Biomedical subjects

X J Xu

Publications and source records attributed to X J Xu.

At least 19 recordsLinked to original sources

PubMed1992

Marked increase in nitric oxide synthase mRNA in rat dorsal root ganglia after peripheral axotomy: in situ hybridization and functional studies.

Using in situ hybridization, we studied nitric oxide (NO) synthase (EC 1.14.23.-) mRNA in lumbar dorsal root ganglia after peripheral transection of the sciatic nerve in rats. The effect of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester on the nociceptive flexor reflex was also studied in axotomized rats. Nerve section induced a dramatic increase in number of NO synthase mRNA-positive cells in the ipsilateral dorsal root ganglia. In some of these cells the peptides galanin and/or vasoactive intestinal polypeptide and/or neuropeptide Y were also strongly up-regulated. Intravenous administration of nitro-L-arginine methyl ester blocked spinal hyperexcitability at much lower dosages in axotomized than in normal animals. The results suggest involvement of NO in the function of lumbar sensory neurons, especially after axotomy, perhaps preferentially at peripheral sites.

Amino Acid Oxidoreductases↗

PubMed1992

Intrathecal CP-96,345 blocks reflex facilitation induced in rats by substance P and C-fiber-conditioning stimulation.

We have examined the effects of intrathecally (i.t.) administered CP-96,345, a non-peptide NK1 receptor ligand, on the spinal nociceptive flexor reflex and on the facilitation of this reflex evoked by i.t. substance P (SP), neurokinin A (NKA) and electrical conditioning stimulation of cutaneous C-afferents. CP-96,345 i.t. at 24 pmol-2.4 nmol had no significant effect on flexor reflex excitability. At the highest dose tested (24 nmol), CP-96,345 caused a brief facilitation of the flexor reflex, which was similar to the effect of the vehicle used at this drug concentration. CP-96,345 did not depress the flexor reflex at any dose. In rats with chronically implanted i.t. catheters, CP-96,345 at 24 nmol caused neither motor impairment nor morphological damage to the spinal cord. Pretreatment with CP-96,345 dose dependently and similarly antagonized facilitation of the flexor reflex induced by 7 pmol i.t. SP or by a 20-s, 1-Hz conditioning stimulus train applied to cutaneous C-fibers in the sural nerve innervation area. The vehicle had no effect. The antagonistic effect of CP-96,345 on the SP- and C-fiber reflex facilitation induced by conditioning stimulation became maximal only 20-30 min after the i.t. injection and lasted 3-4 h at the highest dose. CP-96,345 did not significantly block the facilitatory effect of 7 pmol i.t. NKA on the flexor reflex. These results demonstrate that CP-96,345 is a potent, long-lasting and selective antagonist of SP in rat spinal cord. Furthermore, facilitation of the flexor reflex (central sensitization) induced by conditioning stimulation of cutaneous C-afferents is mediated by NK1 tachykinin receptors, but the NK1 receptor may not be involved in the transmission of the flexor reflex. CP-96,345 is thus useful in experimental studies of the role of SP in the central nervous system.

Analysis of Variance↗

PubMed1992

NK-1, but not NK-2, tachykinin receptors mediate plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw: demonstrated with the NK-1 antagonist CP-96,345 and the NK-2 antagonist Men 10207.

The effects of intradermal injection of CP-96,345 and Men 10207, selective antagonists for NK-1 and NK-2 tachykinin receptors, respectively, on the extravasation of plasma protein induced by antidromic stimulation of unmyelinated sensory fibers in the sciatic nerve was studied in rat hindpaw. Activation of unmyelinated fibers by antidromic sciatic nerve stimulation (1 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans blue on the skin area of the hindpaw innervated by the sciatic nerve, which was not inhibited by intradermal injection of saline or Men 10207 (9 and 35 nmol). In contrast, CP-96,345 (3 and 9 nmol, but not 1 nmol), injected intradermally 15 min prior to nerve stimulation dose-dependently inhibited this response. Plasma extravasation induced by intravenously injected substance P was also inhibited by CP-96,345. Since CP-96,345 is a highly selective antagonist for NK-1 tachykinin receptors, it is suggested that the plasma extravasation induced by antidromic C-fiber stimulation and by systemically applied tachykinins is mediated by NK-1 tachykinin receptors.

Animals↗

PubMed1992

Galanin-mediated control of pain: enhanced role after nerve injury.

The endogenous inhibitory role of the neuropeptide galanin in pain transmission and spinal cord excitability was demonstrated by the use of a high-affinity galanin receptor antagonist, M-35 [galanin-(1-13)-bradykinin-(2-9)-amide]. M-35, which displaced 125I-labeled galanin from membranes of rat dorsal spinal cord with an IC50 of 0.3 nM, dose-dependently antagonized the effect of intrathecal galanin on the flexor reflex. M-35 potentiated the facilitation of the flexor reflex by conditioning stimulation of cutaneous unmyelinated afferents in rats with intact nerves and the potentiating effect of M-35 on the conditioning-stimulation-induced reflex facilitation of the cutaneous unmyelinated afferents was strongly enhanced after axotomy. These results demonstrate that endogenous galanin plays a tonic inhibitory role in the mediation of spinal cord excitability, and it is particularly noteworthy that this function of galanin is remarkably enhanced after peripheral nerve section.

Animals↗

PubMed1992

Protective effect of the NMDA antagonist MK-801 on photochemically induced spinal lesions in the rat.

Photochemically induced ischemic lesions in the rat spinal cord were studied using neurological tests and morphological evaluation in order to investigate ischemia-mediated pathophysiological mechanisms in traumatic spinal cord injury. One week after ischemic lesioning, animals were severely impaired with 85% decrease of performance in neurological tests. During the next 2 weeks considerable recovery occurred. Pretreatment with the noncompetitive N-methyl-D-aspartate antagonist MK-801 at a dose of 0.5-1.0 mg/kg significantly improved the recovery of function after spinal ischemia while lower doses exerted no protection. Morphologically, no dose-response effect on the extent of tissue necrosis was found, but a significant difference between groups with severe neurological deficit versus mildly affected groups was observed. Immunohistochemical staining for glial fibrillary acidic protein in the area close to the lesion revealed extensive gliosis, while neurofilament immunohistochemistry showed an irregular pattern of fiber loss with large variability between animals. The degree of gliosis or loss of neurofilament immunoreactivity in nonnecrotic tissue was not affected by MK-801. These results suggest that excessive stimulation of N-methyl-D-aspartate receptors participates in the development of spinal cord ischemia and possibly also participates after traumatic spinal cord injury.

Animals↗

PubMed1992

Photochemically induced transient spinal ischemia induces behavioral hypersensitivity to mechanical and cold stimuli, but not to noxious-heat stimuli, in the rat.

Pain-like sensory disorders lasting several days were observed in rats after transient ischemia in the lumbar region of the spinal cord. The ischemia was induced with a recently developed photochemical technique. Rats exhibited strong allodynia, a pain-like reaction to innocuous stimuli, to mechanical stimulation of the caudal trunk, hind limbs, and hind paws, which were areas innervated by the ischemic spinal segments. The rats also expressed hypersensitivity to cold stimuli. However, no changes in sensitivity to noxious heat could be detected with the hot-plate test. Furthermore, no morphological damage could be observed in the spinal cord at the light microscopic level in the majority of rats after transient spinal cord ischemia. The present results indicate that allodynia-like symptoms to mechanical stimuli after spinal ischemia may be mediated by myelinated afferents and could be associated with dysfunction of inhibitory transmission in the spinal cord. We suggest that this pain-related syndrome after spinal ischemia could be considered as an animal model of painful states of spinal origin.

Animals↗

PubMed1992

Spinal substance P and N-methyl-D-aspartate receptors are coactivated in the induction of central sensitization of the nociceptive flexor reflex.

We have studied the effects and interactions of the neurokinin-1 receptor antagonist CP-96,345 and the N-methyl-D-aspartate receptor/channel blocker MK-801, both applied intravenously, on the flexor reflex and on the facilitation of the flexor reflex by conditioning stimulation of cutaneous C-afferents in decerebrate, spinalized, unanesthetized rats. The flexor reflex was evoked by subcutaneous electrical stimuli applied to the sural nerve innervation area 1/min at an intensity that activated C-fibers and was recorded as electromyogram from the ipsilateral hamstring muscles. The magnitude of the baseline flexor reflex was usually highly stable in the course of the experiments without experimental manipulations. The same stimulus was used as a conditioning train (0.9 Hz, 20 shocks) and caused a brief facilitation of the flexor reflex, which was maximal 0.5 and 1 min after stimulation (255.1 +/- 23.6% over baseline). During the course of the conditioning stimulus train, the reflex magnitude was gradually increased (wind-up). MK-801 (0.1 and 0.5 mg/kg) consistently depressed the polysynaptic flexor reflex. At a dose of 0.5 mg/kg, but not 0.1 mg/kg, MK-801 reduced the wind-up and blocked the facilitation of the flexor reflex induced by the conditioning stimulus by 90%. The facilitatory effect of 7 pmol intrathecal substance P was also partially reduced by MK-801. CP 96,345 (1 and 3 mg/kg) did not depress the flexor reflex, but dose-dependently antagonized reflex facilitation by the conditioning stimulus train, similarly to its antagonism of intrathecally applied 7 pmol substance P-induced facilitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat.

1. The effect of chronic treatment with CI988, a recently developed selective antagonist of cholecystokinin type-B receptors (CCKB receptors) on the tolerance to morphine analgesia was studied in rats with the hot plate test. 2. Morphine tolerance was induced with the use of two paradigms. Morphine was injected i.p. either in a schedule of increasing doses (1-32 mg kg-1) twice daily for 6 days or at a fixed dose (3 mg kg-1) daily for 29 days. 3. In both series of experiments, tolerance to the analgesic effect of morphine was prevented by simultaneous treatment with i.p. CI988. Chronic treatment with only CI988 daily for up to 29 days did not reduce the analgesic effect of a weekly injection of morphine. 4. CI988 did not diminish the physical dependence to morphine, as examined with naloxone precipitated withdrawal. 5. The present results provide evidence that chronic treatment with a selective CCKB receptor antagonist could prevent tolerance to the analgesic effect of morphine without affecting morphine-induced physical dependence. Application of CCK antagonists may be clinically important in treating chronic pain patients by preventing morphine tolerance and by eliminating the need to increase morphine doses to unacceptable levels.

Animals↗

PubMed1992

Intrathecal neurokinin A facilitates the spinal nociceptive flexor reflex evoked by thermal and mechanical stimuli and synergistically interacts with substance P.

The neuropeptide neurokinin A was injected intrathecally and its effect on the spinal nociceptive flexor reflex was examined. The reflex, which was evoked by electrical, thermal or mechanical stimulation of the foot and was recorded from the ipsilateral hamstring muscles, was substantially facilitated by 7 pmol intrathecally injected neurokinin A. The facilitatory effect of neurokinin A to thermal stimulation was, however, significantly stronger than to electrical or mechanical stimuli. Furthermore, co-administration of neurokinin A with substance P induced a significant synergistic facilitation of the reflex. It is suggested that neurokinin A, like substance P, may be released in association with activation of polymodal C-nociceptors.

Animals↗

PubMed1992

Transient spinal cord ischemia induces temporary hypersensitivity of dorsal horn wide dynamic range neurons to myelinated, but not unmyelinated, fiber input.

1. The activity of 197 single dorsal horn neurons was recorded extracellularly in the spinal cord of decerebrate, spinalized, unanesthetized rats. The response properties of 174 wide dynamic range (WDR) neurons to electrical, mechanical, and thermal stimulation in three groups of rats were studied:normal, 1-4 days after transient spinal cord ischemia induced photochemically by laser irradiation when the rats exhibited behavioral hypersensitivity to mechanical stimuli (allodynia), and 10-20 days after spinal ischemia when the allodynia had ceased. 2. In normal rats, the responses of dorsal horn WDR neurons to suprathreshold electrical stimulation of their receptive fields consisted of a short-latency (A) and a long-latency (C) response. In 77% of the neurons (57/74), there was a separation between the A- and C-fiber responses. The response threshold (defined as 20% increase in neuronal discharges above background activity) to mechanical stimulation applied with calibrated von Frey hairs was 13.8 g, and the discharges of these neurons to graded stimulation increased linearly. 3. In 68% of WDR neurons in allodynic rats (38/56), the response to suprathreshold electrical stimuli was a single burst with no separation between A- and C-fiber responses. The magnitude and duration of the response were significantly increased compared with those recorded in normal rats. The sensitivity of these neurons to mechanical stimulation was also greatly increased, expressed by a lowered threshold (2.1 +/- 0.3 g, mean +/- SE) and a shift to the left of the nonlinear stimulus-response curve. The background activity of the neurons and the size of the receptive fields were, however, unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischemia; implications for a tonic GABAergic inhibitory control of myelinated fiber input.

1. In the companion paper, we described a state of hypersensitivity that developed in dorsal horn wide dynamic range (WDR) neurons in rats after transient spinal cord ischemia. Thus the WDR neurons exhibited lower threshold and increased responses to low-intensity mechanical stimuli. The response pattern of these neurons to suprathreshold electrical stimulation was also changed. Notably, the response to A-fiber input was increased. No change in response to thermal stimulation was found before and after spinal cord ischemia. 2. In normal rats, the gamma-aminobutyric acid (GABA)B agonist baclofen (0.1 mg/kg ip) administered 1-3 h before neuronal recording suppressed the responses of WDR neurons to high-intensity mechanical pressure without influencing the threshold and the responses to lower-intensity stimuli. 3. In allodynic rats, similar pretreatment with baclofen totally reversed the hypersensitivity of the WDR neurons to mechanical stimuli and normalized the response pattern of neurons to electrical stimulation. 4. The GABAA receptor agonist muscimol (1 mg/kg ip) did not influence the response of WDR neurons in either normal or allodynic animals. 5. The present results demonstrated that the GABAB agonist baclofen is effective in reversing the hypersensitivity of dorsal horn WDR neurons to low-intensity mechanical stimulation after transient spinal cord ischemia, indicating that dysfunction of the GABAergic inhibitory system may be responsible for the development of neuronal hypersensitivity. 6. It is suggested that GABAergic interneurons exert a tonic presynaptic inhibitory control, through baclofen-sensitive B-type GABA receptors, on input from low-threshold mechanical afferents, and that disruption of this control may result in painful reaction to innocuous stimuli (allodynia).

Animals↗

PubMed1992

Systemic mexiletine relieves chronic allodynialike symptoms in rats with ischemic spinal cord injury.

We have recently reported a chronic allodynialike symptom in rats after ischemic spinal cord injury. This pain-related behavior is resistant to a number of pharmacologic treatments, including morphine, clonidine, carbamazepine, baclofen, and muscimol. In the present report, we present evidence indicating that systemic mexiletine, a local anesthetic and antiarrhythmic agent, effectively relieves the allodynia-like symptoms at doses of 15 and 30 mg/kg in these rats without inducing major side effects. It is suggested that systemically applied mexiletine may be useful in treating central pain in patients with spinal cord injury.

Animals↗

PubMed1992

[Nosocomial pneumonia: a report of 372 cases].

Three hundred seventy-two cases of hospital-acquired pneumonia occurring during a 4-year period were reviewed. It was found that the annual incidence of the pneumonia was 1.44% which ranked first in the incidence of nosocomial infections at this institution. Most of the patients had suffered from primary severe underlying diseases with immunosuppression of different degrees. A variety of factors such as antibiotic and steroid therapy, operation, intensive care, endotracheal intubation, tracheostomy, chemotherapy and radiotherapy predisposed to the acquisition of this pneumonia. Most frequent etiologic agents for hospital-acquired pneumonia were Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. The overall mortality rate was 25.3%. However, deaths associated with Pseudomonas aeruginosa and Staphylococcus aureus are particularly high, with rates of 70.6% and 66.7% respectively. The incidence, mortality, pathogenesis, diagnosis, treatment and prevention of the disorder were discussed briefly.

Adolescent↗

PubMed1992

The structural basis of the poor fibrin specificity of urokinase(I)--knowledge-based prediction of kringle structures of urokinase and its related proteins.

The Kringle-1 structure of plasminogen (PGK-1), the Kringle-2 structure of tissue plasminogen activator (PAK-2) and the Kringle structure of prourokinase (UKK) has been modeled on the basis of the three-dimensional structure of Kringle-1 of prothrombin (PTK-1) at 2.8 A resolution. The predicted three-dimensional structure of these Kringles shows that the binding site of PGK-1 is characterized by an apparent dipolar site, the polar parts of which are separated by a hydrophobic region. PAK-2 possesses the anionic center but has not a cationic binding center which might be provided by a guanidinium group from Arg-69 located adjacent to the Arg-71 position. UKK possesses neither the anionic binding center nor the cationic center which are probably the main reason for the poor fibrin specificity of urokinase.

Amino Acid Sequence↗

PubMed1991

Intrathecal administration of clonidine suppresses autotomy, a behavioral sign of chronic pain in rats after sciatic nerve section.

The effect of chronic intrathecal (i.t.) administration of the alpha 2 adrenoceptor agonist clonidine on self-mutilation behavior (autotomy) after unilateral transection of the sciatic nerve was studied in rats. Rats injected with 10 micrograms clonidine twice daily for 21 days, starting 1 h before nerve section, autotomized significantly less than saline controls. However, in the few rats which received clonidine and autotomized, clonidine did not delay the onset of autotomy compared to saline controls. Termination of clonidine injection after 21 days resulted in increased autotomy within 1-4 days. No sedation or motor impairment was found after this dose of i.t. clonidine. It is suggested that clonidine may be useful in treating neuropathic pain in humans.

Animals↗

PubMed1991

M-15: high-affinity chimeric peptide that blocks the neuronal actions of galanin in the hippocampus, locus coeruleus, and spinal cord.

The 20-amino acid peptide M-15 binds with high affinity (IC50 approximately 0.1 nM) to 125I-labeled galanin (125I-GAL) binding sites in membranes from the ventral hippocampus, midbrain, and rat spinal cord. Receptor autoradiographic studies show that M-15 can displace 125I-GAL from all labeled sites. M-15 acts as a reversible high-affinity antagonist in blocking the inhibitory effects of GAL on the evoked release of acetylcholine in vivo in the hippocampus and on the GAL-induced hyperpolarization of locus coeruleus neurons in slices. M-15 also blocks the facilitatory effects of GAL on the spinal flexor reflex. Thus, the chimeric peptide M-15 [GAL-(1-13)-substance P-(5-11)amide] represents the first antagonist to the neuronal actions of GAL.

Acetylcholine↗

PubMed1991

Hypersensitivity of dorsal horn wide dynamic range neurons to cutaneous mechanical stimuli after transient spinal cord ischemia in the rat.

The responsiveness of dorsal horn wide dynamic range (WDR) neurons to cutaneous mechanical stimuli was studied in decerebrate, spinalized, unanesthetized rats before and after transient photochemically induced spinal cord ischemia. In normal rats, the discharges of dorsal horn WDR neurons to the graded mechanical stimuli applied with calibrated von Frey hairs increase linearly. One to four days after spinal ischemia, when the rats exhibit a strong allodynia-like behavioral reaction to cutaneous stimuli, the sensitivity of dorsal horn WDR neurons to mechanical pressure is greatly increased. There is a significant decrease in the threshold pressure to evoke neuronal discharges and the exponential stimulus-response curve is shifted to the left. Thus, transient ischemia of the spinal cord results in hyperexcitability of dorsal horn WDR neurons, which may underly the allodynia-like sensory abnormalities observed in behaving animals. The present results may contribute to understanding the mechanism of the development of chronic central pain in patients after central nervous system injury involving ischemia.

Animals↗

PubMed1991

Low-dose intrathecal morphine facilitates the spinal flexor reflex by releasing different neuropeptides in rats with intact and sectioned peripheral nerves.

The facilitatory effect of intrathecal (i.t.) morphine on the excitability of the nociceptive flexor reflex was examined in decerebrate, spinalized, unanesthetized rats with intact or sectioned sciatic nerves. Low doses of i.t. morphine (10 ng in rats with intact nerves and 10 or 100 ng in rats with sectioned nerves) facilitated the flexor reflex. Higher doses of morphine caused facilitation followed by reflex depression. Facilitation of the flexor reflex induced by 10 or 100 ng morphine was prevented by i.t. naloxone (1 microgram). In rats with intact sciatic nerves the facilitation was partially antagonized by the tachykinin antagonist spantide II (D-NicLys1,3-Pal3,D-Cl2Phe5,Asn6,D-Trp7,9,Nle 11)-substance P (SP), indicating that the reflex facilitation evoked by low doses of morphine may be due to the release of SP and perhaps other neuropeptides. In axotomized animals, 14-20 days after unilateral sciatic nerve section, spantide II failed to antagonize morphine-induced facilitation, suggesting that SP or other tachykinins, no longer played a role in this effect. In contrast, the vasoactive intestinal peptide (VIP) antagonist (N-Ac-Tyr1,D-Phe2)-GRF (1-29)-NH2 blocked morphine-induced reflex facilitation in axotomized rats, but not in rats with intact nerves. The present study provides evidence that low doses of morphine may induce the release of excitatory neuropeptides, thereby facilitating spinal nociceptive transmission. The identity of the neuropeptides depends on whether or not peripheral axons are intact, tachykinins in rats with intact nerves and VIP in axotomized rats.

Animals↗