partly by maintaining intracellular protein integrity and preventing the neuronal degeneration in this experimental paradigm.

Animals↗

PubMed2003

The spinal GDNF level is increased after transient spinal cord ischemia in the rat.

Glial cell line-derived neurotrophic factor (GDNF) is known as the most potent neurotrophic factor against injury. We have characterized spinal GDNF changes after ischemia to clarify its possible physiological role against ischemic damage. Spinal ischemia in the rat was produced by cross-clamping of the thoracic aorta together with systemic hypotension. The spinal tissue GDNF level was measured by enzyme-linked immunoabsorbent assay (ELISA) and the localization of GDNF in the tissue was examined by immunohistochemistry. GDNF was increased reaching two peaks after ischemia. The first peak was at 2 hrs after onset of recirculation derived from alpha motor neurons. The second GDNF peak was at 72 hrs provided by astrocytes. These data suggest a necessity of GDNF to increase to protect against ischemic damage, and that activated astrocytes may have an important role in maintaining the GDNF level.

Animals↗

PubMed2003

Cauda equina syndrome and nitric oxide synthase immunoreactivity in the spinal cord of the dog.

The development of the cauda equina syndrome in the dog and the involvement of spinal nitric oxide synthase immunoreactivity (NOS-IR) and catalytic nitric oxide synthase (cNOS) activity were studied in a pain model caused by multiple cauda equina constrictions. Increased NOS-IR was found two days post-constriction in neurons of the deep dorsal horn and in large, mostly bipolar neurons located in the internal basal nucleus of Cajal seen along the medial border of the dorsal horn. Concomitantly, NOS-IR was detected in small neurons close to the medioventral border of the ventral horn. High NOS-IR appeared in a dense sacral vascular body close to the Lissauer tract in S1-S3 segments. Somatic and fiber-like NOS-IR appeared at five days post-constriction in the Lissauer tract and in the lateral and medial collateral pathways arising from the Lissauer tract. Both pathways were accompanied by a dense punctate NOS immunopositive staining. Simultaneously, the internal basal nucleus of Cajal and neuropil of this nucleus exhibited high NOS-IR. A significant decrease in the number of small NOS immunoreactive somata was noted in laminae I-II of L6-S2 segments at five days post-constriction while, at the same time, the number of NOS immunoreactive neurons located in laminae VIII and IX was significantly increased. Moreover, high immunopositivity in the sacral vascular body persisted along with a highly expressed NOS-IR staining of vessels supplying the dorsal sacral gray commissure and dorsal horn in S1-S3 segments. cNOS activity, based on a radioassay of compartmentalized gray and white matter regions of lower lumbar segments and non-compartmentalized gray and white matter of S1-S3 segments, proved to be highly variable for both post-constriction periods.

Animals↗

PubMed2001

Intrathecal magnesium sulfate attenuates algogenic behavior and spinal amino acids release after kainic acid receptor activation in rats.

Activation of N-methyl-D-asparate (NMDA) receptor and non-NMDA classes of glutamate receptors play a key role in spinal nociceptive processing. Using with a lumbar intrathecal (IT) catheter and a loop dialysis catheter in lightly anesthetized (1% isoflurane) rats, the effect of IT pre-treatment with magnesium sulfate (100, 300 or 500 microg) on IT kainic acid (KA: 1 microg; non-NMDA receptor agonist) evoked amino acids (AAs) release and corresponding behavior was examined. IT KA produced significant increases (mean+/-SD of % baseline concentration) in dialysate concentrations of aspartate (424+/-88%), glutamate (241+/-35%) and taurine (398+/-58%). IT pre-treatment with MgSO(4) resulted in a dose-dependent suppression of the evoked algogenic behavior and aspartate release. These data suggest that activation of spinal KA receptors provides a powerful stimulus for secondary spinal excitatory AAs release and corresponding appearance of pain behavior. The regulation of this release by magnesium suggests the possible role of this divalent cation in regulating this excitatory effect of non-NMDA receptor activation.

Amino Acids↗

PubMed2001

Model of neuropathic intermittent claudication in the rat: methodology and application.

In the present study we characterize a rat neurogenic intermittent claudication model which was accomplished by placing two pieces of silicone rubber of various sizes into the lumbar (L4 and L6) epidural space. After induction of spinal stenosis walking function was measured using a treadmill apparatus and sensory functions were tested by measuring thermal and tactile withdrawal threshold (von Frey filaments) for the period of 28 days after stenosis. In addition, local spinal cord blood flow (SCBF) was measured, periodically, before and after induction of stenosis using laser Doppler. After implantation of two pieces of silicone rubber (width 1.25 mm, height 1.0 mm, length 4.0 mm) a significant running dysfunction, as evidenced by shortening of running distance, was measured as soon as 24 h after stenosis (178.5+/-59.1 m vs 681.3+/-70.2 m). This effect persisted for 28 days after surgery. Similarly, a significant tactile (but not thermal) hypersensitivity was measured for a period of 28 days (1.2+/-0.3 g vs 14.9+/-0.2 g). In this experimental group the measurement of local SCBF revealed a significant (30-50%) reduction in the territory of spinal stenosis measured at 3,7,14 or 28 days after surgery. Implantation of larger pieces of silicon rubber (1.5 mm width) caused a significant increase in the incidence of urinary retention and mortality rate. These data show that chronic partial spinal compression at L4 and L6 spinal level lead to the development of significant motor/sensory dysfunction which resemble those seen in patients with neurogenic intermittent claudication. The lack of motor dysfunction under resting conditions but its appearance during forced exercise also suggest that the development of local spinal ischemia can represent one of the mechanisms.

Animals↗

PubMed2001

Effect of spinal cord compression on cyclic 3',5'-guanosine monophosphate in the white matter columns of rabbit.

Changes in the level of cyclic 3',5'-guanosine monophosphate (cGMP) were studied one day after a surgically induced spinal cord constriction performed at the Th7 segment level in the dorsal, lateral and ventral white matter columns and in the non-compartmentalized white matter of Th5-Th6 segments, i.e., above the site of the spinal cord constriction and in Th8-Th9 segments, located below the spinal cord constriction. The midthoracic spinal cord constriction caused a significant decrease in the level of cGMP in the ventral column of Th5-Th6 segments and a significant increase in the lateral column of Th8-Th9 segments. The level of cGMP in the dorsal column, located either rostrally or caudally to the site of the spinal cord injury, remained unchanged. In addition, no significant changes in the level of cGMP were found in the non-compartmentalized white matter of Th5-Th6 and Th8-Th9 segments in response to constriction of the Th7 segment.

Animals↗

PubMed2001

Cauda equina syndrome.

Single or double-level compression of the lumbosacral nerve roots located in the dural sac results in a polyradicular symptomatology clinically diagnosed as cauda equina syndrome. The cauda equina nerve roots provide the sensory and motor innervation of most of the lower extremities, the pelvic floor and the sphincters. Therefore, in a fully developed cauda equina syndrome, multiple signs of sensory disorders may appear. These disorders include low-back pain, saddle anesthesia, bilateral sciatica, then motor weakness of the lower extremities or chronic paraplegia and, bladder dysfunction. Multiple etiologies can cause the cauda equina syndrome. Among them, non-neoplastic compressive etiologies such as herniated lumbosacral discs and spinal stenosis and spinal neoplasms play a significant role in the development of the cauda equina syndrome. Non-compressive etiologies of the cauda equina syndrome include ischemic insults, inflammatory conditions, spinal arachnoiditis and other infectious etiologies. The use of canine, porcine and rat models mimicking the cauda equina syndrome enabled discovery of the effects of the compression on nerve root neural and vascular anatomy, the impairment of impulse propagation and the changes of the neurotransmitters in the spinal cord after compression of cauda equina. The involvement of intrinsic spinal cord neurons in the compression-induced cauda equina syndrome includes anterograde, retrograde and transneuronal degeneration in the lumbosacral segments. Prominent changes of NADPH diaphorase exhibiting, Fos-like immunoreactive and heat shock protein HSP72 were detected in the lumbosacral segments in a short-and long-lasting compression of the cauda equina in the dog. Developments in the diagnosis and treatment of patients with back pain, sciatica and with a herniated lumbar disc are mentioned, including many treatment options available.

Animals↗

PubMed2001

The regional changes of the catalytic NOS activity in the spinal cord of the rabbit after repeated sublethal ischemia.

The regional distribution of catalytic NOS activity was studied in the lumbosacral segments of the spinal cord of the rabbit during single (8-min), twice (8-, 8-min) and thrice repeated (8-, 8-, 9-min) sublethal ischemia followed each time by 1 h of reperfusion. Single ischemia/reperfusion induced a significant increase of cNOS activity in almost all spinal cord regions, with the exception of non-significant increase in the dorsal horn. Sublethal ischemia repeated twice produced a significant decrease of enzyme activity in the intermediate zone and ventral horn and an increase in the white matter columns. Within thrice repeated ischemia, the activity of cNOS in the gray matter regions was similar to that found after a single ischemia/reperfusion. For all the animals subjected to single and twice repeated sublethal ischemic insults, there was no neurological impairment. Following thrice repeated ischemic insults, four out of five of the experimental animals recovered only partially and one was completely paraplegic. Our results do not indicate a cumulative effect of repeated sublethal ischemia on cNOS activity and, consequently, on NO production. The NO generated during thrice repeated ischemia/reperfusion appears to have a detrimental effect on the neurological outcome.

Animals↗

PubMed2001

Fos protein expression in sacral spinal cord in relation to early phase of cauda equina syndrome in dogs.

1. The aim of the present study is to map the incipient phase of Fos expression in the sacral spinal cord neuronal pools of multiple cauda equina constrictions canine model. 2. Fos-positive neurons were found bilaterally in the lateral portion of superficial dorsal horn layers (Laminae I-III) and along the lateral edge of the dorsal horn accompanied by the lateral collateral pathway, fibers of Lissauer's tract, terminating at the sacral parasympathetic nucleus. Similarly, high Fos expression was detected in the ventral portion of the dorsal sacral commissure and in the dorsomedial portion of the anterior horns at S1-S3 segment level. Finally, a clearly expressed Fos-positivity was disclosed bilaterally in the neuropil of the nucleus Y in the anterior horn. 3. Data from the present study show that continuous stimulation of the central fibers of sacral dorsal root ganglia neurons, i.e., fibers of sacral primary afferents, unlike those using various stimulations of the peripheral fibres offers an unusual pattern of Fos-like immunoreactivity.

Animals↗

PubMed2000

Incipient cauda equina syndrome as a model of somatovisceral pain in dogs: spinal cord structures involved as revealed by the expression of c-fos and NADPH diaphorase activity.

Segmental and laminar distribution of Fos-like immunoreactive, reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-exhibiting and double-labeled (Fos-like immunoreactive and NADPHd-exhibiting) neurons was examined in lower lumbar and sacral segments of the dog spinal cord using the model of multiple cauda equina constrictions. NADPHd histochemistry was used as marker of nitric oxide synthase-containing neurons. The appearance and the time-course of Fos-like immunoreactive, NADPHd and double-labeled neurons was studied at 2 h and 8 h postconstriction characterized as the incipient phase of cauda equina syndrome. The occurrence of Fos-like immunoreactive and NADPHd-exhibiting neurons in fully developed cauda equina syndrome was studied at five days postconstriction. An increase in Fos-like immunoreactivity in superficial laminae (I-II) and an enhanced NADPHd staining of lamina VIII neurons were found. A statistically significant increase in Fos-like immunoreactive neurons was found in laminae I-II and VIII-X 8 h postconstriction, and in contrast, a prominent decrease in Fos-like immunoreactive neurons was found in laminae I-II, accompanied by a statistically significant increase in Fos-like immunoreactive neurons in more ventrally located laminae VII-X at five days postconstriction. Quantitative analysis of laminar distribution of constriction-induced NADPHd-exhibiting neurons revealed a considerable increase in these neurons in laminae VIII-IX 8 h postconstriction and a statistically highly significant increase in NADPHd-exhibiting neurons in laminae VII-X five days postconstriction. Concurrently, the number of NADPHd-exhibiting neurons in laminae I-II was greatly reduced. While a low number of double-labeled neurons was found throughout the gray matter of lower lumbar and sacral segments at 2 h postconstriction, a statistically significant number of double-labeled neurons was found in lamina X 8 h and in laminae VII-X five days postconstriction. The course and distribution of anterograde degeneration resulting five days after multiple cauda equina constrictions are compared with segmental and laminar distribution of Fos-like immunoreactive and NADPHd-exhibiting neurons. Prominent involvement of the spinal cord neurons appearing in the lumbosacral segments at the early beginning and in fully developed cauda equina syndrome results in a Fos-like immunoreactivity and strongly enhanced NADPHd staining of some neuronal pools. Under such circumstances, an early cauda equina decompression surgery is advisable aimed at decreasing or preventing the derangement of the neural circuits in the lumbosacral segments.

Animals↗

PubMed2000

Characterization of spinal amino acid release and touch-evoked allodynia produced by spinal glycine or GABA(A) receptor antagonist.

Intrathecal strychnine (glycine antagonist) or bicuculline (GABA(A) antagonist) yields a touch-evoked agitation that is blocked by N-methyl-D-aspartate receptor antagonism. We examined the effects of intrathecal strychnine and bicuculline on touch-evoked agitation and the spinal release of amino acids. Fifty-two Sprague-Dawley rats were prepared under halothane anesthesia with a lumbar intrathecal catheter and a loop dialysis catheter. Four days after implantation, rats were randomized to receive an intrathecal injection of N-methyl-D-aspartate (3 microg), strychnine (3 microg) or bicuculline (10 microg), or a combination of N-methyl-D-aspartate with bicuculline or strychnine. The agitation produced by brief light tactile stroking of the flank (tactile allodynia), and the spontaneous spinal release of glutamate, taurine and serine was measured. Intrathecal N-methyl-D-aspartate, strychnine and bicuculline produced similar touch-evoked allodynia. Intrathecal bicuculline and N-methyl-D-aspartate alone evoked a transient spinal release of glutamate and taurine, but not serine, in the 0- 10 min sample, while strychnine did not affect spinal transmitter release at any time. As GABA(A) but not glycine receptor inhibition at equi-allodynic doses increases glutamate release, while the allodynia of both is blocked by N-methyl-D-aspartate receptor antagonism, we hypothesize that GABA(A) sites regulate presynaptic glutamate release, while glycine regulates the excitability of neurons postsynaptic to glutamatergic terminals.

Amino Acids↗

PubMed2000

Time course of brain neuronal degeneration and heat shock protein (72) expression following neck tourniquet-induced cerebral ischemia in the rat.

1. The present study was designed to examine the regional expression of HSP72/73 protein after a 7.5-min period of cerebral ischemia and to compare the distribution of HSP neurons with the localization of irreversible neuronal degeneration as analyzed by silver impregnation technique. 2. During 6-24 hr after cerebral ischemia clear-cut neuronal argyrophilia developed in several brain regions including the hippocampal hilus, nucleus reticularis thalami, and colliculi inferiores. With the exception of the hippocampal hilus, the structures which showed silver impregnability were HSP72 negative at 6-24 hr. 3. Despite the clear HSP72 expression seen in hippocampal CA1 neurons, a significant loss of these neurons was seen at 7 days after ischemia. 4. These data show that in some structures the presence of HSP72 is indicative of higher resistance of these neurons to ischemia-induced degeneration, however, the process of delayed neuronal degeneration appears to be independent of the accelerated synthesis of HSP72 seen during the early period of reflow.

Animals↗

PubMed2000

Transient spinal cord ischemia in rat: the time course of spinal FOS protein expression and the effect of intraischemic hypothermia (27 degrees C).

1. In the present study, we characterize the time course of spinal FOS protein expression after transient noninjurious (6-min) or injurious (12-min) spinal ischemia induced by inflation of a balloon catheter placed into the descending thoracic aorta. In addition, this work examined the effects of spinal hypothermia on FOS expression induced either by ischemia or by potassium-evoked depolarization (intrathecal KCl). 2. Short-lasting (6-min) spinal ischemia evoked a transient FOS protein expression. The peak expression was seen 2 hr after reperfusion in all laminar levels in lumbosacral segments. At 4 hr of reperfusion, more selective FOS expression in spinal interneurons localized in the central part of laminae V-VII was seen. At 24 hr no significant increase in FOS protein was detected. 3. After 12 min of ischemia and 2 hr of reflow, nonspecific FOS expression was seen in both white and gray matter, predominantly in nonneuronal elements. Intrathecal KCl-induced FOS expression in spinal neurons in the dorsal horn and in the intermediate zone. Spinal hypothermia (27 degrees C) significantly suppressed FOS expression after 6 or 12 min of ischemia but not after KCl-evoked depolarization. 4. Data from the present study show that an injurious (but not noninjurious) interval of spinal ischemia evokes spinal FOS protein expression in glial cells 2 hr after reflow. The lack of neuronal FOS expression corresponds with extensive neuronal degeneration seen in this region 24 hr after reflow. Noninjurious (6-min) ischemia induced a transient, but typically neuronal FOS expression. The significant blocking effect of hypothermia (27 degrees C) on the FOS induction after ischemia but not after potassium-evoked depolarization also suggests that simple neuronal depolarization is a key trigger in FOS induction.

Animals↗

PubMed2000

Effect of midthoracic spinal cord constriction on catalytic nitric oxide synthase activity in the white matter columns of rabbit.

The distribution and changes of catalytic nitric oxid synthase (cNOS) activity in the dorsal, lateral and ventral white matter columns at midthoracic level of the rabbit's spinal cord were studied in a model of surgically-induced spinal cord constriction performed at Th7 segment level and compared with the occurrence of nicotinamide adenine dinucleotide phosphate diaphorase expressing and neuronal nitric oxide synthase immunoreactive axons in the white matter of the control thoracic segments. Segmental and white-column dependent differences of cNOS activity were found in the dorsal (141.5 +/- 4.2 dpm/microm protein), lateral (87.3 +/- 11.5 dpm/microm protein) and ventral (117.1 +/- 7.6 dpm/microm protein) white matter columns in the Th5-Th6 segments and in the dorsal (103.3 +/- 15.5 dpm/microm protein), lateral (54.9 +/- 4.9 dpm/microm protein), and ventral (86.1 +/- 6.8 dpm/microm protein) white matter columns in the Th8-Th9 segments. A surgically-induced constriction of Th7 segment caused a disproportionate response of cNOS activity in the rostrally (Th5-Th6) and caudally (Th8-Th9) located segments in both lateral and ventral white matter columns. While a statistically significant decrease of cNOS activity was detected above the constriction site in the ventral columns, a considerable, statistically significant increase of cNOS activity was noted in the white lateral columns below the site of constriction. It is reasoned that the changes of cNOS activity may have adverse effects on nitric oxide (NO) production in the white matter close to the site of constriction injury, thus broadening the scope of the secondary mechanisms that play a role in neuronal trauma.

Animals↗

PubMed1999

The spinal biology in humans and animals of pain states generated by persistent small afferent input.

Behavioral models indicate that persistent small afferent input, as generated by tissue injury, results in a hyperalgesia at the site of injury and a tactile allodynia in areas adjacent to the injury site. Hyperalgesia reflects a sensitization of the peripheral terminal and a central facilitation evoked by the persistent small afferent input. The allodynia reflects a central sensitization. The spinal pharmacology of these pain states has been defined in the unanesthetized rat prepared with spinal catheters for injection and dialysis. After tissue injury, excitatory transmitters (e.g., glutamate and substance P) acting though N-methyl-D-aspartate (NMDA) and neurokinin 1 receptors initiate a cascade that evokes release of (i) NO, (ii) cyclooxygenase products, and (iii) activation of several kinases. Spinal dialysis show amino acid and prostanoid release after cutaneous injury. Spinal neurokinin 1, NMDA, and non-NMDA receptors enhance spinal prostaglandin E2 release. Spinal prostaglandins facilitate release of spinal amino acids and peptides. Activation by intrathecal injection of receptors on spinal C fiber terminals (mu,/delta opiate, alpha2 adrenergic, neuropeptide Y) prevents release of primary afferent peptides and spinal amino acids and blocks acute and facilitated pain states. Conversely, consistent with their role in facilitated processing, NMDA, cyclooxygenase 2, and NO synthase inhibitors act to diminish only hyperalgesia. Importantly, spinal delivery of several of these agents diminishes human injury pain states. This efficacy emphasizes (i) the role of facilitated states in humans, (ii) shows the importance of spinal systems in human pain processing, and (iii) indicates that these preclinical mechanisms reflect processes that regulate the human pain experience.

Afferent Pathways↗