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Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation.

To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small- to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

Animals↗

ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.

Activation of extracellular signal-regulated kinase (ERK), a mitogen activated-protein kinase (MAPK), in dorsal horn neurons contributes to inflammatory pain by transcription-dependent and -independent means. We have now investigated if ERK is activated in the spinal cord after a spinal nerve ligation (SNL) and if this contributes to the neuropathic pain-like behavior generated in this model. An L5 SNL induces an immediate (<10 min) but transient (<6 h) induction of phosphoERK (pERK) restricted to neurons in the superficial dorsal horn. This is followed by a widespread induction of pERK in spinal microglia that peaks between 1 and 3 days post-surgery. On Day 10, pERK is expressed both in astrocytes and microglia, but by Day 21 predominantly in astrocytes in the dorsal horn. In the L5 DRG SNL transiently induces pERK in neurons at 10 min, and in satellite cells on Day 10 and 21. Intrathecal injection of the MEK (ERK kinase) inhibitor PD98059 on Day 2, 10 or 21 reduces SNL-induced mechanical allodynia. Our results suggest that ERK activation in the dorsal horn, as well as in the DRG, mediates pain through different mechanisms operating in different cells at different times. The sequential activation of ERK in dorsal horn microglia and then in astrocytes might reflect distinct roles for these two subtypes of glia in the temporal evolution of neuropathic pain.

Animals↗

Entrapped spinal nerve roots in a pseudomeningocoele as a complication of previous spinal surgery.

Pseudomeningocele is a rare but well recognised complication of lumbar surgery (microdiscectomy and laminectomy). Most of the patients tolerate the presence of the cyst well, however some present with back pain and spinal claudication, presumably due to neural compression. We report a case who presented following three operations (microdiscectomy, laminectomy and excision of a pseudomeningocele) with symptoms of spinal claudication and bilateral radicular pain. The cause of her pain was evident only at operation and was due to herniation of nerve roots through the dural defect.

Cauda Equina↗

Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.

Tumor necrosis factor-alpha (TNF) is implicated in the initiation of neuropathic pain. In vitro, TNF activates p38 mitogen-activated kinase. Accordingly, we investigated whether TNF activates the p38 cascade in vivo to trigger pain behavior after spinal nerve ligation (SNL). Treatment starting 2 d before SNL with the TNF antagonist etanercept (1 mg, i.p., every third day) attenuated mechanical allodynia. Treatment starting 1 or 7 d after SNL was ineffective. Similarly, intrathecal infusion of a p38 inhibitor (SB203580, 4 mg/d) was effective only if it was started before but not 7 d after SNL. For both treatments, the cessation of therapy resulted in increased allodynia. In separate experiments using Western blots and immunohistochemistry, ipsilateral lumbar spinal cord and L5 and L6 DRG were analyzed for total and phosphorylated p38 after SNL alone or SNL combined with etanercept pretreatment. In DRG, activated p38 was transiently elevated 5 hr after SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38 was activated between 5 hr and 3 d after SNL and returned to baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL treatment, phosphorylated p38 levels in spinal cord and DRG are transiently elevated. In DRG, p38 activation is blocked by systemic TNF inhibition. Parallel inhibition of p38 activation and allodynia may represent a clinically relevant therapeutic window. These data suggest a sequential role for TNF and p38 in the induction of neuropathic pain.

Animals↗

Spinal nerve root repair and reimplantation of avulsed ventral roots into the spinal cord after brachial plexus injury.

OBJECT: The authors review the first series of 10 cases in which injured intraspinal brachial plexus were surgically repaired. They describe the technique of spinal cord implantation or repair of ruptured nerve roots, as well as patient outcome. METHODS: Spinal root repair/implantation was performed from 10 days to 9 months postinjury. There were nine male patients and one female patient. Postoperatively in most cases, regeneration of motor neurons from the spinal cord to denervated muscles could be demonstrated. The first signs of regeneration were noted approximately 9 to 12 months postoperatively. Useful function with muscle power of at least Medical Research Council Grade 3 occurred in three of 10 cases. Magnetic brain stimulation studies revealed a normal amplitude and latency from the cortex to reinnervated muscles on surgically treated and control sides. A certain degree of cocontraction between antagonistic muscles (for example, biceps-triceps) compromised function. With time there was a reduction of cocontractions, probably due to spinal cord plasticity. In these cases there was also, surprisingly, a return of sensory function, although the mechanism by which this occurred is uncertain. Sensory stimulation (thermal and mechanical) within the avulsed dermatomes was perceived abnormally and/or experienced at remote sites. There was some return of patients' sense of joint position. CONCLUSIONS: A short time lag between the accident and the surgery was recognized as a significant factor for a successful outcome. Reimplantation of avulsed nerve roots may be combined with other procedures such as nerve transfers in severe cases of brachial plexus injury.

Adult↗

Age-related amplitude variations of the posterior tibial nerve spinal SEP P21 component.

The effects of aging on the amplitude of the surface-recorded tibial nerve spinal somatosensory-evoked potential P21 component (L5-T12 electrode derivation) were studied in 79 subjects. The results of this investigation indicate that a significant moderately negative correlation (r = -0.46) exists between subject age and the amplitude of component P21. These findings suggest that the absence of a P21 potential in an elderly patient does not necessarily represent evidence of neural pathology.

Adolescent↗

Lumbar subarachnoid ethylenediaminetetraacetate induces hindlimb tetanic contractions in rats: prevention by CaCl2 pretreatment; observation of spinal nerve root degeneration.

Disodium ethylenediaminetetraacetate (Na2EDTA) has replaced sodium bisulfite as the antioxidant in 2-chloroprocaine, Nesacaine CE. This study was undertaken to determine whether this new formulation has neurotoxic effects when administered in the subarachnoid space. Sprague-Dawley rats receiving subarachnoid injections of 1.5 mM or higher concentrations of Na2EDTA immediately initiated a circling behavior that was followed by the development of tetanic contractions of the hindlimbs lasting for 15-20 min. The tetanic contractions were followed by a brief period of hindlimb paralysis. Pretreatment of rats by subarachnoid injections of 1 mM CaCl2 prevented the development of tetanic contractions and paralysis of the hindlimb. Histologic examination of animals receiving Na2EDTA revealed moderate to severe focal degenerative changes in spinal nerve roots. Control rats receiving subarachnoid injections of normal saline solution did not develop tetanic contraction nor pathological changes on light microscopy. These results suggest that the preservative used in Nesacaine-MPF may be neurotoxic.

Animals↗

Accessory spinal nerve injury.

In 7 cases of peripheral lesion of the spinal accessory nerve 4 were produced by malignancy, two by iatrogenical resection of lymph nodes, one by an en bloc dissection of the neck for arteriovenous malformation. Incapacity following the injury is quite marked and includes weakness of the sternomastoid and trapezius muscles, as well as pain presumably from traction on the brachial plexus. The importance of avoiding the nerve in surgical intervention in the neck must be strongly emphasized. A review of the literature suggests that in fresh injuries the spinal accessory nerve should be explored and resutured. Our own experience, however, with nerve repair has been disappointing.

Accessory Nerve↗

[Effect of embryonal nerve tissue transplantation on regeneration of dorsal roots of the rat spinal nerves].

Using cobalt salts axonal ionophoresis posttraumatic regeneration of TXII dorsal roots nerve fibres in the zone of hemisection in conditions of 14 wks embryo spinal cord transplantation into the zone of trauma of spinal cord. Regro Invasion of dorsal roots nerve fibres into recipients posterior cords and Lissawers tract through the transitional zone "spinal cord--dorsal roots" was observed on posttransplantation d 14-120. It was show that afferent axons predominantly spread in substantia alba and substantia grisea caudal to the level of spinal cord transection with only individual fibres invading rostrad through the neuronal plate. In the transplants neurons were encountered up to d 120 of the observation although transplant neuropil was limited from recipient tissue brain by a glial and connective tissue scar. The influence of embryonal nervous tissue transplantation on intraspinal regeneration of dorsal roots afferents was discussed.

Animals↗

The central-peripheral transition zone of cervical spinal nerve roots in Jimpy mutant and normal mice. Light- and electron-microscopic study.

Comparative morphological and ultrastructural investigations on the cervical dorsal and ventral central-peripheral transition zones (CPTZs) of Jimpys and control mice have been performed at early and advanced myelination stages. After postnatal development a characteristic cone-shaped glial outgrowth extends into the proximal part of the dorsal roots, while the ventral roots exhibit short Schwann cell and peripheral nervous tissue invaginations into the spinal cord at the ventral root-spinal cord junction in both animal groups. In Jimpys, although there is marked central myelin deficiency and absence of oligodendroglial development on the CNS side, the normal general aspect of the CPTZs is maintained. Previously postulated astrocytic and neuroaxonal abnormalities in the mutants do not alter the central-peripheral borderline, and Schwann cell migration from the spinal nerve roots into the cord does not occur.

Animals↗

Symptomatic intradural adrenal adenoma of the spinal nerve root: report of two cases.

The second and third cases of an adrenal adenoma involving the intraspinal space, a rare location for a lesion that occurs rather commonly at a variety of extraneural sites, are reported. The first patient, a 16-year-old girl with a 3-month history of radicular pain, was found to have an intradural, extramedullary mass arising on a spinal nerve root. Its resection resulted in cure. The second patient, a 63-year-old woman with a 10-month history of low back pain with radiation to both lower extremities, had a similar mass arising from one of the nerve roots of the cauda equina. In both cases, ultrastructural examination of these demarcated, oncocytic, lipid-rich lesions demonstrated abundant smooth endoplasmic reticulum and mitochondria with tubular cristae. The presence of steroidogenic enzymes was noted on immunohistochemical examination. The literature is reviewed, as is the differential diagnosis of these rare lesions.

Adenoma↗

Drainage of molecules from subarachnoid space to spinal nerve roots and peripheral nerve of the rat. A study based on Evans blue-albumin and lanthanum as tracers.

The purpose of the present investigation was to find out if a compound injected into the spinal subarachnoid space, after having entered ventral and dorsal nerve roots, can be traced to the epineurial-perineurial sheaths and the endoneurium of peripheral nerves. This would indicate a centrifugal movement of substances from the cerebrospinal fluid along nerves; one route of drainage of cerebrospinal fluid which in the past has been widely discussed. In vivo studies were made using Evans blue-albumin and lanthanum chloride as tracers. Evans blue-albumin is macromolecular in size and emits a red fluorescence after exposure to ultraviolet light. Lanthanum ions are small and easily visible in the electron microscope. The tracers were injected into the cervical subarachnoid space and 15 min to 24 h later samples from roots, dorsal root ganglia, proximal part of spinal nerves and the median nerves were taken and further processed for detection of tracers. Fluorescence microscopy from samples removed 15 min and 24 h after the injection of Evans blue-albumin showed a red fluorescence of low intensity in the endoneurium of nerve roots, ganglia and proximal spinal nerve. After 24 h also the median nerve elicited some fluorescence. The sheaths around these structures were also fluorescent. Lanthanum was detected between cell layers of the nerve root sheath as well as inside the nerve root parenchyma. In about 50% of the samples from dorsal root ganglia extracellular lanthanum was found in the capsule. The tracer was also found in the epineurium of 50% of the spinal nerves and occasionally in the perineurium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Thoracic spinal nerve and root conduction: a magnetic stimulation study.

We describe a technique of magnetic coil (MC) stimulation of the thoracic spinal nerves and roots in 12 normal subjects and a patient with diabetes mellitus. We kept the MC flat against the vertebral column in the midline over T-7, T-8, and T-9 spinous processes and obtained compound muscle action potentials from the upper rectus abdominis, external oblique, and intercostal muscles. We obtained mean latencies to these muscles after stimulation in the posterior axillary line. We noted that the onset latencies remained fixed despite increasing the intensity of stimulation from 30% to 100% and on moving the coil up to 3 cm lateral to the spinous processes suggesting that the stimulation of the fastest conducting fibers was occurring at a fixed site, most likely at the intervertebral foramina. Prolonged latencies in the diabetic patient confirmed the diagnosis of radiculoneuropathy.

Adult↗

Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat.

Evidence indicates a role for tumor necrosis factor-alpha (TNF) in neuropathic pain. We correlated pain behavior in response to mechanical stimulation with immunoreactivity for TNF receptor (TNFR) 1 and 2 at 6, 24, 76 and 120 h following L5 and L6 spinal nerve ligation (SNL). Allodynia began in both L4 and L5 dermatomes within 6 h following SNL, peaking by 24 h. In L5 (injured) dorsal root ganglia (DRG), TNFR1 and TNFR2 levels displayed a bimodal increase, peaking at 6 and 120 h after SNL. In L4 (uninjured) DRG, TNFR1 and TNFR2 immunoreactivity peaked at 24 h returning to basal levels by 120 h. TNFR upregulation in injured and adjacent uninjured DRG neurons may be essential for mediating enhanced TNF effects and thus contribute to the development of pain-related behavior.

Animals↗

Intercostal-lumbar-spinal nerve anastomoses for cord transection. A preliminary investigation.

Since 1978, 10 intercostal nerve-cauda equina anastomoses and 11 intercostal nerve-lumbar anastomoses were performed for thoracolumbar spinal cord transection. Three to four pairs of intercostal nerves above the traumatic level of the cord were anastomosed with two to four pairs of cauda equina or lumbar nerve roots below the traumatic level, using microsurgical technique. The surgical techniques used for the latter 11 cases were performed through an extraperitoneal approach. The operative technique is described in detail. These 21 cases have been followed-up for six to 48 months. Electromyography (EMG) shows that action potentials are present in several previously paralyzed muscles in 11 cases. Muscle strength of some previously paralyzed muscles in three cases recovered to Grades 1 to 3. There is evidence that intercostal-lumbar-spinal nerve anastomoses provide a chance for neuronal regeneration, but unsatisfactory functional results are still questions for further study.

Adult↗