Described here is a case of accidental intrathecal administration of vincristine with pathologic findings in the central nervous system. A 3-year-old boy with acute lymphoblastic leukemia, was given his ninth course chemotherapy. Vincristine was accidentally injected intrathecally. The clinical course was rapidly progressive (6-day course) and resulted in death. An autopsy was done. The brain and spinal cord was grossly edematous and congested without any specific feature. Histologically, profound loss of neuron was noted in the spinal cord. Remaining neurons in the spinal cord, particularly anterior horn cells were markedly swollen. The spinal nerves show diffuse axonal degeneration and myelin loss. The upstream portion of the spinal cord (brain stem, cerebellum, cerebrum) showed patchy loss of neurons, especially Purkinje cells and granular cells of the cerebellar cortex. Many neurons showed axonal reaction (chromatolysis) with swelling. Several neurons show intracytoplasmic eosinophilic inclusion body. Myelin loss, axonal swelling and enlargement of perivascular spaces were seen throughout the white matter of central nervous system.
Antineoplastic Agents/therapeutic use* ; Brain/pathology ; Brain/drug effects ; Case Report ; Central Nervous System/pathology ; Central Nervous System/drug effects* ; Child, Preschool ; Fatal Outcome ; Histocytochemistry ; Human ; Injections, Spinal ; Leukemia, Lymphocytic, Acute/drug therapy* ; Male ; Medication Errors* ; Spinal Cord/pathology ; Spinal Cord/drug effects ; Spinal Nerves/pathology ; Spinal Nerves/drug effects ; Vincristine/therapeutic use* ; Vincristine/administration & dosage

This study was to observe the effect and possible mechanism of somatostatin analogue octreotide (OCT) on cross excitation of adjacent segment of spinal nerve in rat. Cutaneous branches of T9-T13 spinal dorsal rami were chosen and dissected free for the following recording and stimulation. Only single unit fiber was used for recording, and the adjacent segment of nerve stem was used for antidromic electrical stimulation. To investigate the change of discharge rate and mechanical threshold, OCT and (or) somatostatin receptor antagonist cyclo-somatostatin (c-SOM) were applied to the receptive field following the antidromic electrical stimulation. The result showed that injection of OCT inhibited the increase of discharge rate and the decrease of mechanical threshold induced by the electrical stimulation (cross excitation); c-SOM reversed the effects of OCT. Application of c-SOM alone enhanced the cross excitation effects. The results suggest local application of somatostatin analogue OCT can inhibit the cross excitation between the two segments of spinal nerve by somatostatin receptor.
Animals ; Electric Stimulation ; Octreotide ; pharmacology ; Peptides, Cyclic ; pharmacology ; Rats ; Receptors, Somatostatin ; physiology ; Somatostatin ; analogs & derivatives ; Spinal Nerves ; drug effects

OBJECTIVETo explore the possibility of peripheral nerve damage induced by antiepileptic drugs (AEDs) in different age rats and its pathogenesis.

METHODSAdult (2-month-old) and infant (7-day-old) rats were divided into 8 groups (n = 16 in each) and treated with the following 7 AEDs respectively: phenytoin [PHT, 62.5 mg/(kgxd)], phenobarbital [PB, 30.0 mg/(kgxd)], sodium valproate [VPA, 312.5 mg/(kgxd)], clonazepam [CZP, 1.25 mg /(kgxd)], carbamazepine [CBZ, 187.5 mg/(kgxd)], topiramate [TPM, 40 mg/(kgxd)], oxcarbazepine [OXC, 312.5 mg/(kgxd)], remaining one group was used as control. Four weeks later, 8 rats were sacrificed randomly from each group and serum, sciatic nerves and spinal cord samples were collected. The rest half rats were sacrificed 4 week after AEDs withdrawal. Histological observations were performed on the sciatic nerves samples, including teased fibers, semi-thin sections and electron microscopy. The activity of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in serum and sciatic nerves were detected respectively. Expression of apoptosis-related proteins Bcl-2 and Bax was detected by immunohistochemistry. Neurons apoptosis in the anterior horns of spinal cord were detected by TUNEL.

RESULTS(1) Except for TPM group, various incidence (7.2% - 20.2%) of teased fibers abnormalities were observed in all the other different age groups. PHT group showed the most serious changes followed by PB (adult) or VPA (infant), CBZ, CZP and OXC groups. The predominant abnormality of teased fibers was demyelination. (2) There was no significant difference in the incidence of pathologic changes in teased fibers between adult and infant groups. Four weeks after AEDs withdrawal, recovery of pathologic changes in teased fibers in infant groups was much better than adult. (3) Significantly increased expression of Bax protein and ratio of Bax/Bcl-2 was only found in infant rats treated with PB, CNP or VPA compared with control (P < 0.05), the results of TUNEL was in accordance with immunohistochemistry. (4) Compared with control, the activity of T-AOC and SOD decreased in both infant and adult rats treated with PHT, CZP, CBZ and OXC, and the reduction of SOD activity in serum and sciatic nerves samples was also found in PB groups. Serum activity of GSH-PX was decreased in both age groups treated with PHT, PB, VPA, CZP, CBZ and OXC. The reduction of GSH-PX activity in sciatic nerves samples was remarkably in both adult and infant rats treated with PHT, PB, CBZ, OXC as well as the infant rats treated with CZP.

CONCLUSIONSSix AEDs (PHT, PB, CBZ, VPA, CZP, OXC) showed the potential to cause peripheral nerves damage. Demyelination was the predominant pathologic change. Both adult and infant rats had the same susceptibility. Recovery of pathologic changes in teased fibers in both age groups was slow, but infant rats were prone to revive more quickly. There was no significant correlation between spinal cord neuron apoptosis and peripheral nerves damages in rats treated with AEDs. Breakdown of oxidation-antioxidation balance was closely related to development of peripheral nerves damages caused by most AEDs.

Animals ; Anticonvulsants ; adverse effects ; Demyelinating Diseases ; chemically induced ; pathology ; Oxidative Stress ; Peripheral Nerves ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; pathology ; Spinal Cord ; pathology

OBJECTIVETo investigate whether analgesic effect of electroacupuncture (EA) is affected by p38 mitogen-activated protein kinase (p38 MAPK) on microglia.

METHODSThere were two experiments. The experiment 1: 40 male Sprague-Dawley (SD) rats were randomly divided into the normal, surgery, EA and sham EA groups, and the L5 spinal nerve ligation (SNL) on the right side was used to establish neuropathic pain model. EA was applied to bilateral Zusanli (ST36) and Kunlun (BL60) at 24, 48 and 72 h after SNL for 30 min, once per day. The paw withdrawal thresholds (PWTs) were measured before surgery (as base) and at 24, 25, 49 and 73 h after surgery. Phospho-p38 MAPK (p-p38 MAPK), oxycocin-42 (OX-42, marker of microglia), and glial fibrillary acidic protein (GFAP, marker of astrocyte) in bilateral spinal cord dorsal horn (SCDH) were detected by immunofluorescence, respectively. The experiment 2: 40 male SD rats were cannulated for SNL-induced neuropathic pain, and then were randomly divided into the dimethyl sulfoxide (DMSO), EA plus DMSO, 4-(4-fluorophenyl)-2-(4-methylsulfonylpheny)-5-(4-pyridyl)-1H-imidazole (SB203580) and EA plus SB203580 groups. SB203580 (30 nmol/L) was administered 5 min prior to EA treatment. The PWTs and OX-42 in bilateral SCDH were measured as mentioned above.

RESULTSSNL-induced neuropathic pain reduced PWTs and increased the expression of p-p38 MAPK and OX-42 in bilateral lumbar SCDH of rats (P<0.01). Spinal p-p38 MAPK was only co-localized with OX-42 in our study. EA treatment significantly alleviated SNL-mediated mechanical hyperalgesia, and suppressed the expression of p-p38 MAPK and OX-42 in lumbar SCDH (P<0.05 or P<0.01). Intrathecal injection of low dose SB203580 had no influence on PWTs (P>0.05), but significantly inhibited the expression of OX-42 positive cells in bilateral SCDH (P<0.01 or P<0.05). EA plus SB203580 synergistically increased PWTs, and reduced the expression of bilateral spinal OX-42 (P<0.01 or P<0.05).

CONCLUSIONSThe central mechanism of EA-induced anti-hyperalgesia may be partially associated with the reduced expression of p-p38 MAPK, and subsequently reducing the activation of OX-42 in neuropathic pain. Therefore, EA may be a new complementary and alternative therapy for neuropathic pain.

Animals ; Biomarkers ; metabolism ; CD11b Antigen ; metabolism ; Electroacupuncture ; Fluorescent Antibody Technique ; Hyperalgesia ; pathology ; therapy ; Imidazoles ; pharmacology ; Ligation ; Male ; Microglia ; drug effects ; enzymology ; pathology ; Neuroglia ; drug effects ; metabolism ; Phosphorylation ; drug effects ; Posterior Horn Cells ; drug effects ; enzymology ; pathology ; Pyridines ; pharmacology ; Rats, Sprague-Dawley ; Spinal Nerves ; drug effects ; pathology ; p38 Mitogen-Activated Protein Kinases ; metabolism

PURPOSE: Lamotrigine, a novel anticonvulsant, is a sodium channel blocker that is efficacious in certain forms of neuropathic pain. Recently, microglial and astrocytic activation has been implicated in the development of nerve injury-induced neuropathic pain. We have assessed the effects of continuous intrathecal administration of lamotrigine on the development of neuropathic pain and glial activation induced by L5/6 spinal-nerve ligation in rats. MATERIALS AND METHODS: Following left L5/6 spinal nerve ligation (SNL), Sprague-Dawley male rats were intrathecally administered lamotrigine (24, 72, or 240 microg/day) or saline continuously for 7 days. Mechanical allodynia of the left hind paw to von Frey filament stimuli was determined before surgery (baseline) and once daily for 7 days postoperatively. On day 7, spinal activation of microglia and astrocytes was evaluated immunohistochemically, using antibodies to the microglial marker OX-42 and the astrocyte marker glial fibrillary acidic protein (GFAP). RESULTS: Spinal-nerve ligation induced mechanical allodynia in saline-treated rats, with OX-42 and GFAP immunoreactivity being significantly increased on the ipsilateral side of the spinal cord. Continuously administered intrathecal lamotrigine (240 microg/day) prevented the development of mechanical allodynia, and lower dose of lamotrigine (72 microg/day) ameliorated allodynia. Intrathecal lamotrigine (72 and 240 microg/day) inhibited nerve ligation-induced microglial and astrocytic activation, as evidenced by reduced numbers of cells positive for OX-42 and GFAP. CONCLUSION: Continuously administered intrathecal lamotrigine blocked the development of mechanical allodynia induced by SNL with suppression of microglial and astrocytic activation. Continuous intrathecal administration of lamotrigine may be a promising therapeutic intervention to prevent neuropathy.
Animals ; Astrocytes/drug effects/*physiology ; Disease Models, Animal ; Hyperalgesia/*drug therapy ; Infusions, Spinal ; Ligation ; Male ; Microglia/drug effects/*physiology ; Neuralgia/drug therapy ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves/*injuries ; Triazines/administration & dosage/*therapeutic use ; Voltage-Gated Sodium Channel Blockers/administration & dosage/*therapeutic use

We examined the antiallodynic interaction between gabapentin and adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation for drug administration. Mechanical allodynia was measured by applying von Frey filaments. Gabapentin and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED50). Fractions of ED50s were administered concurrently to establish the ED50 of the drug combination. The drug interaction between gabapentin and R-PIA was analyzed using the isobolographic method. Adenosine A1 receptor antagonist was administered intrathecally to examine the reversal of the antiallodynic effect. Locomotor function changes were evaluated by rotarod testing. Intrathecal gabapentin and R-PIA and their combination produced a dose-dependent antagonism against mechanical allodynia without severe side effects. Intrathecal gabapentin synergistically enhanced the antiallodynic effect of R-PIA when coadministered. There were no significant changes in rotarod performance time, except gabapentin 300 microgram. In the combination group, the maximal antiallodynic effect was reversed by A1 adenosine receptor antagonist. These results suggest that activation of adenosine A1 receptors at the spinal level is required for the synergistic interaction on the mechanical allodynia.
Adenosine/administration & dosage/*analogs & derivatives ; Amines/*administration & dosage ; Animals ; Cyclohexanecarboxylic Acids/*administration & dosage ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Injections, Spinal ; Ligation ; Male ; Pain/*drug therapy ; Rats ; Rats, Sprague-Dawley ; Receptor, Adenosine A1/drug effects/physiology ; Spinal Nerves/*injuries ; Xanthines/pharmacology ; gamma-Aminobutyric Acid/*administration & dosage

Recent studies in western countries have reported that the mechanism pf pain are concorded with gate control opiage receptor binding sites and the release of intrinsic morphine like substances, sodium glutamate and also with bradykinin, seroconin, histamine and prostaglandin E. Otherwise the mechanism of the stimulstion producing analgesia has been reported to involve a neurophysiologic and neurohumoral inhibitory effect at the level of spinal cord, brain stem, thalamus and cortex. This has been clarified but further study should improve the chance of understanding the mechanism of pain. From the standpoint of pain management, medications used to manage pain have some unfortunate side effects. nerve blocks cause anesthesia toxicity, major neurosurgical procedures have many complications. Subarachnoidal and epidural analgesics have unknown irritation pneumonia and drug toxicity, and plexus or pituitary gland block with phenol or alcohol has uneventful complication. From January 1980 to December 1982, electrical acupuncture stimulation has been used on 210 cases at HANYANG university hospital in the pain clinic. I found it useful in relieving pain which has not responded to various conventional methods which included medications, nerve blocks, neurosurgical intervantion and neuropolytics. The results are as follows: 1) There are two kinds of treated patients: One is consultation case-12 from internal medicine, 16 from orthopedic surgery, 10 from neurosurgical and 2 from psychiatry. Another 170 cases were patients who directly to the clinic. And the age distribution shows the highset number of patients in the 3rd decade(21%) and in the 4th decade(24.8%). 2) The region of pain was 21% lumbar, 13.8% shoulder, 10% lower leg and head or face with 9.5%. 3) The duration of the pain showed 10 days 25.7%, 1~2 month 18.6%, one year 11.4% and the longest up to 20 years. 4) Patients who were able to walk into the clinic were 19.5%, moderate cases who to be accompanied were 58.6% and bedridden cases were 21.9%. 5) Treatment was conducted mainly on low frequency stimulation with various waves that included the general dynamic activity point plus reactive electro permeable point (REPP) 81.9% and REER plus head in situ needle 18.1%. 6) In 16.7% only one treatment was administered, in 46.1% 2~5 treatments were given, in 28.6% 6~10 treatments were given and in 3 cases more than 100 treatments were administered. 7) Of the 210 cases, 43.3% showed marked improvement, 41.4% were improved, 13.8% showed translent improvement and there were 3 cases of no improvement. The total confidence was 84.7%. 8) There are no serious complications except hypertensive shock case, submucosal hemorrhagic petechia 7 cases and generalized fatigue 18 cases. In conclusion, electrical acupuncture stimulation of the peripheral nervous system can be used to relieve pain replacing such conventional means as medications, nerve blocks, major neurosurgical procedures, neuroytics and physiopsychic therapy which are generally less effective.
Acupuncture ; Age Distribution ; Analgesia ; Analgesics ; Anesthesia ; Binding Sites ; Bradykinin ; Brain Stem ; Drug-Related Side Effects and Adverse Reactions ; Electric Stimulation* ; Fatigue ; Head ; Histamine ; Humans ; Internal Medicine ; Leg ; Morphine ; Needles ; Nerve Block ; Neurosurgical Procedures ; Orthopedics ; Pain Clinics ; Pain Management ; Peripheral Nerves* ; Peripheral Nervous System ; Phenol ; Pituitary Gland ; Pneumonia ; Shock ; Shoulder ; Sodium Glutamate ; Spinal Cord ; Thalamus