Lumbar Intrathecal Injection Research Articles

Improved Ventilatory Efficiency with Locomotor Muscle Afferent Inhibition is Strongly Associated with Leg Composition in Heart Failure

BackgroundSkeletal muscle atrophy contributes to increased afferent feedback (group III and IV) and may influence ventilatory control (high VE/VCO2 slope) in heart failure (HF). ObjectiveThis study examined the influence of muscle mass on the change in VE/VCO2 with afferent neural block during exercise in HF. Methods17 participants [9 HF (60±6yrs) and 8 controls (CTL) (63±7yrs, mean±SD)] completed 3 sessions. Session 1: dual energy x-ray absorptiometry and graded cycle exercise to volitional fatigue. Sessions 2 and 3: 5min of constant-work cycle exercise (65% of peak power) randomized to lumbar intrathecal injection of fentanyl (afferent blockade) or placebo. Ventilation (VE) and gas exchange (oxygen consumption, VO2; carbon dioxide production, VCO2) were measured. ResultsPeak work and VO2 were lower in HF (p<0.05). Leg fat was greater in HF (34.4±3.0 and 26.3±1.8%) and leg muscle mass was lower in HF (63.0±2.8 and 70.4±1.8%, respectively, p<0.05). VE/VCO2 slope was reduced in HF during afferent blockade compared with CTL (−18.8±2.7 and −1.4±2.0%, respectively, p=0.02) and was positively associated with leg muscle mass (r2=0.58, p<0.01) and negatively associated with leg fat mass (r2=0.73, p<0.01) in HF only. ConclusionsHF patients with the highest fat mass and the least leg muscle mass had the greatest improvement in VE/VCO2 with afferent blockade with leg fat mass being the only predictor for the improvement in VE/VCO2 slope. Both leg muscle mass and fat mass are important contributors to ventilatory abnormalities and strongly associated to improvements in VE/VCO2 slope with locomotor afferent inhibition in HF.

Changes of laboratory indices in serum and cerebrospinal fluid for children retinoblastoma before and after chemotherapy

Objective To analyze the changes of laboratory indices in serum and cerebrospinal fluid(CSF)for children retinoblastoma(RB)before and after chemotherapy between central nervous system (CNS) metastasis group and extraocular stage group, and to conclude the clinical significance. Methods From September 2005 to December 2013, 11 cases were collected in Beijing Tongren Hospital who were diagnosed as CNS metastasis and were assorted into CNS metastasis group.According to age, gender and eye difference, 11 cases were chosen for the extraocular stage group.Twenty-two cases were given 6 cycles of chemotherapy.The chemotherapy protocol was Carboplatin + Teniposide + Vincristine(CTV) or Carboplatin + Etoposide + Vincristine(CEV). In each chemotherapy cycle all patients underwent lumbar puncture and intrathecal injection therapy.Serum levels of neuron specific enolase (NSE), serum lactate dehydrogenase (LDH) and CSF levels of NSE, quantitative protein and white blood cell count of the two groups were monitored before initiating chemotherapy and after the third and sixth cycles of chemotherapy.Multi factor variance analysis of the data was compared between the two groups in the dynamic changes of laboratory indices before and after chemotherapy using repeated measurements. Results The serum NSE levels of CNS metastasis group before initiating chemotherapy and after the 6th cycle of chemotherapy were (120.19±105.19) μg/L and (39.07±24.10) μg/L, respectively.The serum NSE levels of extraocular stage group before initiating chemotherapy and after the 6th cycle of chemotherapy were (29.03±11.94) μg/L and (21.03±5.01) μg/L, respectively.Serum NSE levels of the two groups showed significant changes before and after chemotherapy (F=7.115, P=0.000). Serum NSE level of CNS metastasis group was significantly higher than that of the extraocular stage group(F=41.500, P=0.007). Serum LDH levels of the two groups showed no statistically significant changes before and after chemotherapy (F=0.892, P=0.525). The CSF-NSE level of CNS metastasis group was significantly higher than that of extraocular stage group(F=15.706, P=0.001). CSF quantitative protein level of the CNS metastasis group was significantly higher than that of extraocular stage group(F=15.228, P=0.001). CSF white blood cell count of the CNS metastasis group were significantly higher than that of extraocular stage group(F=5.514, P=0.003). Conclusions Serum NSE level can be used as a laboratory indicator for monitoring CNS metastasis stage and extraocular stage of RB.The CSF-NSE values can be used as a diagnostic tool for CNS metastasis and monitoring of disease progression.CSF quantitative protein and white blood cell count can be used as auxiliary laboratory index for CNS metastasis diagnosis.Serum LDH cannot be used as a valuable laboratory index for diagnosis of CNS metastasis cases and extraocular cases. Key words: Retinoblastoma; Neuron specific enolase; Lactate dehydrogenase; Cerebrospinal fluid

Diagnosis and treatment of intracranial infection after endoscopic transsphenoidal surgery

Objective To discuss the diagnosis and treatment of intracranial infection after endoscopic transsphenoidal surgeries. Methods From January 2011 to January 2013, 459 patients undergoing endoscopic transsphenoidal surgery were analyzed.9 patients (2.0%) developed intracranial infection. 9 patients treated by CSF lumbar drainage and intravenous vancomycin and meropenem treatment. At the same time, CSF and cranial CT were monitored. 2 of 9 patients were healed by intravenous vancomycin and meropenem and CSF lumbar drainage. Other 7 patients were healed by endoscopic transphenoidal repair of CSF leakage, intrathecal and intravenous injection of vancomycin and meropenem alternately (One case developed subdural empyema and treated by key-hole drainage meanwhile). Results All 9 patients were healed according to the above-mentioned methods. During the follow-up period between 12 and 24 months, 8 patients recovered well without any complication. One patient suffered from hydrocephalus after 6 months and healed by V-P shunt. Conclusion The treatment of endoscopic transphenoidal repair of CSF leakage, CSF lumbar drainage, intravenous and intrathecal injection of vancomycin and meropenem were effective for intracranial infection after endoscopic transsphenoidal surgery. Key words: Endoscopy; Transphenoidal surgery; Intracranial infection

Rapid sedation induced by fentanyl combined with propofol via an intrathecal chemotherapy injection for leukemia in children.

This study explored the sedative and analgesic effects of fentanyl combined with propofol via an intrathecal chemotherapy injection for acute leukemia (acute lymphocytic leukemia or acute myelocytic leukemia) among children, to relieve pain and difficulty during intrathecal injection, improve treatment compliance, increase the success rate of single puncture, and reduce procedure failure, with the aim of developing a painless procedure for children with acute leukemia. Fifty person-times received fentanyl combined with propofol via an intrathecal chemotherapy injection among the hospitalized children with leukemia. The patients' cooperation with the procedure, response to the medication, dosages of fentanyl and propofol, reaction to the procedures, wake-up time, and changes in oxygen saturation (SpO2), heart rate (HR), respiration, and blood pressure (BP) before, during, and after the procedures were observed. The doctors who performed the procedures assessed the quality of sedation and analgesia. In the treatment group, the patients were quiet during the lumbar puncture and intrathecal injection, showing good sedation and analgesia. HR and respiration decreased slightly. There were no changes in SpO2 and BP. No obvious respiratory depression occurred with proper dosages. Only a few patients showed stertorous respiration, which stopped soon after the procedures. In the control group, the patients were agitated, crying, and not cooperative before and during the procedures, which made the procedures very difficult. During intrathecal injection, pain obviously reduced and the success rate of single lumbar puncture increased. It is safe and effective to apply fentanyl combined with propofol for sedation and analgesia.

Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist.

Experimental studies have shown that dopaminergic mechanisms can modulate both nociception and chronic pain perception, but such property is not exploited pharmacologically at the clinical level. We have previously shown that levodopa produces D2-receptor-mediated antiallodynic effects in rats with peripheral mononeuropathy. Here, we test the effects of a D2-type receptor (D2R) agonist, quinpirole, on neuropathic pain in rats. Allodynic responses to cooling and light touch were measured in the hind limbs of rats with chronic constriction injury of one sciatic nerve. Single intraperitoneal injection of quinpirole (1 mg/kg) totally inhibited cold and tactile allodynic responses for over 3 and 48 h, respectively. At that dose, quinpirole had no effect on nocifensive responses to heat. Lumbar intrathecal injection of quinpirole produced short-term inhibition of the responses to cold and tactile stimuli, suggesting that spinal mechanisms may contribute to the antiallodynic activity of quinpirole. Chronic subcutaneous infusion of quinpirole by implanted Alzet pumps (0.025 mg/kg·day) provided a slowly progressing inhibition of cold and tactile allodynic responses, which re-emerged after the pumps were removed. These experiments show the involvement of dopaminergic systems in the modulation of chronic allodynias and provide experimental support for proposing the use of D2R agonists for neuropathic pain relief.

Exercise capacity and ventilatory efficiency with afferent blockade in heart failure (884.3)

Increased locomotor muscle afferent feedback may be linked to the reduced exercise capacity (peak VO2) and poor ventilatory efficiency (high VE/VCO2 slope) observed in heart failure (HF). We examined the relationship between peak VO2 and change in VE/VCO2 with afferent inhibition during exercise in HF. 9 HF (60±6 yr) and 9 controls (CTL) (63±7 yr) completed 3 visits. Visit 1: cycle exercise to volitional exhaustion. Visits 2‐ 3: 5 min constant‐load cycling (65% of peak work) randomized to lumbar intrathecal fentanyl injection (afferent block) or placebo. VO2, ventilation (VE), carbon dioxide production (VCO2), and end‐tidal CO2 (PETCO2) were measured. In HF, peak work (120±34 vs 176±54 W, p&lt;0.05) and VO2 (18.4±2.7 vs 27.2±4.7 ml/kg/min, p&lt;0.05) were reduced, whereas VE/VCO2 slope was elevated (39.7±1.8 vs 35.3±0.8, p&lt;0.05) compared with CTL. With afferent inhibition, HF patients had a greater reduction in VE/VCO2 (‐18.8±8.1 vs ‐5.4±13.3%, p&lt;0.05) and increase in PETCO2 (20.3±10.5 vs 6.1±9.5%, p&lt;0.01) during constant‐load cycling. Lower VO2peak was related to a greater decline in VE/VCO2 and rise in PETCO2 after afferent inhibition in HF (r=0.82, p&lt;0.01 and r=‐0.69, p&lt;0.05, respectively) but not CTL (p&gt;0.05). Our data demonstrate that patients with the lowest VO2peak have the greatest improvement in VE/VCO2, suggesting a close link between afferent feedback, ventilatory efficiency and exercise capacity in HF.Grant Funding Source: Supported by AHA 12GRNT11630027 and National Center for Advancing Translational Science KL2TR000136.

Reversal of Peripheral Nerve Injury-induced Hypersensitivity in the Postpartum Period

Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored. We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined. Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban. These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

Investigation of intrathecal transport of NPT002, a prospective therapeutic based on phage M13, in nonhuman primates.

Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-β, tau and α-synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50% of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure.

Neuropeptide Y receptor-expressing dorsal horn neurons: Role in nocifensive reflex and operant responses to aversive cold after CFA inflammation

The spinal Neuropeptide Y (NPY) system is a potential target for development of new pain therapeutics. NPY and two of its receptors (Y1 and Y2) are found in the superficial dorsal horn of the spinal cord, a key area of nociceptive gating and modulation. Lumbar intrathecal injection of (NPY) is antinociceptive, reducing hyper-reflexia to thermal and mechanical stimulation, particularly after nerve injury and inflammation. We have also shown that intrathecal injection of the targeted cytotoxin, Neuropeptide Y-sap (NPY-sap), is also antinociceptive, reducing nocifensive reflex responses to noxious heat and formalin. In the present study, we sought to determine the role of dorsal horn Y1R-expressing neurons in pain by destroying them with NPY-sap and testing the rats on three operant tasks. Lumbar intrathecal NPY-sap (1) reduced Complete Freund’s Adjuvant (CFA)-induced hyper-reflexia on the 10°C cold plate, (2) reduced cold aversion on the thermal preference and escape tasks, (3) was analgesic to noxious heat on the escape task, (4) reduced the CFA-induced allodynia to cold temperatures experienced on the thermal preference, feeding interference, and escape tasks, and (5) did not inhibit or interfere with morphine analgesia.

The Effects of Subarachnoid Administration of Preservative-Free S(+)-Ketamine on Spinal Cord and Meninges in Dogs

The N-methyl-d-aspartate receptor antagonist ketamine and its active enantiomer, S(+)-ketamine, have been injected in the epidural and subarachnoid spaces to treat acute postoperative pain and relieve neuropathic pain syndrome. In this study we evaluated the effects of a single dose of preservative-free S(+)-ketamine, in doses usually used in clinical practice, in the spinal cord and meninges of dogs. Under anesthesia (IV etomidate (2 mg/kg) and fentanyl (0.005 mg/kg), 16 dogs (6 to 15 kg) were randomized to receive a lumbar intrathecal injection (L5/6) of saline solution of 0.9% (control group) or S(+)-ketamine 1 mg/kg(-1) (ketamine group). All doses were administered in a volume of 1 mL over a 10-second interval. Accordingly, injection solution ranged from 0.6% to 1.5%. After 21 days of clinical observation, the animals were killed; spinal cord, cauda equina root, and meninges were removed for histological examination with light microscopy. Tissues were examined for demyelination (Masson trichrome), neuronal death (hematoxylin and eosin) and astrocyte activation (glial fibrillary acidic protein). No clinical or histological alterations of spinal tissue or meninges were found in animals from either control or ketamine groups. A single intrathecal injection of preservative-free S(+)-ketamine, at 1 mg/kg(-1) dosage, over a concentration range of 6 to 15 mg/mL injected in the subarachnoid space in a single puncture, did not produce histological alterations in this experimental model.

Oxytocin Inhibits the Membrane Depolarization-Induced Increase in Intracellular Calcium in Capsaicin Sensitive Sensory Neurons

Lumbar intrathecal injection of oxytocin produces antinociception in rats and analgesia in humans. Classically, oxytocin receptors couple to stimulatory G proteins, increase inositol-3-phosphate production, and result in neuronal excitation. Most work to date has focused on a spinal site of oxytocin to excite γ-aminobutyric acid interneurons to produce analgesia. Here we ask whether oxytocin might also affect primary sensory afferents by modulating high voltage-gated calcium channels, such as it does in the brain. Dorsal root ganglion cells from adult rats were acutely dissociated and cultured, and changes in intracellular calcium determined by fluorescent microscopy using an indicator dye. The effects of oxytocin alone and in the presence of transient depolarization from increased extracellular KCl concentration were determined, and the pharmacology of these effects were studied. Cells from injured dorsal root ganglion cells after spinal nerve ligation were also studied. Oxytocin produced a concentration-dependent inhibition of the increase in intracellular calcium from membrane depolarization, an effect blocked more efficiently by oxytocin- than vasopressin-receptor selective antagonists. Oxytocin-induced inhibition was present in cells responding to capsaicin, and when internal stores of calcium were depleted with thapsigargin. Oxytocin produced similar inhibition in cells from animals with spinal nerve ligation. These data suggest that oxytocin produces antinociception after intrathecal delivery in part by reducing excitatory neurotransmitter release from the central terminals of nociceptors.

Galanin receptor-expressing dorsal horn neurons: Role in nociception

Galanin, along with enkephalins and neuropeptide Y, has been hypothesized to negatively modulate nociception in the superficial dorsal horn of the spinal cord. In the present study, we sought to determine the role of presumably excitatory dorsal horn galanin receptor-expressing neurons in nociception by selectively destroying GalR1-expressing superficial dorsal horn interneurons using lumbar intrathecal injections of the targeted cytotoxin, galanin-saporin (Gal-sap). Lumbar intrathecal injection of Gal-sap (500 ng) reduced immunoperoxidase staining for GalR1 in the superficial dorsal horn without affecting primary afferent neurons in lumbar dorsal root ganglia. Lumbar intrathecal Gal-sap also: 1--reduced nocifensive reflex responding on the thermal plate at 0.3 °C, 44 °C, and 47 °C; 2--increased hot side occupancy in a thermal preference task (15 °C vs 45 °C); and, 3--decreased escape from 44 °C and 47 °C, but not 20 °C. Thus, similar to lesions of mu opiate receptor-expressing dorsal horn interneurons, selective destruction of GalR1-expressing superficial dorsal horn neurons produces heat hypo-algesia, likely due to loss of GalR1-expressing excitatory interneurons leading to reduced activation of nociceptive projection neurons in response to aversive heat. These results are different than those seen with intrathecal neuropeptide Y-saporin and suggest the potential value of selectively targeting GalR1-expressing dorsal horn neurons to control pain.

Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue-induced increase in intracortical inhibition in healthy humans

We investigated the influence of spinal opioid receptor-sensitive muscle afferents on cortical changes following fatiguing unilateral knee-extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right-quadriceps contractions, each consisting of eight submaximal contractions [63 ± 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor-sensitive lower limb muscle afferents. To quantify exercise-induced peripheral fatigue, quadriceps twitch force (Q(tw,pot)) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre-activation period immediately following exercise. End-exercise quadriceps fatigue was significant and similar in both conditions (Q(tw,pot) -35 and -39% for placebo and fentanyl, respectively; P = 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre-exercise baseline, CSP in the placebo trial was 21 ± 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre-exercise baseline (6 ± 4%). Our findings suggest that the central effects of spinal opioid receptor-sensitive muscle afferents might facilitate the fatigue-induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition.

Gene transfer using self-assembled ternary complexes of cationic magnetic nanoparticles, plasmid DNA and cell-penetrating Tat peptide

Nonviral magnetofection facilitates gene transfer by using a magnetic field to concentrate magnetic nanoparticle-associated plasmid delivery vectors onto target cells. In light of the well-established effects of the Tat peptide, a cationic cell-penetrating peptide, that enhances the cytoplasmic delivery of a variety of cargos, we tested whether the combined use of magnetofection and Tat-mediated intracellular delivery would improve transfection efficiency. Through electrostatic interaction, gene transfer complexes were generated by mixing polyethylenimine-coated cationic magnetic iron beads with plasmid DNA, followed by addition of a bis(cysteinyl) histidine-rich Tat peptide. These ternary magnetofection complexes provided a 4-fold improvement in transgene expression at a dose of 1 μg of plasmid DNA per 20,000 cells over the binary complexes without the Tat peptide and transfected up to 60% of cells in vitro. The enhanced transfection efficiency was also observed in vivo in the rat spinal cord after lumbar intrathecal injection. Moreover, the injected ternary magnetofection complexes in the cerebrospinal fluid responded to a moving magnetic filed by shifting away from the injection site and mediating transgene expression in a remote region. Thus, our approach could potentially be useful for effective gene therapy treatments of localized diseases.

Neuropeptide Y receptor-expressing dorsal horn neurons: Role in nocifensive reflex responses to heat and formalin

Lumbar intrathecal injection of neuropeptide Y (NPY) is antinociceptive, particularly in models of nerve injury and inflammation. Intrathecal NPY does not alter nociception in mice null for the Y1 neuropeptide Y receptor (Y1R) and these mice show enhanced nocifensive reflex responses to aversive thermal, mechanical, visceral and chemical stimuli. Y1R and NPY receptor type 2 (Y2R) are present in the spinal dorsal horn presynaptically on primary afferent, and possibly interneuron terminals, but only Y1R is found postsynaptically on dorsal horn neurons. In the present study, we sought to assess the anatomic effects of lumbar intrathecal disulfide conjugate of neuropeptide Y and saporin (NPY-sap) and to determine the role of Y1R-expressing dorsal horn neurons in nocifensive responses to aversive thermal and chemical stimulation. Lumbar intrathecal injection of NPY-sap was used to selectively destroy Y1R-expressing lumbar dorsal horn neurons followed by testing nocifensive reflex responses on the hotplate and after hind-paw formalin injection. NPY-saporin decreased superficial dorsal horn staining for Y1R, but not neurokinin-1 receptor, mu opiate receptor or NPY peptide, and had no effect on Y1R cell counts in fourth lumbar spinal segment dorsal root ganglia. Loss of Y1R-expressing dorsal horn neurons was associated with increased first response latencies on the 44 °C hotplate and reduced total time rats spent licking and guarding hind paws during 600 s trials at 44 °C or 200 s trials at 47 °C. First hind-paw response latencies to high intensity phasic stimulation at 52 °C were unaffected. NPY-sap also reduced formalin-induced nocifensive behaviors during both interphase and phase II. These data demonstrate that selective destruction of Y1R-expressing superficial dorsal horn neurons, probably excitatory interneurons and/or projection neurons, reduces nocifensive reflex responses, particularly to activation of C nociceptors, and suggest a possible role for Y1R-expressing dorsal horn neurons in pain.

Gene Transfer to Dorsal Root Ganglia by Intrathecal Injection: Effects on Regeneration of Peripheral Nerves

Gene delivery to sensory neurons of the dorsal root ganglion (DRG) offers the prospect of developing new clinical interventions against peripheral nerve diseases and disorders. Here we show that genes can be transferred to rat DRG through lumbar intrathecal injection of delivery vectors into the cerebrospinal fluid. Genes could be transferred to DRG using polyethylenimine (PEI)/DNA complexes, Lipofectamine 2000/DNA complexes, adeno-associated virus vectors, or baculovirus vectors. We also show that nerve growth factor cDNA, delivered through lumbar intrathecal injection of PEI complexes, was able to improve regeneration of transected rat sciatic nerves. These data demonstrate the viability of using an intrathecal gene delivery approach for treating peripheral neuropathies.

Nonopioid actions of intrathecal dynorphin evoke spinal excitatory amino acid and prostaglandin E2 release mediated by cyclooxygenase-1 and -2.

Spinal dynorphin is hypothesized to contribute to the hyperalgesia that follows tissue and nerve injury or sustained morphine exposure. We considered that these dynorphin actions are mediated by a cascade involving the spinal release of excitatory amino acids and prostaglandins. Unanesthetized rats with lumbar intrathecal injection and loop dialysis probes received intrathecal NMDA, dynorphin A(1-17), or dynorphin A(2-17). These agents elicited an acute release of glutamate, aspartate, and taurine but not serine. The dynorphin peptides and NMDA also elicited a long-lasting spinal release of prostaglandin E2. Prostaglandin release evoked by dynorphin A(2-17) or NMDA was blocked by the NMDA antagonist amino-5-phosphonovalerate as well the cyclooxygenase (COX) inhibitor ibuprofen. To identify the COX isozyme contributing to this release, SC 58236, a COX-2 inhibitor, was given and found to reduce prostaglandin E2 release evoked by either agent. Unexpectedly, the COX-1 inhibitor SC 58560 also reduced dynorphin A(2-17)-induced, but not NMDA-induced, release of prostaglandin E2. These findings reveal a novel mechanism by which elevated levels of spinal dynorphin seen in pathological conditions may produce hyperalgesia through the release of excitatory amino acids and in part by the activation of a constitutive spinal COX-1 and -2 cascade.

Spinal Carbonic Anhydrase Contributes to Nociceptive Reflex Enhancement by Midazolam, Pentobarbital, and Propofol

Systemic administration of acetazolamide blocks nociceptive hyperreflexia induced by pentobarbital. The authors assessed the effect of intrathecal carbonic anhydrase inhibitors (CAIs) on nociceptive reflex enhancement by pentobarbital, propofol, and midazolam. Twenty-seven rats with chronic indwelling subarachnoid catheters were studied. Nociceptive paw reflex latency (PWL) for paw withdrawal from radiant heat was measured in forelimbs and hind limbs. Measurements were obtained under control conditions, 15 min after lumbar intrathecal injection of 10 microl artificial cerebrospinal fluid containing the CAIs acetazolamide or ethoxyzolamide, and during the 55 min after intraperitoneal injection of three sedative drugs: 30 mg/kg pentobarbital, 50 mg/kg propofol, or 1.9 mg/kg midazolam. Control values of PWL averaged 10.9 +/- 1.5 s in the forelimbs and 11.1 +/- 1.6 s in the hind limbs (P = 0.18). Intrathecal injection of 50 microm ethoxyzolamide reduced PWL by 8% and 4% in the forelimbs and hind limbs, respectively (P = 0.01); all other CAI injections had no effect on PWL. Following anesthetic injection, PWL in the forelimbs was reduced by approximately 35-40% of control values; in the hind limbs, CAI treatment decreased the PWL reduction to 8-16% for pentobarbital (P < 0.001), 30-32% for propofol (P < 0.02), and 9-16% for midazolam (P < 0.001). The hind limb reduction of hyperreflexia by CAI was less for propofol than for midazolam or pentobarbital (P < 0.002). Spinal carbonic anhydrase contributes to nociceptive hyperreflexia induced by pentobarbital and midazolam and to a lesser extent with propofol. These findings are consistent with a role for carbonic anhydrase in nociceptive signal enhancement by these drugs.

A murine model of coccidioidal meningitis.

Coccidioidal meningitis is lethal in humans. A reproducible murine model was established by lumbar intrathecal injection of Coccidioides immitis arthroconidia. Cerebrospinal fluid (CSF) samples were obtained by cisternal puncture. Lethal infection developed in all mice given 10-60 colony-forming units (cfu). Lethargy, ataxia, or paralysis preceded death. Temporal studies after challenge with 27 cfu revealed positive brain (4/5 mice) and spinal cord (2/5 mice) cultures on day 3; CSF samples contained 688 leukocytes/mm(3) and 33 cfu/mL. The results of histopathologic analysis were unremarkable. By day 8, all mice were culture positive (5.0 log(10) cfu in brain tissue and 4.1 log(10) cfu in spinal cord tissue); CSF samples contained 4833 leukocytes/mm(3) and 3425 cfu/mL. Histopathologic examinations showed acute meningitis of the brain and spinal cord, some parenchymal invasion and abscesses, and meningeal arteritis. Groups of mice given ketoconazole had prolonged survival and suppressed lung disease; histopathologic examination demonstrated granulomatous meningitis, possibly a more chronic form. With the development of these models, studies of pathogenesis, host response, and therapy are possible.

Managing severe lower limb spasticity in multiple sclerosis: does intrathecal phenol have a role?

Objective: Established treatment options for managing severe lower limb spasticity and associated pain are of limited value in people with advanced multiple sclerosis (MS). This has resulted in a resurgence...