Adaptive locomotor plasticity in chronic spinal cats after ankle extensors neurectomy.
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After lateral gastrocnemius-soleus (LGS) nerve section in intact cats, a rapid locomotor compensation involving synergistic muscles occurs and is accompanied by spinal reflex changes. Only some of these changes are maintained after acute spinalization, indicating the involvement of descending pathways in functional recovery. Here, we address whether the development of these adaptive changes is dependent on descending pathways. The left LGS nerve was cut in three chronic spinal cats. Combined kinematics and electromyographic (EMG) recordings were obtained before and for 8 d after the neurectomy. An increased yield at the ankle was present early after neurectomy and, as in nonspinal cats, was gradually reduced within 8 d. Compensation involved transient changes in step cycle structure and a longer term increase in postcontact medial gastrocnemius (MG) EMG activity. Precontact MG EMG only increased in one of three cats. In a terminal experiment, the influence of group I afferents from MG and LGS on stance duration was measured in two cats. LGS effectiveness at increasing stance duration was largely decreased in both cats. MG effectiveness was only slightly changed: increased in one cat and decreased in another. In cat 3, the plantaris nerve was cut after LGS recovery. The recovery time courses from both neurectomies were similar (p > 0.8), suggesting that this spinal compensation is likely a generalizable adaptive strategy. From a functional perspective, the spinal cord therefore must be considered capable of adaptive locomotor plasticity after motor nerve lesions. This finding is of prime importance to the understanding of functional plasticity after spinal injury. (+info)
Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model.
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Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two major members of the neurotrophin family. Using immunohistochemistry and in situ hybridization histochemistry, we examined the effect of L5 spinal nerve ligation (SPNL), a neuropathic pain model, on the expression of BDNF in the uninjured L4 dorsal root ganglion (DRG). After L5 SPNL, both immunoreactivity for BDNF and the hybridization intensity for BDNF mRNA increased mainly in the small- and medium-sized neurons. The percentage of BDNF mRNA-expressing neurons increased in the ipsilateral L4 DRG compared with the contralateral DRG from the third to 28th day after ligation. A significantly greater number of BDNF-immunoreactive neurons were observed in the ipsilateral L4 DRG than contralateral side 14 d after ligation. To test the contribution of BDNF to the thermal hyperalgesia produced in this model, we intrathecally injected anti-BDNF antibody at third day after ligation. This treatment clearly attenuated thermal hyperalgesia for a few hours. Almost all BDNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor, mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significantly increased in the ipsilateral L4 DRG 14 d after ligation. Furthermore, we examined the contribution of NGF on this phenotypic change using ELISA, Northern blot analysis, and anti-NGF antibody. NGF content in the ipsilateral L4 DRG linearly increased and reached a statistical significant level 14 d after L5 SPNL. Moreover, at this time point, the increase in NGF mRNA was observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsilateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody to the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented the development of thermal hyperalgesia for 5 d after ligation. Our data suggest that BDNF, which increased in the uninjured L4 DRG neurons, acts as a sensory neuromodulator in the dorsal horn and contributes to thermal hyperalgesia in this neuropathic pain model. The contribution of locally synthesized NGF to thermal hyperalgesia was also demonstrated. These dynamic alterations in the expression and content of BDNF and NGF in the uninjured DRG neurons might be involved in the pathomechanisms of neuropathic pain. (+info)
Confluent peripheral multiple mononeuropathy associated to acute hepatitis B: a case report.
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A thirty three year-old, male patient was admitted at the Hospital of the Sao Paulo University School of Medicine, at the city of Sao Paulo, Brazil, with complaint of pains, tingling and decreased sensibility in the right hand for the last four months. This had progressed to the left hand, left foot and right foot, in addition to a difficulty of flexing and stretching in the left foot. Tests were positive for HBeAg, IgM anti-HBc and HBsAg, thus characterizing the condition of acute hepatitis B. The ALT serum level was 15 times above the upper normal limit. Blood glucose, cerebral spinal fluid, antinuclear antibodies (ANA) and anti-HIV and anti-HCV serum tests were either normal or negative. Electroneuromyography disclosed severe peripheral neuropathy with an axon prevalence and signs of denervation; nerve biopsy disclosed intense vasculitis. The diagnosis of multiple confluent mononeuropathy associated to acute hepatitis B was done. This association is not often reported in international literature and its probable cause is the direct action of the hepatitis B virus on the nerves or a vasculitis of the vasa nervorum brought about by deposits of immune complexes. (+info)
The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats.
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Hypersensitivity resulting from nerve injury or morphine tolerance/hyperalgesia is predicted to involve similar cellular and molecular mechanisms. One expected but incompletely explored mechanism is the activation of central neuroimmune responses associated with these conditions. To begin to address this, we undertook three separate studies: First, we determined the acute antinociceptive action of morphine, the rate of development of opioid tolerance, and withdrawal-induced hyperalgesia/allodynia in nerve-injured and sham-operated rats using noxious (thermal and mechanical) and non-noxious (mechanical allodynia) behavioral paradigms. Second, we investigated the impact of chronic morphine treatment on spinal glial activation and cytokine expression after L5 spinal nerve transection or sham surgery. Third, we examined the consequences of spinal administration of cytokine inhibitors on the development of morphine tolerance and morphine withdrawal-induced hyperalgesia and allodynia. Results demonstrated that after nerve injury, the antinociceptive effect of acute morphine was significantly decreased, and the rate of development of tolerance and opioid withdrawal-induced hyperalgesia/allodynia was significantly enhanced compared with that after sham surgery. Chronic administration of morphine to sham-operated rats activated spinal glia and upregulated proinflammatory cytokines [interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha]. This neuroimmune activation was further enhanced in nerve-injured rats after chronic morphine treatment. Spinal inhibition of proinflammatory cytokines restored acute morphine antinociception in nerve-injured rats and also significantly reversed the development of morphine tolerance and withdrawal-induced hyperalgesia and allodynia in nerve-injured or sham-operated rats. Targeting central cytokine production and glial activation may improve the effectiveness of morphine and reduce the incidence of morphine withdrawal-induced hyperalgesia and allodynia in neuropathic pain conditions. (+info)
Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids.
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Demyelinating diseases can be associated with painful sensory phenomena such as tactile allodynia and hyperalgesia. To study the mechanisms underlying demyelination-induced pain, we have characterized a novel model of demyelination of the sciatic or saphenous nerve. Topical lysolecithin application causes focal demyelination of afferent nerve A-fibers without axonal loss, as assessed either by electron and light microscopy or by immunohistochemical analysis of dorsal root ganglia (DRG) for a neuronal injury marker, activating transcription factor 3. Focal demyelination is accompanied by spontaneous action potentials in afferents and increased expression of neuropeptide Y and Na(v)1.3 sodium channels specifically in DRG neurons that coexpress a specific marker of myelinated afferents. In contrast, expression of tetrodotoxin-resistant, Na(v)1.8 sodium channels is specifically decreased in the same subgroup of DRG cells. Central sensitization of somatosensory processing is also induced, with increased behavioral reflex responsiveness to thermal and mechanical stimuli. These changes are reversed by intrathecal administration of an NMDA receptor antagonist or cannabinoid (CB) receptor agonist, but not by a mu-opioid receptor agonist. Recovery of behavioral reflexes occurred approximately 3 weeks after lysolecithin treatment. This is the first time that demyelination of afferent A-fibers has been shown to specifically induce neuropathic pain and indicates that axonal damage is not a prerequisite for development of the pain state. The profile of phenotypic changes in DRG is distinct from other pain models and displays a sensitivity to NMDA and CB receptor agents that may be exploitable therapeutically. (+info)
Mononeuritis multiplex in diabetes mellitus: evidence for underlying immune pathogenesis.
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Four patients with type 2 diabetes mellitus developed mononeuritis multiplex subacutely. Sural nerve biopsies showed multifocal axonal loss in all patients, with epineurial perivascular inflammation affecting small calibre vessels in three. Three patients improved with immunotherapy. These observations suggest that mononeuritis multiplex in diabetes may be caused by an immune mediated vasculopathy and that it is pathogenetically akin to the more common and better recognised diabetic amyotrophy. (+info)
Evidence for an involvement of supraspinal delta- and spinal mu-opioid receptors in the antihyperalgesic effect of chronically administered clomipramine in mononeuropathic rats.
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The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 microg/kg i.v., which selectively blocks the mu-opioid receptor, inhibited the anti-hyperalgesic effect of clomipramine and hence indicated that mu-opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP), mu; naltrindole (NTI), delta; and nor-binaltorphimine (nor-BNI), kappa] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: delta-receptors at the supraspinal level and mu-receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed. (+info)
Microinjection of neuropeptide Y into periaqueductal grey produces anti-nociception in rats with mononeuropathy.
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The present study was carried out to investigate the effects of neuropeptide Y (NPY) in the midbrain periaqueductal grey (PAG) on the nociceptive modulation in mononeuropathic rats. NPY was microinjected into the PAG. The latency of paw withdrawal (PWL), assessed by the hot-plate (52 ) and the Randall Selitto test, was measured. Intra-PAG administration of 0.05, 0.1 and 0.2 nmol of NPY significantly increased the PWLs in a dose-dependent manner. Co-administration of 0.2 nmol of NPY(28-36) and 5.5 nmol of naloxone significantly attenuated the NPY-induced increase in PWLs. The results suggest that Y(1) receptor may mediate NPY-induced anti-nociception, and that the opioid receptors in PAG may also be involved in this process in mononeuropathic rats. (+info)