Neurobiology of disease
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Neurobiology of disease · Jan 2009
Insular cortex representation of dynamic mechanical allodynia in trigeminal neuropathic rats.
Dynamic mechanical allodynia is a widespread symptom of neuropathic pain for which mechanisms are still poorly understood. The present study investigated the organization of dynamic mechanical allodynia processing in the rat insular cortex after chronic constriction injury to the infraorbital nerve (IoN-CCI). Two weeks after unilateral IoN-CCI, rats showed a dramatic bilateral trigeminal dynamic mechanical allodynia. ⋯ Stimulus-evoked pERK-1/2 immunopositive cell bodies displayed rostrocaudal gradient and layer selective distribution in the insula, being predominant in the rostral insula and in layers II-III of the dysgranular and to a lesser extent, of the agranular insular cortex. In layers II-III of the rostral dysgranular insular cortex, intense pERK also extended into distal dendrites, up to layer I. These results demonstrate that trigeminal nerve injury induces a significant alteration in the insular cortex processing of tactile stimuli and suggest that ERK phosphorylation contributes to the mechanisms underlying abnormal pain perception under this condition.
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Neurobiology of disease · Jan 2009
The endocannabinoid system is modulated in response to spinal cord injury in rats.
Endocannabinoids are lipid mediators with protective effects in many diseases of the nervous system. We have studied the modulation of the endocannabinoid system after a spinal cord contusion in rats. In early stages, lesion induced increases of anandamide and palmitoylethanolamide (PEA) levels, an upregulation of the synthesizing enzyme NAPE-phospholipase D and a downregulation of the degradative enzyme FAAH. ⋯ We observed that CB(1) was constitutively expressed by neurons and oligodendrocytes and induced in reactive astrocytes. CB(2) receptor was strongly upregulated after lesion, and mostly expressed by immune infiltrates and astrocytes. The endocannabinoid system may represent an interesting target for new therapeutical approaches to spinal cord injury.
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Neurobiology of disease · Oct 2008
Comparative StudyLow-frequency stimulation of the tuberomammillary nucleus facilitates electrical amygdaloid-kindling acquisition in Sprague-Dawley rats.
Histamine plays a suppressive role in seizure. The tuberomammillary nucleus (TM) is the only locus of histaminergic neurons in the brain. To determine whether deep brain stimulation (DBS) of the TM provides protection against seizures, we tested the effects of low-frequency stimulation (LFS, 1 Hz), high frequency stimulation (HFS, 100 Hz), and electrolytic lesions of the TM on seizures generated by amygdaloid kindling, pentylenetetrazol (PTZ) and maximal electroshock (MES) in rats. ⋯ In addition, both HFS and bilateral lesions of the TM exacerbated the progression of amygdaloid-kindling seizures. These results suggest that specific negative sites for DBS exist in the brain, such as the TM. This study indicates that it is crucial to choose a suitable target for DBS in the clinical treatment of epilepsy.
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Neurobiology of disease · Apr 2008
Randomized Controlled Trial Multicenter Study Clinical TrialAn inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients.
Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. ⋯ Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.
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Neurobiology of disease · Apr 2008
The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury.
Identification of cellular targets pertinent for the development of effective therapies against pathological pain constitutes a difficult challenge. We combined several approaches to show that 3alpha-hydroxysteroid oxido-reductase (3alpha-HSOR), abundantly expressed in the spinal cord (SC), is a key target, the modulation of which markedly affects nociception. 3alpha-HSOR catalyzes the biosynthesis and oxidation of 3alpha,5alpha-reduced neurosteroids as allopregnanolone (3alpha,5alpha-THP), which stimulates GABA(A) receptors. Intrathecal injection of Provera (pharmacological inhibitor of 3alpha-HSOR activity) in naive rat SC decreased thermal and mechanical nociceptive thresholds assessed with behavioral methods. ⋯ In animals subjected to sciatic nerve injury-evoked neuropathic pain, molecular and biochemical experiments revealed an up-regulation of 3alpha-HSOR reductive activity in the SC. Enhancement of 3alpha,5alpha-THP concentration in the SC induced analgesia in neuropathic rats while Provera exacerbated their pathological state. Possibilities are opened for chronic pain control with drugs modulating 3alpha-HSOR activity in nerve cells.