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PubMedDate not supplied

Correlation of substance P-induced desensitization with substance P amino terminal metabolites in the mouse spinal cord.

Intrathecal injection of mice with substance P (SP) or its C-terminal fragments results in a behavioral syndrome characterized by reciprocal caudally directed biting and scratching. Repeated injection of SP, but not SP C-terminal fragments, results in a decrease in the intensity of, or desensitization to, these SP-induced behaviors. Peptidase inhibitors, phosphoramidon (PH), bacitracin (BAC), diprotin A (DPA) and angiotensin converting enzyme inhibitor (ACEI OR SQ20881), together with [3H]SP, were used to investigate the possible accumulation of tritiated N-terminal metabolites in the mouse spinal cord in vivo during the development of desensitization to SP. SP N-terminal metabolites in the spinal cord were quantified by reverse-phase HPLC. The magnitude of SP-induced desensitization correlated well (r = .95) with total SP N-terminal metabolites recovered from the spinal cords of the same mice studied in vivo. The magnitude of SP-induced desensitization was also found to be negatively correlated (r = .95) with total recovered intact [3H]SP. The rank order of potency of the peptidase inhibitors in decreasing the magnitude of SP-induced desensitization was BAC = PH much greater than ACEI greater than DPA. The order of potency for in vitro inhibition of SP metabolism using synaptic membrane-derived peptidases was BAC greater than PH much greater than ACEI. These results support the hypothesis that desensitization to SP-induced behaviors depends, at least in part, on the concentration of SP N-terminal metabolites in the spinal cord.

Amino Acid Sequence↗
PubMed1993

Pentamidine, an inhibitor of spinal flexor reflexes in rats, is a potent N-methyl-D-aspartate (NMDA) antagonist in vivo.

The present study examined whether the antimicrobial agent pentamidine exerts an antagonistic action at the N-methyl-D-aspartate (NMDA) receptor as tested on spinal reflexes in rats in vivo. After intrathecal injection both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and pentamidine dose-dependently reduced the magnitude of the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of pentamidine on the flexor reflex was prevented by coadministration with NMDA but not with the non-NMDA agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. These data suggest that pentamidine exerts an antagonistic action at the NMDA receptor in vivo.

2-Amino-5-phosphonovalerate↗
PubMed1993

Evidence for endogenous inhibition of autotomy by galanin in the rat after sciatic nerve section: demonstrated by chronic intrathecal infusion of a high affinity galanin receptor antagonist.

We have studied the effect of M-35 [Galanin(1-12)-Pro-bradykinin(2-9)-amide], a newly developed high affinity antagonist for galanin receptors, on self-mutilation (autotomy) behavior of the deafferented limb in rats after unilateral section of sciatic nerves. M-35 (1.3 micrograms/microliters) or saline was applied to the lumbar spinal cord through a chronically implanted intrathecal catheter at a rate of 0.5 microliter/h for 10 days post axotomy via an osmotic minipump. Axotomized rats infused with M-35 autotomized significantly more than those perfused intrathecally with saline or those axotomized rats not implanted with an intrathecal catheter. The severity of autotomy was also markedly greater in the group treated with M-35 than in the two other groups. M-35 did not noticeably influence either the galanin mRNA level in corresponding dorsal root ganglia and dorsal horn region or the percent of lumbar sensory neurons expressing detectable levels of mRNA for galanin. It is suggested that galanin can endogenously suppress autotomy behavior in rats after nerve injury and thus may play an important role in the control of the development of neuropathic pain.

Animals↗
PubMed2005

Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38.

Spinal nerve ligation (SNL) results in a profound long lasting allodynia and increases in phosphorylated p38 in dorsal root ganglia (DRG) neurons and spinal cord microglia. We have previously shown that systemic etanercept, a tumor necrosis factor (TNF) antagonist, reduced allodynia by 42% and blocked SNL-induced increases in P-p38 levels in the L5 and L6 DRG, but not in the ipsilateral lumbar spinal cord. The present experiments demonstrated that intrathecal etanercept (100 microg) prevents SNL-induced increased levels of spinal P-p38. Pretreatment, but not posttreatment, with intrathecal etanercept (100 microg), given every third day, reduced mechanical allodynia by 50%. This therapeutic benefit was maintained for at least 7 days after cessation of treatment. Combined systemic and intrathecal administration of etanercept was no more effective than intrathecal treatment alone. These data imply that TNF provides the trigger for phosphorylation of p38 in both DRG neurons and spinal microglia.

Analysis of Variance↗
PubMedDate not supplied

Spinal cord compression from intrathecal catheter-tip inflammatory mass: case report and a review of etiology.

OBJECTIVES: The majority of intrathecal pumps are implanted by anesthesiologists. Despite a recent increase in case reports involving intrathecal catheter-tip inflammatory masses, this complication is rarely reported in the anesthesiology literature. The present case report describes a patient with spinal cord compression as a result of an inflammatory mass and reviews the current literature as to the etiology of inflammatory mass formation. CASE REPORT: A 47-year-old man with intractable neck and arm pain received an intrathecal pump implantation in 2001, at a stable dose of morphine 8 mg and clonidine 40 microg/d. After an injury in late 2001, his dose requirement for intrathecal morphine steadily increased. In May 2002, hydromorphone was substituted for morphine. The concentrations of hydromorphone and clonidine were 12.5 mg/mL and 150 microg/mL, respectively, infusing at 0.3 mL/d. In October 2003, he developed progressive T9 paraparesis. A computed tomography scan with myelogram showed complete blockage of contrast flow at T8-9. Surgical exploration found an intradural-extramedullary mass compressing the spinal cord anteriorly and to the left. Four weeks after surgical removal of the mass, the patient's neurologic function had improved minimally. All the microbiological analyses were negative. Review of the current literature suggests that the development of an inflammatory mass is related to the delivery of the high dose opioids in the intrathecal space. CONCLUSION: Delivery of high-dose intrathecal opioids can result in the formation of an inflammatory mass, leading to poor pain control and neurologic complications. Anesthesiologists should be vigilant as to these complications when managing patients receiving intrathecal pump therapy.

Anesthesia, Spinal↗
PubMed1987

Antitumor and antinociceptive approaches to control cancer pain.

Patients with cancer pain often present with specific clinical syndromes that allow specific anti-tumor approaches. If these approaches are not feasible, neurosurgical procedures for pain relief should be considered. The major advantage of neurosurgical procedures is freedom from the excessive side effects of narcotic therapy. The most durable pain procedure is cordotomy, while intraspinal narcotics offer a rational treatment alternative in selected patients. Spinal and plexopathy syndromes that are amenable to more specific anti-tumor therapy should be looked for, since newer surgical approaches offer the prospect of both pain relief and tumor control.

Analgesics, Opioid↗
PubMed1999

Antagonistic effects of naloxone and naloxonazine on sufentanil-induced antinociception and respiratory depression in rats.

Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially binds to the high affinity micro(1) sites, is often used to discriminate between pharmacological effects mediated by micro(1) and micro(2) binding sites. The present series of experiments were undertaken to compare the opioid antagonistic properties of naloxonazine and naloxone (NLX) (a non-selective micro(1)-antagonist) on intravenous (i.v.) and intrathecal (i.t.) sufentanil (SUF)-induced antinociception and respiratory depression. The opioid antagonists were given either intravenously at 5 min after SUF, or subcutaneously (s.c.) 24 h prior to the opioid. Intravenous NLX and NLZ reduced the i.v. and i. t. SUF-induced antinociception, hypercapnia and hypoxia when given directly after the opioid. There were no major differences in activity between both antagonists. Pretreatment with 30 mg/kg NLX did not reverse the i.v. or i.t. SUF-induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg NLX only partially antagonized the i.v. SUF-induced antinociception, while a complete reversal was present of the opioid-induced hypercapnia and hypoxia. With regard to i.t. SUF, doses up to 30 mg/kg NLZ were unable to reduce the antinociception. The respiratory depression was partially affected; with 30 mg/kg NLZ, the i.t. SUF-induced hypercapnia returned to baseline levels, whereas the SUF-induced hypoxia was only minimally affected. These results challenge the classical view of the selectivity of NLZ for the high affinity micro(1) binding sites. They further fail to conform an exclusive role for micro(2) receptor sites in the respiratory depression and spinal analgesia induced by a strong lipophilic opioid such as SUF in rats.

Analgesics, Opioid↗
PubMed1990

[Severe tetanus and intrathecal baclofen].

Case report of a 48-year-old man with a severe tetanus managed with conventional treatment associated with subarachnoid administration of baclofen. An epidural catheter was placed in spinal fluid at level L3-L4. Two injections of 1 mg baclofen at an interval of 1 hour amended the spasticity. Thereafter the treatment was maintained with a continuous infusion of 2 mg.24 h-1 over 20 days which resulted in an efficient control of spasticity. The final outcome was favourable.

Baclofen↗
PubMedDate not supplied

Spectral analysis of sudden bradycardia during intrathecal meperidine anesthesia.

BACKGROUND AND OBJECTIVES: Severe bradycardia occurring suddenly during spinal anesthesia, although rare, is potentially fatal. Bradycardias are more common after intrathecal meperidine. We report two such episodes occurring in elderly male patients undergoing transurethral surgery. METHODS: Subarachnoid block was provided using 50 mg meperidine. Autonomic function was assessed by measuring heart rate (HR) variability using R-R intervals from standard electrocardiographic recordings. Frequency-domain spectra were constructed from 512 heartbeats, and an autoregressive method was used to calculate spectral power. RESULTS: In both patients, bradycardia (HR <50 beats/min) occurred after about 10 minutes and was associated with severe hypotension and a 10- to 100-fold increase in spectral density in both the low (0.04-0.15 Hz), mainly sympathetic, and the high (0.15-0.40 Hz), mainly parasympathetic, frequency bands. These spectral increases were subsequently attenuated by intravenous atropine. Heart rate slowing was noted to be periodic, or oscillatory, in one patient. CONCLUSION: Sudden increases in vagal, or parasympathetic, activity probably accounted for bradycardia.

Adjuvants, Anesthesia↗
PubMedDate not supplied

Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia.

BACKGROUND AND OBJECTIVES: Lipophilic opioids, especially fentanyl and sufentanil, are increasingly being administered intrathecally as adjuncts to spinal anesthesia. This review analyzes the efficacy of these opioids for subarachnoid anesthesia. METHODS: Medline search of the literature from 1980 to the present and a survey of recent meeting abstracts are reviewed. RESULTS: A significant number of citations regarding intrathecal lipophilic opioids as adjuncts to spinal anesthesia were found: 59 are cited in this review. Most clinical experience has been in obstetric surgery, but lipophilic spinal opioid administration is being used with greater frequency for other surgical procedures as well. The benefits include reduction of minimal alveolar concentration (MAC) when general anesthesia is combined with spinal anesthesia and enhancement of the quality of spinal anesthesia without prolongation of motor block. Intrathecal fentanyl and sufentanil allow clinicians to use smaller doses of spinal local anesthetic, yet still provide excellent anesthesia for surgical procedures. Furthermore, lipophilic opioid/local anesthetic combination permits more rapid motor recovery; short outpatient procedures are therefore more amenable to spinal anesthesia. Finally, the side-effect profiles of intrathecal lipophilic opioids are now well characterized and appear less troublesome than intrathecal morphine. CONCLUSIONS: The anesthesia-enhancing properties and side-effect profile of lipophilic opioids administered intrathecally suggest significant roles for these agents as adjuncts to spinal anesthesia for obstetric and outpatient procedures.

Adjuvants, Anesthesia↗
PubMed1999

In vivo pathway of thermal hyperalgesia by intrathecal administration of alpha,beta-methylene ATP in mouse spinal cord: involvement of the glutamate-NMDA receptor system.

1. The aim of the present study is to characterize the role of the P2X receptor in spinal nociceptive processing in vivo. We investigated the mechanisms of the P2X receptor agonist alpha,beta-methylene ATP (alpha,betameATP)-induced modulation of acute nociceptive signalling in mouse spinal cord. 2. Intrathecal administration of alpha,betameATP produced a significant and dose-dependent thermal hyperalgesic response. This response was completely blocked by intrathecal pretreatment with the non-selective P2 receptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate (PPADS) and the selective P2X1, P2X3 and P2X2-3 receptor antagonist, 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP). Pretreatment with alpha,betameATP 15, 30 and 60 min prior to administration of a second dose of alpha,betameATP diminished the alpha,betameATP-induced thermal hyperalgesia. 3. A potent agonist for the P2X1 receptor, beta,gamma-methylene-L-ATP, did not show the hyperalgesic response, indicating that the P2X1 receptor is not involved in the spinal nociceptive pathway. 4. In fura-2 experiments using mouse dorsal root ganglion (DRG) neurons, alpha,betameATP (100 microM) increased intracellular Ca2+ ([Ca2+]i). This was not produced by a second application of alpha,betameATP. The same DRG neurons also showed a marked [Ca2+]i increase in response to capsaicin (3 microM). 5. Intrathecal pretreatment with the Ca2+-dependent exocytosis inhibitor, botulinum neurotoxin B, abolished the thermal hyperalgesia by alpha,betameATP. Furthermore, thermal hyperalgesia was significantly inhibited by the N-methyl-D-aspartate (NMDA) receptor antagonists, 2-amino-5-phosphonopentanoate (APV), dizocilpine and ifenprodil. 6. These findings suggest that alpha,betameATP-induced thermal hyperalgesia may be mediated by the spinal P2X3 receptor subtype that causes unresponsiveness by repetitive agonist applications, and that alpha,betameATP (perhaps through P2X3 receptors) may evoke spinal glutamate release which, in turn, leads to the generation of thermal hyperalgesia via activation of NMDA receptors.

Adenosine Triphosphate↗
PubMedDate not supplied

Comparison of technical and block characteristics of different combined spinal and epidural anesthesia techniques.

BACKGROUND AND OBJECTIVES: The combined spinal and epidural (CSE) technique can reduce or eliminate some of the disadvantages of spinal and epidural anesthesia, while still preserving their advantages. CSE anesthesia is now commonly performed with a single-segment needle-through-needle technique; however, this technique involves some controversies about needle handling and the risk of catheter migration. To avoid some of these potential problems, special CSE sets have been produced. In the present study, 2 of these sets were compared with the traditional double-segment technique. METHODS: Ninety patients undergoing orthopedic surgery of the lower extremity were randomly allocated into 3 groups of equal size: Group 1, CSE set with an interlocking device between the spinal and epidural needle; group 2, CSE set with a "backeye" at the epidural needle curve for the passage of the spinal needle; group 3, double-segment technique. All epidural needles were 18-gauge, and spinal needles were 27-gauge with a pencil-point tip. In groups 1 and 2, the puncture was performed at the L3-4 interspace, and in group 3 the epidural catheter was first inserted at the L2-3 interspace followed by spinal puncture one interspace lower. Hyperbaric 0.5% bupivacaine, 2 mL, was used for the spinal block, and 4 mL of 2% lidocaine with epinephrine through the epidural catheter was used as a test dose. The block performance characteristics were recorded, and the level of analgesia was studied in a blinded fashion. Postoperatively, a bolus of epidural morphine 2 to 4 mg was used for the control of postoperative pain. All patients were interviewed on the 1st and the 7th postoperative days. Afterwards, the needles and catheters were examined by microscopy. RESULTS: The frequency of the successful CSE block was higher in groups 3 (100%) and 2 (90%) than in group 1 (63%) (P <.05). The mean duration of successful block performance, as well as the median level of analgesia, were similar in all the groups. One case of epidural catheter migration intrathecally was observed (group 1). Postoperative nausea and vomiting occurred in 23% of patients, and the incidence of postdural puncture headache was 2.2%. The incidence of backache at the puncture site was similar in the groups. Microscopy showed 6 distorted spinal needle tips (all in group 1), but no material damage to the epidural catheters. CONCLUSIONS: The use of the CSE sets does not seem to save time compared with the double-segment technique. Technical problems, unsuccessful CSE block, and damaged spinal needle tip were noted relatively often with the interlocking CSE set. Anesthetic characteristics in the successful blocks were similar with the different techniques.

Adult↗