Neuroscience
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Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.
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A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve both in mice and in rats. ⋯ The behavioral improvement was accompanied by structural modifications, as revealed by the expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve, and by the immunofluorescence expression of S100β and glial fibrillary acidic protein (GFAP) Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and immunohistochemistry/blotting analysis. These results may have important implications in the therapy of neuropathic pain.
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Following unilateral chronic constriction injury (CCI) of the sciatic nerve, histochemical and gene expression changes were examined in the rat nucleus accumbens (NAcc), a region critical to affective-motivational regulation. Rats were categorised as having Pain alone (45%) or Pain and Disability (30%), on the basis of either unaltered or decreased dominance behaviour in the resident-intruder paradigm, respectively. Tyrosine hydroxylase (TH) expression was significantly increased bilaterally, throughout the rostrocaudal extent of the NAcc in Pain alone animals. ⋯ In summary, unilateral CCI in rats induces specific and lateralised adaptations in the dopaminergic circuitry of the NAcc. These distinct neural adaptations correlate with changes in social behaviour, and likely underlie some of the affective-motivational state changes associated with neuropathic pain in a subset of rats (i.e. Pain and Disability group).
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To investigate the minimum neuron and neurite densities required for synchronized bursts, we cultured rat cortical neurons on planar multi-electrode arrays (MEAs) at five plating densities (2500, 1000, 500, 250, and 100 cells/mm(2)) using two culture media: Neuron Culture Medium and Dulbecco's Modified Eagle Medium supplemented with serum (DMEM/serum). Long-term recording of spontaneous electrical activity clarified that the cultures exhibiting synchronized bursts required an initial plating density of at least 250 cells/mm(2) for Neuron Culture Medium and 500 cells/mm(2) for DMEM/serum. Immediately after electrical recording, immunocytochemistry of microtubule-associated protein 2 (MAP2) and Neurofilament 200 kD (NF200) was performed directly on MEAs to investigate the actual densities of neurons and neurites forming the networks. ⋯ By comparing both the results of electrophysiological recording and immunocytochemical observation, we revealed that there is a minimum threshold of neuron densities that must be met for the exhibition of synchronized bursts. Interestingly, these minimum densities of MAP2-positive final neurons did not differ between the two culture media; the density was approximately 50 neurons/mm(2). This value was obtained in the cultures with the initial plating densities of 250 cells/mm(2) for Neuron Culture Medium and 500 cells/mm(2) for DMEM/serum.
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Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle (SV) phosphoproteins implicated in the regulation of synaptic transmission and plasticity. Synapsin I, II, I/II and I/II/III knockout mice are epileptic and SYN1/2 genes have been identified as major epilepsy susceptibility genes in humans. We analyzed cortico-hippocampal epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from presymptomatic (3-weeks-old) and symptomatic (1-year-old) Syn I/II/III triple knockout (TKO) mice and aged-matched triple wild type (TWT) controls and assessed the effect of the SV-targeted antiepileptic drug (AED) levetiracetam (LEV) in reverting the epileptic phenotype. ⋯ The lower LEV potency in TKO slices of both ages was associated with a decreased expression of SV2A, a SV protein acting as LEV receptor, in cortex and hippocampus. The results demonstrate that deletion of Syn genes is associated with a higher propensity to 4AP-induced epileptic paroxysms that precedes the onset of epilepsy and consolidates with age. LEV ameliorates such hyper excitability by enhancing the inhibition/excitation ratio, although the effect is hindered in TKO slices which exhibit a concomitant decrease in the levels of the LEV receptor SV2A.